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1
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Dykes KC, Ball ED. A review of antibody-based immunotherapy clinical trials for adult acute myeloid leukemia (AML): monoclonal antibodies (mAbs) and beyond. Expert Opin Biol Ther 2025; 25:345-362. [PMID: 40069930 DOI: 10.1080/14712598.2025.2479014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/10/2025] [Indexed: 03/18/2025]
Abstract
INTRODUCTION Antibody-based immunotherapies are a class of therapeutics under active investigation in clinical trials for the treatment of acute myeloid leukemia (AML). Our review provides a comprehensive examination of trials published to date, focusing on recurrent challenges and promising aspects of antibody-based therapeutics. AREAS COVERED We described antibody-based immunotherapies for AML, specifically, an overview of the most prominent antigen targets in published clinical trials investigating monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor therapies. Manuscripts and abstracts describing clinical trials investigating antibody-based therapies for AML published through December 2024, identified by searching Google Scholar and PubMed, were included. EXPERT OPINION Antibody-based immunotherapies for AML have encountered limitations, including imperfect target antigens with significant associated toxicity such as myelosuppression, in addition to challenges specific to the AML patient population. The majority of trials have targeted CD33, CD123, CD371 (CLL1/Clec12), and CD47. For successful implementation of antibody-based therapeutics in AML treatment, future directions require creative applications of antibody-based therapeutics specifically engineered to minimize limiting toxicities and tailoring of therapies for this unique patient population.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/drug therapy
- Immunotherapy/methods
- Immunotherapy/adverse effects
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/pharmacology
- Adult
- Clinical Trials as Topic
- Antibodies, Bispecific/administration & dosage
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Affiliation(s)
- Kaitlyn C Dykes
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Edward D Ball
- Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego, La Jolla, CA, USA
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2
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Richardson P, Htut M, Scott E, Prada CP, Gupta I. Tagraxofusp in combination with pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma shows encouraging preliminary efficacy with a manageable safety profile. Haematologica 2025; 110:488-492. [PMID: 39363849 PMCID: PMC11788639 DOI: 10.3324/haematol.2024.285380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024] Open
Abstract
Not available.
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Affiliation(s)
| | | | - Emma Scott
- Oregon Health and Science University, Portland, OR
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3
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Kan WL, Weekley CM, Nero TL, Hercus TR, Yip KH, Tumes DJ, Woodcock JM, Ross DM, Thomas D, Terán D, Owczarek CM, Liu NW, Martelotto LG, Polo JM, Pant H, Tvorogov D, Lopez AF, Parker MW. The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities. Immunol Rev 2025; 329:e13430. [PMID: 39748163 DOI: 10.1111/imr.13430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 12/10/2024] [Indexed: 01/04/2025]
Abstract
Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL-3 receptor ternary complex forms higher-order assemblies, like those found earlier for the GM-CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL-3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine-receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism-based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.
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Affiliation(s)
- Winnie L Kan
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Claire M Weekley
- Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
| | - Tracy L Nero
- Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
| | - Timothy R Hercus
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Kwok Ho Yip
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Damon J Tumes
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Joanna M Woodcock
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - David M Ross
- Discipline of Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, Adelaide, South Australia, Australia
- Acute Leukemia Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Daniel Thomas
- Discipline of Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, Adelaide, South Australia, Australia
| | - David Terán
- Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
| | - Catherine M Owczarek
- CSL, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia
| | - Nora W Liu
- Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Epigenetics Program, South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Luciano G Martelotto
- Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Epigenetics Program, South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Jose M Polo
- Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Epigenetics Program, South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Harshita Pant
- Discipline of Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Denis Tvorogov
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
| | - Angel F Lopez
- Cytokine Receptor Laboratory, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia
- Discipline of Medicine, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Michael W Parker
- Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
- Australian Cancer Research Foundation Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
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4
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Bhagwat AS, Torres L, Shestova O, Shestov M, Mellors PW, Fisher HR, Farooki SN, Frost BF, Loken MR, Gaymon AL, Frazee D, Rogal W, Frey N, Hexner EO, Luger SM, Loren AW, Martin ME, McCurdy SR, Perl AE, Stadtmauer EA, Brogdon JL, Fraietta JA, Hwang WT, Siegel DL, Plesa G, Aplenc R, Porter DL, June CH, Gill SI. Cytokine-mediated CAR T therapy resistance in AML. Nat Med 2024; 30:3697-3708. [PMID: 39333315 PMCID: PMC12118809 DOI: 10.1038/s41591-024-03271-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/27/2024] [Indexed: 09/29/2024]
Abstract
Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123+ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5-0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07-0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).
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Affiliation(s)
- Anand S Bhagwat
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Leonel Torres
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Olga Shestova
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maksim Shestov
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick W Mellors
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Han R Fisher
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Saamia N Farooki
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Benjamin F Frost
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Avery L Gaymon
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Diane Frazee
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Walter Rogal
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Noelle Frey
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth O Hexner
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Selina M Luger
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alison W Loren
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Mary Ellen Martin
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Shannon R McCurdy
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Alexander E Perl
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Edward A Stadtmauer
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Joseph A Fraietta
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA
| | - Don L Siegel
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gabriela Plesa
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Richard Aplenc
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - David L Porter
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Saar I Gill
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Center for Cell Therapy and Transplant, University of Pennsylvania, Philadelphia, PA, USA.
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5
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Reuvekamp T, Bachas C, Cloos J. Immunophenotypic features of early haematopoietic and leukaemia stem cells. Int J Lab Hematol 2024; 46:795-808. [PMID: 39045906 DOI: 10.1111/ijlh.14348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/10/2024] [Indexed: 07/25/2024]
Abstract
Many tumours are organised in a hierarchical structure with at its apex a cell that can maintain, establish, and repopulate the tumour-the cancer stem cell. The haematopoietic stem cell (HSC) is the founder cell for all functional blood cells. Like HSCs, the leukaemia stem cells (LSC) are hypothesised to be the leukaemia-initiating cells, which have features of stemness such as self-renewal, quiescence, and resistance to cytotoxic drugs. Immunophenotypically, CD34+CD38- defines HSCs by adding lineage negativity and CD90+CD45RA-. At which stage of maturation the further differentiation is blocked, determines the type of leukaemia, and determines the immunophenotype of the LSC specific to the leukaemia type. No apparent LSC phenotype has been described in lymphoid leukaemia, and it is debated if a specific acute lymphocytic leukaemia-initiating cell is present, as all cells are capable of engraftment in a secondary mouse model. In chronic lymphocytic leukaemia, a B-cell clone is responsible for uncontrolled proliferation, not a specific LSC. In chronic and acute myeloid leukaemia, LSC is described as CD34+CD38- with the expression of a marker that is aberrantly expressed (LSC marker), such as CD45RA, CD123 or in the case of chronic myeloid leukaemia CD26. In acute myeloid leukaemia, the LSC load had prognostic relevance and might be a biomarker that can be used for monitoring and as an addition to measurable residual disease. However, challenges such as the CD34-negative immunophenotype need to be explored.
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Affiliation(s)
- Tom Reuvekamp
- Department of Hematology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands
- Department of Hematology, Amsterdam UMC Location Universiteit van Amsterdam, Amsterdam, The Netherlands
| | - Costa Bachas
- Department of Hematology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands
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6
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Kegyes D, Thiagarajan PS, Ghiaur G. MRD in Acute Leukemias: Lessons Learned from Acute Promyelocytic Leukemia. Cancers (Basel) 2024; 16:3208. [PMID: 39335179 PMCID: PMC11430625 DOI: 10.3390/cancers16183208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Introduction: Advances in molecular biology, polymerase chain reaction (PCR), and next-generation sequencing (NGS) have transformed the concept of minimal residual disease (MRD) from a philosophical idea into a measurable reality. Current Treatment Paradigms and Lessons Learned from APL: Acute promyelocytic leukemia (APL) leads the way in this transformation, initially using PCR to detect MRD in patients in remission, and more recently, aiming to eliminate it entirely with modern treatment strategies. Along the way, we have gained valuable insights that, when applied to other forms of acute leukemia, hold the potential to significantly improve the outcomes of these challenging diseases. Does the BM Microenvironment Play a Role in MRD?: In this review, we explore the current use of MRD in the management of acute leukemia and delve into the biological processes that contribute to MRD persistence, including its overlap with leukemia stem cells and the role of the bone marrow microenvironment.
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Affiliation(s)
- David Kegyes
- MedFuture Research Center for Advanced Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
- The Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD 21205, USA
| | | | - Gabriel Ghiaur
- The Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD 21205, USA
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Sabile JMG, Swords R, Tyner JW. Evaluating targeted therapies in older patients with TP53-mutated AML. Leuk Lymphoma 2024; 65:1201-1218. [PMID: 38646877 DOI: 10.1080/10428194.2024.2344057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 04/23/2024]
Abstract
Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.
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Affiliation(s)
- Jean M G Sabile
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Ronan Swords
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey W Tyner
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
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Reed DR, Lum LG. Looking ahead to CD3, T-cell engager bispecific antibodies for hematological malignancies. Expert Opin Biol Ther 2024; 24:761-772. [PMID: 39069893 DOI: 10.1080/14712598.2024.2384086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/21/2024] [Indexed: 07/30/2024]
Abstract
INTRODUCTION Since the approval of the bispecific antibody blinatumomab in 2017 for the treatment of acute lymphoblastic leukemia in relapse, the development of numerous bispecific antibody constructs has dramatically expanded in hematologic malignancies. Many have recently received Food Drug Administration and European Medicines Agency approvals in various stages of treatment for lymphomas, leukemias, and multiple myeloma. AREAS COVERED The purpose of this review is to provide an overview of bispecific antibody treatment including the mechanisms leading to effector T cells targeting tumor-associated antigens, the treatment indications, efficacies, toxicities, and challenges of the different constructs. A literature search was performed through access to PubMed and clinicaltrials.gov. EXPERT OPINION While there has been substantial success in the treatment of NHL, MM, and ALL, there are still hematologic malignancies such as AML where there has been limited progress. It is important to continue to investigate new designs, tumor antigen targets, and further refine where current approved bispecific antibodies fit in terms of sequencing of therapy. Hopefully, with the knowledge gained in recent years and the explosion of these therapies, patients with blood cancers will continue to benefit from these treatments for years to come.
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Affiliation(s)
- Daniel R Reed
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA, USA
| | - Lawrence G Lum
- Department of Medicine, Division of Hematology and Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA, USA
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Das N, Panda D, Gajendra S, Gupta R, Thakral D, Kaur G, Khan A, Singh VK, Vemprala A, Bakhshi S, Seth R, Sahoo RK, Sharma A, Rai S, Prajapati VK, Singh S. Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10-colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity. Int J Lab Hematol 2024; 46:646-656. [PMID: 38456256 DOI: 10.1111/ijlh.14250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 01/30/2024] [Indexed: 03/09/2024]
Abstract
INTRODUCTION Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing. MATERIALS AND METHODS Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single-cell sequencing of the whole transcriptome was also done in a bone marrow sample. RESULTS LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34- LSCs (n = 41), no difference was observed between the groups. More than one sub-population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods. CONCLUSION A single tube-10-colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter- and intra-sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression.
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Affiliation(s)
- Nupur Das
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Devasis Panda
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Smeeta Gajendra
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Ritu Gupta
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Deepshi Thakral
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Gurvinder Kaur
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Aafreen Khan
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Vivek Kumar Singh
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Arushi Vemprala
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Rachna Seth
- Department of Paediatrics, Dr. BRAIRCH, AIIMS, New Delhi, India
| | | | - Atul Sharma
- Department of Medical Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Sandeep Rai
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Vijay K Prajapati
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
| | - Saroj Singh
- Department of Laboratory Oncology, Dr. BRAIRCH, AIIMS, New Delhi, India
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Larrue C, Mouche S, Angelino P, Sajot M, Birsen R, Kosmider O, Mckee T, Vergez F, Recher C, Mas VMD, Gu Q, Xu J, Tsantoulis P, Sarry JE, Tamburini J. Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models. Sci Transl Med 2024; 16:eadk1731. [PMID: 39047119 DOI: 10.1126/scitranslmed.adk1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 03/18/2024] [Accepted: 07/02/2024] [Indexed: 07/27/2024]
Abstract
Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contribute to therapeutic failure, relapse, and adverse outcome. This study investigates the role of quiescence and related molecular mechanisms in AML pathogenesis and LSC functions to identify potential therapeutic targets. Transcriptomic analysis revealed that the LSC-enriched quiescent cell population has a distinct gene signature with prognostic relevance in patients with AML. Mechanistically, quiescent blasts exhibit increased autophagic activity, which contributes to their sustained viability. Proteomic profiling uncovered differential requirements for iron metabolism between quiescent and cycling cells, revealing a unique dependence of quiescent cells on ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron bioavailability. We evaluated the therapeutic potential of inhibiting NCOA4-mediated ferritinophagy using genetic knockdown and chemical inhibition approaches. In vitro assays showed that suppression of NCOA4 was toxic to leukemic blasts, particularly the CD34+CD38- LSC-enriched population, without affecting normal CD34+ hematopoietic progenitors. In vivo studies using murine patient-derived xenograft (PDX) models of AML confirmed that NCOA4 inhibition reduced tumor burden and impaired LSC viability and self-renewal, indicating a specific vulnerability of these cells to ferritinophagy disruption. Our findings underscore the role of NCOA4-mediated ferritinophagy in maintaining LSC quiescence and function and suggest that targeting this pathway may be an effective therapeutic strategy for AML. This study highlights the potential of NCOA4 inhibition to improve AML outcomes and paves the way for future research and clinical development.
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Affiliation(s)
- Clement Larrue
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
- Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France
- LabEx Toucan, 31100 Toulouse, France
- Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France
| | - Sarah Mouche
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
| | - Paolo Angelino
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
- Translational Data Science, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Maxime Sajot
- Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France
- LabEx Toucan, 31100 Toulouse, France
- Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France
| | - Rudy Birsen
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
- Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France
| | - Olivier Kosmider
- Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France
| | - Thomas Mckee
- Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - François Vergez
- Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France
| | - Christian Recher
- Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France
| | - Véronique Mansat-De Mas
- Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France
| | - Qiong Gu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Jun Xu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Petros Tsantoulis
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
| | - Jean-Emmanuel Sarry
- Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France
- LabEx Toucan, 31100 Toulouse, France
- Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France
| | - Jerome Tamburini
- Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland
- Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France
- Oncology Department, Geneva University Hospitals, 1205 Geneva, Switzerland
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11
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Ruszkowska-Ciastek B, Kwiatkowska K, Marques-da-Silva D, Lagoa R. Cancer Stem Cells from Definition to Detection and Targeted Drugs. Int J Mol Sci 2024; 25:3903. [PMID: 38612718 PMCID: PMC11011379 DOI: 10.3390/ijms25073903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs' involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.
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Affiliation(s)
- Barbara Ruszkowska-Ciastek
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland
| | - Katarzyna Kwiatkowska
- Department of Laboratory Diagnostics, Jan Biziel University Hospital No. 2, 85-168 Bydgoszcz, Poland;
| | - Dorinda Marques-da-Silva
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Ricardo Lagoa
- Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials (LSRE-LCM), Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal; (D.M.-d.-S.); (R.L.)
- Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
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12
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Seipel K, Mandhair H, Bacher U, Pabst T. FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol 2024; 46:2946-2960. [PMID: 38666914 PMCID: PMC11049208 DOI: 10.3390/cimb46040184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/22/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Targeting the FLT3 receptor and the IL-1R associated kinase 4 as well as the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. AML cells represented all major morphologic and molecular subtypes, including FLT3-ITD and NPM1 mutant AML cell lines and a variety of patient-derived AML cells. Emavusertib in combination with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in MOLM-13 cells. In primary AML cells, the response to emavusertib was associated with the presence of the FLT3 gene mutation with an allelic ratio >0.5 and the presence of NPM1 gene mutations. S63845 was effective in all tested AML cell lines and primary AML samples. Blast cell percentage was positively associated with the response to CA4948, S63845, and venetoclax, with elevated susceptibility of primary AML with blast cell fraction >80%. Biomarkers of the response to venetoclax included the blast cell percentage and bone marrow infiltration rate, as well as the expression levels of CD11b, CD64, and CD117. Elevated susceptibility to CA4948 combination treatments with S63845 or PU-H71 was associated with FLT3-mutated AML and CD34 < 30%. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML.
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Affiliation(s)
- Katja Seipel
- Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland;
| | - Harpreet Mandhair
- Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland;
| | - Ulrike Bacher
- Department of Hematology, University Hospital Bern, 3010 Bern, Switzerland;
| | - Thomas Pabst
- Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland
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13
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Chea M, Rigolot L, Canali A, Vergez F. Minimal Residual Disease in Acute Myeloid Leukemia: Old and New Concepts. Int J Mol Sci 2024; 25:2150. [PMID: 38396825 PMCID: PMC10889505 DOI: 10.3390/ijms25042150] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/01/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells remaining in a patient after treatment, and is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. Patients with a negative MRD tend to have superior disease-free and overall survival rates. Considerable effort has been made to standardize MRD practices. A variety of techniques, including flow cytometry and molecular methods, are used to assess MRD, each with distinct strengths and weaknesses. MRD is recognized not only as a predictive biomarker, but also as a prognostic tool and marker of treatment efficacy. Expected advances in MRD assessment encompass molecular techniques such as NGS and digital PCR, as well as optimization strategies such as unsupervised flow cytometry analysis and leukemic stem cell monitoring. At present, there is no perfect method for measuring MRD, and significant advances are expected in the future to fully integrate MRD assessment into the management of AML patients.
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Affiliation(s)
- Mathias Chea
- Laboratoire d’Hématologie Biologique, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse, France; (M.C.); (L.R.); (A.C.)
| | - Lucie Rigolot
- Laboratoire d’Hématologie Biologique, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse, France; (M.C.); (L.R.); (A.C.)
- School of Medicine, Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Alban Canali
- Laboratoire d’Hématologie Biologique, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse, France; (M.C.); (L.R.); (A.C.)
- School of Medicine, Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Francois Vergez
- Laboratoire d’Hématologie Biologique, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse, France; (M.C.); (L.R.); (A.C.)
- School of Medicine, Université Toulouse III Paul Sabatier, 31062 Toulouse, France
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14
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Song J, Li W, Bai Y, Zhou P, Niu J, Niu X, Liu Y, Liu X, Drokow EK, Sun K, Zhou H. A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia. Ann Hematol 2024; 103:463-473. [PMID: 38183444 DOI: 10.1007/s00277-023-05594-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 12/17/2023] [Indexed: 01/08/2024]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.
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Affiliation(s)
- Juanjuan Song
- Department of Hematology, Affiliated Tumor Hospital of Zhengzhou University, Tumor Hospital of Henan Province, Institute of Hematology of Henan Province, No.127 Dongming Road, Jinshui District, Zhengzhou, 450000, Henan, People's Republic of China
| | - Weiya Li
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Yanliang Bai
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Pan Zhou
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Junwei Niu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Xiaona Niu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Ying Liu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Xiaobo Liu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Emmanuel Kwateng Drokow
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China
| | - Kai Sun
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People's Republic of China.
| | - Hu Zhou
- Department of Hematology, Affiliated Tumor Hospital of Zhengzhou University, Tumor Hospital of Henan Province, Institute of Hematology of Henan Province, No.127 Dongming Road, Jinshui District, Zhengzhou, 450000, Henan, People's Republic of China.
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15
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Seipel K, Kohler S, Bacher U, Pabst T. HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. Curr Issues Mol Biol 2023; 45:7011-7026. [PMID: 37754227 PMCID: PMC10529370 DOI: 10.3390/cimb45090443] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/11/2023] [Accepted: 08/21/2023] [Indexed: 09/28/2023] Open
Abstract
Targeting the molecular chaperone HSP90 and the anti-apoptotic proteins MCL1 and BCL2 may be a promising novel approach in the treatment of acute myeloid leukemia (AML). The HSP90 inhibitor PU-H71, MCL1 inhibitor S63845, and BCL2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and TP53 mutant AML cell lines and a variety of patient-derived AML cells. Results: PU-H71 and combination treatments with MCL1 inhibitor S63845 or BCL2 inhibitor venetoclax induced cell cycle arrest and apoptosis in susceptible AML cell lines and primary AML. The majority of the primary AML samples were responsive to PU-H71 in combination with BH3 mimetics. Elevated susceptibility to PU-H71 and S63845 was associated with FLT3 mutated AML with CD34 < 20%. Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity.
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Affiliation(s)
- Katja Seipel
- Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland;
| | - Scarlett Kohler
- Department for Biomedical Research, University of Bern, 3008 Bern, Switzerland;
| | - Ulrike Bacher
- Department of Hematology, University Hospital Bern, 3010 Bern, Switzerland;
| | - Thomas Pabst
- Department of Medical Oncology, University Hospital Bern, 3010 Bern, Switzerland;
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16
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Vasseur L, Fenwarth L, Lambert J, de Botton S, Figeac M, Villenet C, Heiblig M, Dumas PY, Récher C, Berthon C, Lemasle E, Lebon D, Lambert J, Terré C, Celli-Lebras K, Dombret H, Preudhomme C, Cheok M, Itzykson R, Duployez N. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study. Blood Adv 2023; 7:4024-4034. [PMID: 37205853 PMCID: PMC10410128 DOI: 10.1182/bloodadvances.2023010155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/24/2023] [Accepted: 05/09/2023] [Indexed: 05/21/2023] Open
Abstract
Whether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing-based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.
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Affiliation(s)
- Loïc Vasseur
- Adolescents and Young Adults Hematology Department, St-Louis University Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
- Biostatistical Department, St-Louis University Hospital, AP-HP, Paris, France
| | - Laurène Fenwarth
- CNRS, INSERM, CHU Lille, UMR9020-U1277 - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, Lille, France
- Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
| | - Jérôme Lambert
- Biostatistical Department, St-Louis University Hospital, AP-HP, Paris, France
| | - Stéphane de Botton
- Département d’hématologie et Département d’innovation thérapeutique, Gustave Roussy, Villejuif, France
| | - Martin Figeac
- CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, University of Lille, Lille, France
| | - Céline Villenet
- CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, University of Lille, Lille, France
| | - Maël Heiblig
- Hematology Department, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre-Benite, France
| | - Pierre-Yves Dumas
- Department of Clinical Hematology, Bordeaux University Hospital, PESSAC, France
| | - Christian Récher
- Service d'Hématologie, CHU de Toulouse - Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | | | - Emilie Lemasle
- Hematology Department, Henri-Becquerel Cancer Center, Rouen, France
| | - Delphine Lebon
- Service d’Hématologie Clinique et Thérapie cellulaire, CHU d’Amiens, Amiens, France
| | - Juliette Lambert
- Service d'Hématologie et Oncologie, Centre Hospitalier de Versailles, Le Chesnay, France
| | - Christine Terré
- Laboratory of Hematology, Centre Hospitalier de Versailles, Le Chesnay, France
| | | | - Hervé Dombret
- Department of Hematology, St-Louis University Hospital, AP-HP, Paris, France
| | - Claude Preudhomme
- CNRS, INSERM, CHU Lille, UMR9020-U1277 - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, Lille, France
- Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
| | - Meyling Cheok
- CNRS, INSERM, CHU Lille, UMR9020-U1277 - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Raphael Itzykson
- Department of Hematology, St-Louis University Hospital, AP-HP, Paris, France
- Génomes, biologie cellulaire et thérapeutique U944, INSERM, CNRS, Université Paris Cité, Paris, France
| | - Nicolas Duployez
- CNRS, INSERM, CHU Lille, UMR9020-U1277 - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, Lille, France
- Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
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17
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Li SQ, Chen M, Huang XY, Wang H, Chang YJ. Challenges facing minimal residual disease testing for acute myeloid leukemia and promising strategies to overcome them. Expert Rev Hematol 2023; 16:981-990. [PMID: 37978882 DOI: 10.1080/17474086.2023.2285985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/16/2023] [Indexed: 11/19/2023]
Abstract
INTRODUCTION Minimal residual disease (MRD) has been an important biomarker for relapse prediction and treatment choice in patients with acute myeloid leukemia (AML). False-positive or false-negative MRD results due to the low specificity and sensitivity of techniques such as multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction, and next-generation sequencing, as well as the biological characteristics of residual leukemia cells, including antigen shift, clone involution, heterogeneous genome of the blast cells, and lack of specific targets, all restrict the clinical use of MRD. AREAS COVERED We summarized the challenges of the techniques for MRD detection, and their application in the clinical setting. We also discussed strategies to overcome these challenges, such as the MFC MRD method based on leukemia stem cells, single-cell DNA sequencing or single-cell RNA sequencing for the investigation of biological characteristics of residual leukemia cells, and the potential of omics techniques for MRD detection. We further noted out that prospective clinical trials are needed to answer clinical questions related to MRD in patients with AML. EXPERT OPINION MRD is an important biomarker for individual therapy of patients with AML. In the future, it is important to increase the specificity and sensitivity of the detection techniques.
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Affiliation(s)
- Si-Qi Li
- National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, Xicheng District, P.R.C
| | - Man Chen
- Department of Laboratory Medicine, Hebei Yanda Ludaopei Hospital, Langfang, Hebei, P.R.C
| | - Xi-Yi Huang
- Department of Experimental Medicine, School of Public Health, Xiamen University, Xiamen, P.R.C
| | - Hui Wang
- Department of Laboratory Medicine, Hebei Yanda Ludaopei Hospital, Langfang, Hebei, P.R.C
| | - Ying-Jun Chang
- National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, Xicheng District, P.R.C
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18
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Largeaud L, Collin M, Monselet N, Vergez F, Fregona V, Larcher L, Hirsch P, Duployez N, Bidet A, Luquet I, Bustamante J, Dufrechou S, Prade N, Nolla M, Hamelle C, Tavitian S, Habib C, Meynier M, Bellanne-Chantelot C, Donadieu J, De Fontbrune FS, Fieschi C, Ferster A, Delhommeau F, Delabesse E, Pasquet M. Somatic genetic alterations predict hematological progression in GATA2 deficiency. Haematologica 2023; 108:1515-1529. [PMID: 36727400 PMCID: PMC10230419 DOI: 10.3324/haematol.2022.282250] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/19/2023] [Indexed: 02/03/2023] Open
Abstract
Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.
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Affiliation(s)
- Laetitia Largeaud
- Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse, France; Universite de Toulouse, Inserm, CNRS, Universite Toulouse III-Paul Sabatier, Centre de Recherches en Cancerologie de Toulouse, Toulouse
| | - Matthew Collin
- Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne
| | - Nils Monselet
- Department of bioinformatic, Institut Claudius Rigaud, Toulouse
| | - Francois Vergez
- Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse
| | - Vincent Fregona
- Universite de Toulouse, Inserm, CNRS, Universite Toulouse III-Paul Sabatier, Centre de Recherches en Cancerologie de Toulouse, Toulouse
| | - Lise Larcher
- Laboratory of Hematology, Hopital Saint-Louis, APHP
| | - Pierre Hirsch
- Sorbonne Universite, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hopital Saint-Antoine, Service d'Hematologie Biologique, 75012, Paris
| | | | | | - Isabelle Luquet
- Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse
| | - Jacinta Bustamante
- Center for the Study of Primary Immunodeficiencies, Paris Cite University, Necker Hospital for Sick Children, APHP, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY
| | | | - Nais Prade
- Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse
| | - Marie Nolla
- Department of Pediatric Hematology and Immunology, CHU Toulouse
| | - Camille Hamelle
- Department of Pediatric Hematology and Immunology, CHU Toulouse
| | | | | | | | | | - Jean Donadieu
- Pediatric Hematology Department, Hopital Trousseau, APHP
| | | | - Claire Fieschi
- Clinical immunology Department, Hopital Saint-Louis, APHP, Universite Paris Cite
| | - Alina Ferster
- Pediatric hematology, Hopital Reine Fabiola, Bruxelles, Belgium
| | - Francois Delhommeau
- Sorbonne Universite, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hopital Saint-Antoine, Service d'Hematologie Biologique, 75012, Paris
| | - Eric Delabesse
- Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse, France; Universite de Toulouse, Inserm, CNRS, Universite Toulouse III-Paul Sabatier, Centre de Recherches en Cancerologie de Toulouse, Toulouse
| | - Marlene Pasquet
- Universite de Toulouse, Inserm, CNRS, Universite Toulouse III-Paul Sabatier, Centre de Recherches en Cancerologie de Toulouse, Toulouse, France; Department of Pediatric Hematology and Immunology, CHU Toulouse.
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19
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Satta T, Li L, Chalasani SL, Hu X, Nkwocha J, Sharma K, Kmieciak M, Rahmani M, Zhou L, Grant S. Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax. Clin Cancer Res 2023; 29:1332-1343. [PMID: 36652560 PMCID: PMC10073266 DOI: 10.1158/1078-0432.ccr-22-2729] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/29/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
PURPOSE Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition. EXPERIMENTAL DESIGN Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells overexpressing MCL-1, constitutively active AKT, BAK, and/or BAX knockout, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models. RESULTS Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 downregulation and dependent upon MCL-1 downregulation and BAK/BAX upregulation as MCL-1 overexpression and BAX/BAK knockout abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax-resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased antileukemia effects in in vivo xenograft and PDX models. CONCLUSIONS The venetoclax/INK128 regimen exerts significant antileukemic activity in various preclinical models through mechanisms involving MCL-1 downregulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax-resistant AML cells, and in in vivo AML models. Further investigation of this strategy appears warranted.
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Affiliation(s)
- Toshihisa Satta
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
- Department of Laboratory Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
- Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lin Li
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Sri Lakshmi Chalasani
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Xiaoyan Hu
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Jewel Nkwocha
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Kanika Sharma
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Maciej Kmieciak
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohamed Rahmani
- Department of Molecular Biology and Genetics, College of Medicine & Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Liang Zhou
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
| | - Steven Grant
- Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA. USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
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20
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Ciotti G, Marconi G, Sperotto A, Giannini MB, Gottardi M, Martinelli G. Biological therapy in elderly patients with acute myeloid leukemia. Expert Opin Biol Ther 2023; 23:175-194. [PMID: 36715330 DOI: 10.1080/14712598.2023.2174015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The introduction of target molecules and immunological therapies is changing the treatment landscape of acute myeloid leukemia (AML). AREAS COVERED We recapitulate the biological therapies that can be employed in the treatment of elderly patients with AML. Alongside small molecules inhibitors that target specific gene mutations, antibodies, tumor microenvironment modulators, and cellular therapies are being developed for the cure of the disease. Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers. Cellular therapies are considered, even if a large trial is still pending for the feasibility of the approach. In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms. EXPERT OPINION Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.
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Affiliation(s)
- Giulia Ciotti
- Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Giovanni Marconi
- IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alessandra Sperotto
- Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Maria B Giannini
- IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michele Gottardi
- Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Giovanni Martinelli
- IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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21
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Pelosi E, Castelli G, Testa U. CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. Int J Mol Sci 2023; 24:2718. [PMID: 36769040 PMCID: PMC9917129 DOI: 10.3390/ijms24032718] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
In spite of consistent progress at the level of basic research and of clinical treatment, acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. To improve the outcomes of these patients, it is necessary to identify new therapeutic targets. IL3RA (CD123, alpha subunit of the interleukin 3 receptor) is a cell membrane protein overexpressed in several hematologic malignancies, including AML blastic plasmocytoid dendritic cell neoplasms (BPDCN). Given the higher expression of CD123 on leukemic cells compared to normal hematopoietic cells and its low/absent expression on normal hematopoietic stem cells, it appears as a suitable and attractive target for therapy. Various drugs targeting CD123 have been developed and evaluated at clinical level: interleukin-3 conjugated with diphtheria toxin; naked neutralizing anti-CD123 antibodies; drug-antibody conjugates; bispecific antibodies targeting both CD123 and CD3; and chimeric antigen receptor (CAR) T cells engineered to target CD123. Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.
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Affiliation(s)
| | | | - Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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22
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Pant H, Hercus TR, Tumes DJ, Yip KH, Parker MW, Owczarek CM, Lopez AF, Huston DP. Translating the biology of β common receptor-engaging cytokines into clinical medicine. J Allergy Clin Immunol 2023; 151:324-344. [PMID: 36424209 DOI: 10.1016/j.jaci.2022.09.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/16/2022] [Accepted: 09/29/2022] [Indexed: 11/23/2022]
Abstract
The family of cytokines that comprises IL-3, IL-5, and GM-CSF was discovered over 30 years ago, and their biological activities and resulting impact in clinical medicine has continued to expand ever since. Originally identified as bone marrow growth factors capable of acting on hemopoietic progenitor cells to induce their proliferation and differentiation into mature blood cells, these cytokines are also recognized as key mediators of inflammation and the pathobiology of diverse immunologic diseases. This increased understanding of the functional repertoire of IL-3, IL-5, and GM-CSF has led to an explosion of interest in modulating their functions for clinical management. Key to the successful clinical translation of this knowledge is the recognition that these cytokines act by engaging distinct dimeric receptors and that they share a common signaling subunit called β-common or βc. The structural determination of how IL-3, IL-5, and GM-CSF interact with their receptors and linking this to their differential biological functions on effector cells has unveiled new paradigms of cell signaling. This knowledge has paved the way for novel mAbs and other molecules as selective or pan inhibitors for use in different clinical settings.
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Affiliation(s)
- Harshita Pant
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Timothy R Hercus
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
| | - Damon J Tumes
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
| | - Kwok Ho Yip
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
| | - Michael W Parker
- Bio 21 Institute, The University of Melbourne, Melbourne, Australia; St Vincent's Institute of Medical Research, Melbourne, Australia
| | | | - Angel F Lopez
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Adelaide Medical School, University of Adelaide, Adelaide, Australia.
| | - David P Huston
- Texas A&M University School of Medicine, Houston, Tex; Houston Methodist Hospital and Research Institute, Houston, Tex.
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23
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Canali A, Vergnolle I, Bertoli S, Largeaud L, Nicolau ML, Rieu JB, Tavitian S, Huguet F, Picard M, Bories P, Vial JP, Lechevalier N, Béné MC, Luquet I, Mansat-De Mas V, Delabesse E, Récher C, Vergez F. Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia. Clin Cancer Res 2023; 29:134-142. [PMID: 36318706 DOI: 10.1158/1078-0432.ccr-22-2237] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/24/2022] [Accepted: 10/28/2022] [Indexed: 11/07/2022]
Abstract
PURPOSE Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays. EXPERIMENTAL DESIGN We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment. RESULTS The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-. CONCLUSIONS In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.
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Affiliation(s)
- Alban Canali
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Inès Vergnolle
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Sarah Bertoli
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Laetitia Largeaud
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Marie-Laure Nicolau
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Jean-Baptiste Rieu
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Suzanne Tavitian
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Françoise Huguet
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Muriel Picard
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Pierre Bories
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Jean Philippe Vial
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Nicolas Lechevalier
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Marie Christine Béné
- Laboratoire d'Hématologie, CHU de Nantes, Nantes, CRCI²NA INSERM UMR1307, CNRS UMR 6075, France
| | - Isabelle Luquet
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Véronique Mansat-De Mas
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Eric Delabesse
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Christian Récher
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - François Vergez
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
- Université Toulouse III Paul Sabatier, Toulouse, France
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
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24
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Lai Q, Song J, Zha J, Zheng H, Deng M, Liu Y, Lin W, Zhu Z, Zhang H, Xu B, Yang C. Microfluidic chip with reversible interface for noninvasive remission status monitoring and prognosis prediction of acute myeloid leukemia. Biosens Bioelectron 2023; 219:114803. [PMID: 36252315 DOI: 10.1016/j.bios.2022.114803] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/01/2022] [Accepted: 10/09/2022] [Indexed: 11/19/2022]
Abstract
Acute myeloid leukemia (AML) requires close monitoring of remission status for timely disease management. Liquid biopsy serves as a noninvasive approach for evaluating treatment response and guiding therapeutic modifications. Herein, we designed a non-invasive Leukemic stem cell Specific Capture Chip (LSC-Chip) with reversible recognition interface for AML remission status monitoring and prognosis prediction. A stem cell marker CD34 antibody coated herringbone chip with disulfide linkers was designed to capture and release leukemic stem cells (LSCs) in peripheral blood for efficient LSC enumeration and downstream single-cell analysis. Samples from 32 AML patients and 10 healthy donors were recruited for LSC enumeration and prognosis-associated subtyping with panels of official LSC markers (CD34+/CD123+/CD38-) and (Tie2+/CD34+/CD123+/CD38-), respectively. A cutoff value of 2.5 LSCs per milliliters of peripheral blood can be used to precisely distinguish non-remission AML patients from complete remission group. Moreover, single-cell RNA-seq of LSCs was performed to check different transcriptional profiles of LSC subtypes. Overall, the LSC-Chip with reversible recognition interface enabled reliable detection of LSCs from AML patient samples for noninvasive remission status monitoring and prognosis prediction in clinical AML management.
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Affiliation(s)
- Qian Lai
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Juan Song
- Discipline of Intelligent Instrument and Equipment, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Jie Zha
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Huijian Zheng
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Manman Deng
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Yilong Liu
- The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Wei Lin
- Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China
| | - Zhi Zhu
- The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China
| | - Huimin Zhang
- Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China.
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
| | - Chaoyong Yang
- Discipline of Intelligent Instrument and Equipment, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory for Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China; Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen, 361005, China.
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25
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Caruso S, De Angelis B, Del Bufalo F, Ciccone R, Donsante S, Volpe G, Manni S, Guercio M, Pezzella M, Iaffaldano L, Silvestris DA, Sinibaldi M, Di Cecca S, Pitisci A, Velardi E, Merli P, Algeri M, Lodi M, Paganelli V, Serafini M, Riminucci M, Locatelli F, Quintarelli C. Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia. J Hematol Oncol 2022; 15:163. [PMID: 36335396 PMCID: PMC9636687 DOI: 10.1186/s13045-022-01376-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/04/2022] [Indexed: 11/08/2022] Open
Abstract
Background Paediatric acute myeloid leukaemia (AML) is characterized by poor outcomes in patients with relapsed/refractory disease, despite the improvements in intensive standard therapy. The leukaemic cells of paediatric AML patients show high expression of the CD123 antigen, and this finding provides the biological basis to target CD123 with the chimeric antigen receptor (CAR). However, CAR.CD123 therapy in AML is hampered by on-target off-tumour toxicity and a long “vein-to-vein” time.
Methods We developed an off-the-shelf product based on allogeneic natural killer (NK) cells derived from the peripheral blood of healthy donors and engineered them to express a second-generation CAR targeting CD123 (CAR.CD123). Results CAR.CD123-NK cells showed significant anti-leukaemia activity not only in vitro against CD123+ AML cell lines and CD123+ primary blasts but also in two animal models of human AML-bearing immune-deficient mice. Data on anti-leukaemia activity were also corroborated by the quantification of inflammatory cytokines, namely granzyme B (Granz B), interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α), both in vitro and in the plasma of mice treated with CAR.CD123-NK cells.
To evaluate and compare the on-target off-tumour effects of CAR.CD123-T and NK cells, we engrafted human haematopoietic cells (hHCs) in an immune-deficient mouse model. All mice infused with CAR.CD123-T cells died by Day 5, developing toxicity against primary human bone marrow (BM) cells with a decreased number of total hCD45+ cells and, in particular, of hCD34+CD38− stem cells. In contrast, treatment with CAR.CD123-NK cells was not associated with toxicity, and all mice were alive at the end of the experiments. Finally, in a mouse model engrafted with human endothelial tissues, we demonstrated that CAR.CD123-NK cells were characterized by negligible endothelial toxicity when compared to CAR.CD123-T cells.
Conclusions Our data indicate the feasibility of an innovative off-the-shelf therapeutic strategy based on CAR.CD123-NK cells, characterized by remarkable efficacy and an improved safety profile compared to CAR.CD123-T cells. These findings open a novel intriguing scenario not only for the treatment of refractory/resistant AML patients but also to further investigate the use of CAR-NK cells in other cancers characterized by highly difficult targeting with the most conventional T effector cells.
Supplementary Information The online version contains supplementary material available at 10.1186/s13045-022-01376-3.
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Affiliation(s)
- Simona Caruso
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Biagio De Angelis
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Francesca Del Bufalo
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Roselia Ciccone
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Samantha Donsante
- grid.7841.aDepartment of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Gabriele Volpe
- grid.414125.70000 0001 0727 6809Research Laboratories, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
| | - Simona Manni
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Marika Guercio
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Michele Pezzella
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Laura Iaffaldano
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Domenico Alessandro Silvestris
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Matilde Sinibaldi
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Stefano Di Cecca
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Angela Pitisci
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Enrico Velardi
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Pietro Merli
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Mattia Algeri
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Mariachiara Lodi
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Valeria Paganelli
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Marta Serafini
- grid.7563.70000 0001 2174 1754Department of Pediatrics, Tettamanti Research Center, Fondazione MBBM/San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Mara Riminucci
- grid.7841.aDepartment of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Franco Locatelli
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy ,grid.8142.f0000 0001 0941 3192Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Concetta Quintarelli
- grid.414125.70000 0001 0727 6809Department of Oncology-Haematology, and Cell and Gene Therapy, Bambino Gesù Children Hospital, IRCCS, Rome, Italy ,grid.4691.a0000 0001 0790 385XDepartment of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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26
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Daver NG, Maiti A, Kadia TM, Vyas P, Majeti R, Wei AH, Garcia-Manero G, Craddock C, Sallman DA, Kantarjian HM. TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions. Cancer Discov 2022; 12:2516-2529. [PMID: 36218325 PMCID: PMC9627130 DOI: 10.1158/2159-8290.cd-22-0332] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/24/2022] [Accepted: 09/14/2022] [Indexed: 01/12/2023]
Abstract
TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity. SIGNIFICANCE Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent-based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.
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Affiliation(s)
- Naval G. Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Abhishek Maiti
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tapan M. Kadia
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paresh Vyas
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Ravindra Majeti
- Department of Medicine, Division of Hematology, Cancer Institute, Stanford University, Stanford, California
| | - Andrew H. Wei
- Peter MacCallum Centre, Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | | | - Charles Craddock
- Blood and Marrow Transplant Unit, Centre for Clinical Haematology, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom
| | - David A. Sallman
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Hagop M. Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
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27
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Xu S, Zhang M, Fang X, Hu X, Xing H, Yang Y, Meng J, Wen T, Liu J, Wang J, Wang C, Xu H. CD123 Antagonistic Peptides Assembled with Nanomicelles Act as Monotherapeutics to Combat Refractory Acute Myeloid Leukemia. ACS APPLIED MATERIALS & INTERFACES 2022; 14:38584-38593. [PMID: 35977045 DOI: 10.1021/acsami.2c11538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Due to the development of drug resistance to traditional chemotherapies and high relapse rate, AML still has a low survival rate and there is in an urgent need for better treatment strategies. CD123 is widely expressed by AML cells, also associated with the poor prognosis of AML. In this study, we fabricated nanomicelles loaded with a lab-designed CD123 antagonistic peptide, which were referred to as mPO-6. The antagonistic and therapeutic effects were investigated with CD123+ AML cell lines and a refractory AML mouse (AE and CKITD816V) model. Results show that mPO-6 can specifically bind to the CD123+ AML cells and inhibit the cell viability effectively. Intravenous administration of mPO-6 significantly reduces the percentage of AML cells' infiltration and prolongs the median survival of AML mice. Further, the efficiency of mPO-6 is demonstrated to interfere with the axis of CD123/IL-3 via regulating the activation of STAT5, PI3K/AKT, and NF-κB signaling pathways related to cell proliferation or apoptosis at the level of mRNA and protein in vivo and in vitro. In conclusion, the novel CD123 antagonistic peptide micelle formulation mPO-6 can significantly enhance apoptosis and prolong the survival of AML mice by effectively interfering with the axis of CD123/IL-3 and therefore is a promising therapeutic candidate for the treatment of refractory AML.
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Affiliation(s)
- Shilin Xu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Meichen Zhang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Xiaocui Fang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center of Nanoscience and Technology, Beijing 100190, China
- University of the Chinese Academy of Sciences, Beijing 100190, China
| | - Xuechun Hu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Yanlian Yang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center of Nanoscience and Technology, Beijing 100190, China
- University of the Chinese Academy of Sciences, Beijing 100190, China
| | - Jie Meng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Tao Wen
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Jian Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - Chen Wang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center of Nanoscience and Technology, Beijing 100190, China
- University of the Chinese Academy of Sciences, Beijing 100190, China
| | - Haiyan Xu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
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28
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Vergez F, Largeaud L, Bertoli S, Nicolau ML, Rieu JB, Vergnolle I, Saland E, Sarry A, Tavitian S, Huguet F, Picard M, Vial JP, Lechevalier N, Bidet A, Dumas PY, Pigneux A, Luquet I, Mansat-De Mas V, Delabesse E, Carroll M, Danet-Desnoyers G, Sarry JE, Récher C. Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia. Blood Cancer J 2022; 12:117. [PMID: 35973983 PMCID: PMC9381519 DOI: 10.1038/s41408-022-00712-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/09/2022] Open
Abstract
Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte-monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.
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Affiliation(s)
- François Vergez
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France. .,Université Toulouse III Paul Sabatier, Toulouse, France. .,Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. .,Stem Cell and Xenograft Core, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
| | - Laetitia Largeaud
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.,Université Toulouse III Paul Sabatier, Toulouse, France.,Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Sarah Bertoli
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France.,Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Marie-Laure Nicolau
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Jean-Baptiste Rieu
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Inès Vergnolle
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Estelle Saland
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France
| | - Audrey Sarry
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Suzanne Tavitian
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Françoise Huguet
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Muriel Picard
- Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Jean-Philippe Vial
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Nicolas Lechevalier
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Audrey Bidet
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Pierre-Yves Dumas
- Service d'Hématologie Clinique et de Thérapie Cellulaire, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Arnaud Pigneux
- Service d'Hématologie Clinique et de Thérapie Cellulaire, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
| | - Isabelle Luquet
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Véronique Mansat-De Mas
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Eric Delabesse
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Martin Carroll
- Stem Cell and Xenograft Core, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Gwenn Danet-Desnoyers
- Stem Cell and Xenograft Core, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Jean-Emmanuel Sarry
- Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France.,Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
| | - Christian Récher
- Université Toulouse III Paul Sabatier, Toulouse, France. .,Cancer Research Center of Toulouse, UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. .,Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
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29
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An LSC-based MRD assay to complement the traditional MFC method for prediction of AML relapse: a prospective study. Blood 2022; 140:516-520. [PMID: 35613411 DOI: 10.1182/blood.2021014604] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 05/17/2022] [Indexed: 11/20/2022] Open
Abstract
Li et al delineate a novel technique for assessing measurable residual disease (MRD) by the assessment of isolated leukemia stem cells (LSCs). They report that assessment of MRD in LSCs provides a better prediction of outcome than standard multiparameter flow cytometry.
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30
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Ishii H, Yano S. New Therapeutic Strategies for Adult Acute Myeloid Leukemia. Cancers (Basel) 2022; 14:2806. [PMID: 35681786 PMCID: PMC9179253 DOI: 10.3390/cancers14112806] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 05/27/2022] [Accepted: 05/29/2022] [Indexed: 12/19/2022] Open
Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous hematological malignancy. Chromosomal and genetic analyses are important for the diagnosis and prognosis of AML. Some patients experience relapse or have refractory disease, despite conventional cytotoxic chemotherapies and allogeneic transplantation, and a variety of new agents and treatment strategies have emerged. After over 20 years during which no new drugs became available for the treatment of AML, the CD33-targeting antibody-drug conjugate gemtuzumab ozogamicin was developed. This is currently used in combination with standard chemotherapy or as a single agent. CPX-351, a liposomal formulation containing daunorubicin and cytarabine, has become one of the standard treatments for secondary AML in the elderly. FMS-like tyrosine kinase 3 (FLT3) inhibitors and isocitrate dehydrogenase 1/2 (IDH 1/2) inhibitors are mainly used for AML patients with actionable mutations. In addition to hypomethylating agents and venetoclax, a B-cell lymphoma-2 inhibitor is used in frail patients with newly diagnosed AML. Recently, tumor protein p53 inhibitors, cyclin-dependent kinase inhibitors, and NEDD8 E1-activating enzyme inhibitors have been gaining attention, and a suitable strategy for the use of these drugs is required. Antibody drugs targeting cell-surface markers and immunotherapies, such as antibody-drug conjugates and chimeric antigen receptor T-cell therapy, have also been developed for AML.
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Affiliation(s)
| | - Shingo Yano
- Division of Clinical Oncology & Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan;
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31
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Laszlo GS, Orozco JJ, Kehret AR, Lunn MC, Huo J, Hamlin DK, Wilbur DS, Dexter SL, Comstock ML, O’Steen S, Sandmaier BM, Green DJ, Walter RB. Development of [ 211At]astatine-based anti-CD123 radioimmunotherapy for acute leukemias and other CD123+ malignancies. Leukemia 2022; 36:1485-1491. [PMID: 35474099 PMCID: PMC9177726 DOI: 10.1038/s41375-022-01580-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/14/2022] [Accepted: 04/19/2022] [Indexed: 11/09/2022]
Abstract
Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome (MDS). Of increasing interest are alpha-particle-emitting radionuclides such as astatine-211 (211At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123NULL MOLM-13 subline, a single dose of up to 40 µCi of 211At delivered via anti-CD123 mAb decreased tumor burdens and substantially prolonged survival dose dependently in mice bearing CD123+ but not CD123- leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211At-CD123 RIT toward clinical application.
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Affiliation(s)
- George S. Laszlo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Johnnie J. Orozco
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA
| | - Allie R. Kehret
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Margaret C. Lunn
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jenny Huo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Donald K. Hamlin
- Department of Radiation Oncology, University of Washington, Seattle, WA
| | - D. Scott Wilbur
- Department of Radiation Oncology, University of Washington, Seattle, WA
| | - Shannon L. Dexter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Melissa L. Comstock
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shyril O’Steen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Brenda M. Sandmaier
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA
| | - Damian J. Green
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA
| | - Roland B. Walter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Medicine, Division of Hematology, University of Washington, Seattle, WA,Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA,Department of Epidemiology, University of Washington, Seattle, WA
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32
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Kamel AM, Elsharkawy NM, Kandeel EZ, Hanafi M, Samra M, Osman RA. Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia. Front Oncol 2022; 12:867684. [PMID: 35530356 PMCID: PMC9069678 DOI: 10.3389/fonc.2022.867684] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/03/2022] [Indexed: 11/17/2022] Open
Abstract
Acute myeloid leukemia (AML) is a heterogenous disease in which the initiation and maintenance of the malignant clone is blamed on a rare population of leukemia stem cells (LSCs). The persistence of such a malignant population is referred to as measurable/minimal residual disease (MRD). Evaluation of MRD is the gold standard for follow-up of therapy and constitutes an independent prognostic parameter. As LSCs are the main contributor to the persistence of MRD, then MRD should correlate with the bulk of LSCs at the individual case level. MRD is measured at defined time points during therapy. However, LSCs can be evaluated at diagnosis, which ensures the advantage of early prediction of high-risk patients and allows for early therapeutic decisions. Using two simple four-color monoclonal antibody combinations (CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33) and the prism function of the Coulter Navios flow cytometer, the frequency of LSC subsets was evaluated in 84 newly diagnosed adult AML patients. For each panel, 16 possible combinations were detected. Our results showed that there was extreme variability in the percentage of the LSC fraction between different cases, as well as at the individual case level. For each LSC subset, the median value was used to divide cases into low and high expressors. LSC subsets that showed an impact on overall survival (OS) and disease-free survival (DFS) included CD123+, CD 123+/CD34-, CD34-/CD38+/CD123+, CD34+/CD38-/CD123+, CD133+, and CD133+/CD33-. On multivariate analysis, only CD123 (p ≤ 0.001, SE = 0.266, HR = 2.8, 95% CI = 1.74.7) and CD133+/CD33- (p = 0.017, SE = 0.263, HR = 1.9, 95% CI = 1.1–3.1) retained their significance for OS. Likewise, only CD34+/CD38-/CD123+ (p ≤ 0.001, HR 2.3, SE: 0.499, 95% CI: 2.4–17.4) and CD133 (p = 0.015, HR 2.3, SE 0.34, 95% CI: 1.2–4.4) retained their statistical significance for DFS. The LSC frequency at diagnosis showed a moderate to strong correlation with MRD status at day 14 and day 28. In conclusion, the level of LSCs at diagnosis correlated with MRD status at day 14 and day 28 in AML patients and had a deleterious impact on OS and DFS. It may be used as an early marker for high-risk patients allowing for early therapeutic decisions.
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Affiliation(s)
- Azza M Kamel
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Nahla M Elsharkawy
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Eman Z Kandeel
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Marwa Hanafi
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohammed Samra
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Randa A Osman
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
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33
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Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2049901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman
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34
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Petersen MA, Rosenberg CA, Brøndum RF, Aggerholm A, Kjeldsen E, Rahbek O, Ludvigsen M, Hasle H, Roug AS, Bill M. Immunophenotypically defined stem cell subsets in paediatric AML are highly heterogeneous and demonstrate differences in BCL-2 expression by cytogenetic subgroups. Br J Haematol 2022; 197:452-466. [PMID: 35298835 DOI: 10.1111/bjh.18094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 12/11/2022]
Abstract
In adult acute myeloid leukaemia (AML), immunophenotypic differences enable discrimination of leukaemic stem cells (LSCs) from healthy haematopoietic stem cells (HSCs). However, immunophenotypic stem cell characteristics are less explored in paediatric AML. Employing a 15-colour flow cytometry assay, we analysed the expression of eight aberrant surface markers together with BCL-2 on CD34+ CD38- bone marrow stem cells from 38 paediatric AML patients and seven non-leukaemic, age-matched controls. Furthermore, clonality was investigated by genetic analyses of sorted immunophenotypically abnormal stem cells from six patients. A total of 50 aberrant marker positive (non-HSC-like) subsets with 41 different immunophenotypic profiles were detected. CD123, CLEC12A, and IL1RAP were the most frequently expressed markers. IL1RAP, CD93, and CD25 expression were not restricted to stem cells harbouring leukaemia-associated mutations. Differential BCL-2 expression was found among defined cytogenetic subgroups. Interestingly, only immunophenotypically abnormal non-HSC-like subsets demonstrated BCL-2 overexpression. Collectively, we observed pronounced immunophenotypic heterogeneity within the stem cell compartment of paediatric AML patients. Additionally, certain aberrant markers used in adults seemed to be ineligible for detection of leukaemia-representing stem cells in paediatric patients implying that inference from adult studies must be done with caution.
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Affiliation(s)
- Marianne A Petersen
- Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Carina A Rosenberg
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rasmus F Brøndum
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Haematology, Aalborg University Hospital, Aalborg, Denmark
| | - Anni Aggerholm
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Eigil Kjeldsen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - Ole Rahbek
- Department of Orthopaedic Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Maja Ludvigsen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Henrik Hasle
- Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anne S Roug
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marie Bill
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
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35
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Brivio E, Baruchel A, Beishuizen A, Bourquin JP, Brown PA, Cooper T, Gore L, Kolb EA, Locatelli F, Maude SL, Mussai FJ, Vormoor-Bürger B, Vormoor J, von Stackelberg A, Zwaan CM. Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma. Eur J Cancer 2022; 164:1-17. [PMID: 35121370 DOI: 10.1016/j.ejca.2021.12.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/16/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022]
Abstract
Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody-drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3-ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A-directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A-rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2, RAS, MEK, Bruton's tyrosine kinase, JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance.
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Affiliation(s)
- Erica Brivio
- Princess Ma´xima Center for Pediatric Oncology, Utrecht, the Netherlands; Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - André Baruchel
- Hématologie-Immunologie Pédiatrique, Hoˆ pital Universitaire Robert Debré (APHP) and Université de Paris, Paris, France
| | - Auke Beishuizen
- Princess Ma´xima Center for Pediatric Oncology, Utrecht, the Netherlands; Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Jean-Pierre Bourquin
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Patrick A Brown
- Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Todd Cooper
- Aflac Cancer and Blood Disorders Center/Children's Healthcare of Atlanta/Emory University, Atlanta, GA, USA
| | - Lia Gore
- University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, USA
| | - E Anders Kolb
- Nemours Center for Cancer and Blood Disorders, Nemours/Alfred I DuPont Hospital for Children, Wilmington, DE, USA
| | - Franco Locatelli
- Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Sapienza, University of Rome, Italy
| | - Shannon L Maude
- Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Francis J Mussai
- Institute for Immunology and Immunotherapy, Cancer Research UK Birmingham Centre, The University of Birmingham, Birmingham, United Kingdom
| | | | - Josef Vormoor
- Princess Ma´xima Center for Pediatric Oncology, Utrecht, the Netherlands; University Medical Center, Utrecht, the Netherlands; Newcastle University, Newcastle, UK
| | | | - C Michel Zwaan
- Princess Ma´xima Center for Pediatric Oncology, Utrecht, the Netherlands; Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; The Innovative Therapies for Children with Cancer Consortium, Paris, France.
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36
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Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia. J Clin Med 2022; 11:jcm11051333. [PMID: 35268423 PMCID: PMC8911345 DOI: 10.3390/jcm11051333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/22/2022] [Accepted: 02/27/2022] [Indexed: 01/21/2023] Open
Abstract
Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 × CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.
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37
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Watts J, Lin TL, Mims A, Patel P, Lee C, Shahidzadeh A, Shami P, Cull E, Cogle CR, Wang E, Uckun FM. Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA. Front Oncol 2022; 11:806243. [PMID: 35096610 PMCID: PMC8793782 DOI: 10.3389/fonc.2021.806243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/21/2021] [Indexed: 11/13/2022] Open
Abstract
APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients' T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.
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Affiliation(s)
- Justin Watts
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - Tara L Lin
- Cancer Center and Medical Pavillon, University of Kansas, Westwood, KS, United States
| | - Alice Mims
- Wexner Medical Center/James Cancer Hospital, The Ohio State University, Columbus, OH, United States
| | - Prapti Patel
- Harold C. Simmons Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Cynthia Lee
- Department of Regulatory Affairs and Clinical Research, Aptevo Therapeutics, Seattle, WA, United States
| | - Anoush Shahidzadeh
- Department of Regulatory Affairs and Clinical Research, Aptevo Therapeutics, Seattle, WA, United States
| | - Paul Shami
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Elizabeth Cull
- Greenville Health System, Institute for Translational Oncology Research, Greenville, SC, United States
| | - Christopher R Cogle
- Department of Medicine, Division of Hematology & Oncology, University of Florida, Gainesville, FL, United States
| | - Eunice Wang
- Roswell Park Comprehensive Cancer Center, Department of Medicine, Buffalo, NY, United States
| | - Fatih M Uckun
- Department of Regulatory Affairs and Clinical Research, Aptevo Therapeutics, Seattle, WA, United States.,Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN, United States
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38
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Wang SSY. Relationship between leukaemic stem cells and hematopoietic stem cells and their clinical application. Leuk Lymphoma 2022; 63:1524-1533. [PMID: 35067128 DOI: 10.1080/10428194.2022.2027401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The world is aging and with it an associated increase in malignancies. Haematological malignancies especially Acute Myeloid Leukemia (AML) are no exception to this trend. With scientific advances, development of new AML treatments has improved patient mortality. One future research interest would be Leukeamic Stem Cells (LSC). This review aims to briefly highlight main LSC characteristics and their relationship with hematopoietic stem cells. Key LSC characteristics include dysregulated apoptosis, capacity for self-renewal, genomic instability, dysregulated energetics, immune privilege and an altered tumor microenvironment. Similar characteristics are also found in HSCs though in a regulated form. Classifying these characteristics will aid in the development of clinical biomarkers for LSC which is a potential clinical application of LSC biology. LSC biomarkers might prove to be critical in future AML management through improving accuracy of AML diagnosis, providing targeted treatment to minimize side effects, refinement of prognosis and relapse risk for earlier intervention.
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Affiliation(s)
- Samuel S Y Wang
- Department of Haematology, Tan Tock Seng Hospital, Singapore, Singapore
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39
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Lamble AJ, Eidenschink Brodersen L, Alonzo TA, Wang J, Pardo L, Sung L, Cooper TM, Kolb EA, Aplenc R, Tasian SK, Loken MR, Meshinchi S. CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group. J Clin Oncol 2022; 40:252-261. [PMID: 34855461 PMCID: PMC8769096 DOI: 10.1200/jco.21.01595] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981). MATERIALS AND METHODS AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels. RESULTS The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations (P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations (P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis. CONCLUSION CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.
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Affiliation(s)
- Adam J. Lamble
- Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, WA,Adam J. Lamble, MD, University of Washington–Seattle Children's Hospital, M/S MB.8.501, PO Box 5371, Seattle, WA 98145-5005; e-mail:
| | | | - Todd A. Alonzo
- Children's Oncology Group, Monrovia, CA,University of Southern California, Keck School of Medicine, Los Angeles, CA
| | - Jim Wang
- Children's Oncology Group, Monrovia, CA
| | | | - Lillian Sung
- Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, CA
| | - Todd M. Cooper
- Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, WA
| | - E. Anders Kolb
- Division of Oncology, Nemours/Alfred I. Dupont Hospital for Children, Wilmington, DE
| | - Richard Aplenc
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Sarah K. Tasian
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | - Soheil Meshinchi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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40
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Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia. Cancers (Basel) 2022; 14:cancers14030497. [PMID: 35158765 PMCID: PMC8833567 DOI: 10.3390/cancers14030497] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell "safety switches", TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality.
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41
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Dupont M, Huart M, Lauvinerie C, Bidet A, Guitart AV, Villacreces A, Vigon I, Desplat V, El Habhab A, Pigneux A, Ivanovic Z, Brunet De la Grange P, Dumas PY, Pasquet JM. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells. Cancers (Basel) 2022; 14:cancers14020453. [PMID: 35053612 PMCID: PMC8796021 DOI: 10.3390/cancers14020453] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 12/19/2022] Open
Abstract
Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.
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Affiliation(s)
- Marine Dupont
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Mathilde Huart
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Claire Lauvinerie
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Audrey Bidet
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Service d’Hématologie Biologique, CHU Bordeaux, 33000 Bordeaux, France
| | - Amélie Valérie Guitart
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Arnaud Villacreces
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Isabelle Vigon
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Vanessa Desplat
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Ali El Habhab
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
| | - Arnaud Pigneux
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Service d’Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, 33000 Bordeaux, France
| | - Zoran Ivanovic
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Etablissement Français du Sang Nouvelle Aquitaine, 33035 Bordeaux, France
| | - Philippe Brunet De la Grange
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Etablissement Français du Sang Nouvelle Aquitaine, 33035 Bordeaux, France
| | - Pierre-Yves Dumas
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Service d’Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, 33000 Bordeaux, France
| | - Jean-Max Pasquet
- Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.D.); (M.H.); (C.L.); (A.B.); (A.V.G.); (A.V.); (I.V.); (V.D.); (A.E.H.); (A.P.); (Z.I.); (P.B.D.l.G.); (P.-Y.D.)
- Correspondence: ; Tel.: +33-07-85-42-59-25
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Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia. Cancers (Basel) 2021; 14:cancers14010105. [PMID: 35008269 PMCID: PMC8744886 DOI: 10.3390/cancers14010105] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/14/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary This review summarizes various therapeutic immune approaches representing their targets, the efficacy and toxicity in the treatment of acute myeloid leukemia. In particular, immune checkpoint inhibitors, bispecific T-cell engager antibodies and chimeric antigen receptor-T-cell approaches are highlighted. Abstract The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.
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43
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Kan WL, Cheung Tung Shing KS, Nero TL, Hercus TR, Tvorogov D, Parker MW, Lopez AF. Messing with βc: A unique receptor with many goals. Semin Immunol 2021; 54:101513. [PMID: 34836771 DOI: 10.1016/j.smim.2021.101513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/23/2021] [Indexed: 11/16/2022]
Abstract
Our understanding of the biological role of the βc family of cytokines has evolved enormously since their initial identification as bone marrow colony stimulating factors in the 1960's. It has become abundantly clear over the intervening decades that this family of cytokines has truly astonishing pleiotropic capacity, capable of regulating not only hematopoiesis but also many other normal and pathological processes such as development, inflammation, allergy and cancer. As noted in the current pandemic, βc cytokines contribute to the cytokine storm seen in acutely ill COVID-19 patients. Ongoing studies to discover how these cytokines activate their receptor are revealing insights into the fundamental mechanisms that give rise to cytokine pleiotropy and are providing tantalizing glimpses of how discrete signaling pathways may be dissected for activation with novel ligands for therapeutic benefit.
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Affiliation(s)
- Winnie L Kan
- The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia 5000, Australia.
| | - Karen S Cheung Tung Shing
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
| | - Tracy L Nero
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
| | - Timothy R Hercus
- The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia 5000, Australia.
| | - Denis Tvorogov
- The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia 5000, Australia.
| | - Michael W Parker
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia; Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
| | - Angel F Lopez
- The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia 5000, Australia; Department of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia; Australian Cancer Research Foundation Cancer Genomics Facility, SA Pathology, Adelaide, South Australia 5000, Australia.
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44
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Marchand T, Pinho S. Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front Immunol 2021; 12:775128. [PMID: 34721441 PMCID: PMC8554324 DOI: 10.3389/fimmu.2021.775128] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/28/2021] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. While complete remission can be obtained with intensive chemotherapy in young and fit patients, relapse is frequent and prognosis remains poor. Leukemic cells are thought to arise from a pool of leukemic stem cells (LSCs) which sit at the top of the hierarchy. Since their discovery, more than 30 years ago, LSCs have been a topic of intense research and their identification paved the way for cancer stem cell research. LSCs are defined by their ability to self-renew, to engraft into recipient mice and to give rise to leukemia. Compared to healthy hematopoietic stem cells (HSCs), LSCs display specific mutations, epigenetic modifications, and a specific metabolic profile. LSCs are usually considered resistant to chemotherapy and are therefore the drivers of relapse. Similar to their HSC counterpart, LSCs reside in a highly specialized microenvironment referred to as the “niche”. Bidirectional interactions between leukemic cells and the microenvironment favor leukemic progression at the expense of healthy hematopoiesis. Within the niche, LSCs are thought to be protected from genotoxic insults. Improvement in our understanding of LSC gene expression profile and phenotype has led to the development of prognosis signatures and the identification of potential therapeutic targets. In this review, we will discuss LSC biology in the context of their specific microenvironment and how a better understanding of LSC niche biology could pave the way for new therapies that target AML.
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Affiliation(s)
- Tony Marchand
- Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France.,Faculté de médecine, Université Rennes 1, Rennes, France.,Institut National de la Santé et de la Recherche Médicale (INSERM) U1236, Rennes, France
| | - Sandra Pinho
- Department of Pharmacology & Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
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45
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Abstract
The β common chain (βc) cytokine family includes granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and IL-5, all of which use βc as key signaling receptor subunit. GM-CSF, IL-3 and IL-5 have specific roles as hematopoietic growth factors. IL-3 binds with high affinity to the IL-3 receptor α (IL-3Rα/CD123) and then associates with the βc subunit. IL-3 is mainly synthesized by different subsets of T cells, but is also produced by several other immune [basophils, dendritic cells (DCs), mast cells, etc.] and non-immune cells (microglia and astrocytes). The IL-3Rα is also expressed by immune (basophils, eosinophils, mast cells, DCs, monocytes, and megacaryocytes) and non-immune cells (endothelial cells and neuronal cells). IL-3 is the most important growth and activating factor for human and mouse basophils, primary effector cells of allergic disorders. IL-3-activated basophils and mast cells are also involved in different chronic inflammatory disorders, infections, and several types of cancer. IL-3 induces the release of cytokines (i.e., IL-4, IL-13, CXCL8) from human basophils and preincubation of basophils with IL-3 potentiates the release of proinflammatory mediators and cytokines from IgE- and C5a-activated basophils. IL-3 synergistically potentiates IL-33-induced mediator release from human basophils. IL-3 plays a pathogenic role in several hematologic cancers and may contribute to autoimmune and cardiac disorders. Several IL-3Rα/CD123 targeting molecules have shown some efficacy in the treatment of hematologic malignancies.
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46
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Uckun FM, Watts J. CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients. FRONTIERS IN AGING 2021; 2:757276. [PMID: 35822053 PMCID: PMC9261311 DOI: 10.3389/fragi.2021.757276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/14/2021] [Indexed: 11/26/2022]
Abstract
There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients. This article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates. T-cell engaging BiAB targeting the CD123 antigen may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML.
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Affiliation(s)
- Fatih M. Uckun
- Aptevo Therapeutics, Seattle, WA, United States
- Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN, United States
| | - Justin Watts
- University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, United States
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47
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Tahk S, Vick B, Hiller B, Schmitt S, Marcinek A, Perini ED, Leutbecher A, Augsberger C, Reischer A, Tast B, Humpe A, Jeremias I, Subklewe M, Fenn NC, Hopfner KP. SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells. J Hematol Oncol 2021; 14:155. [PMID: 34579739 PMCID: PMC8477557 DOI: 10.1186/s13045-021-01163-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 09/07/2021] [Indexed: 02/04/2023] Open
Abstract
Background Acute myeloid leukaemia (AML) stem cells (LSCs) cause disease relapse. The CD47 “don’t eat me signal” is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 has been successful, but the ubiquitous expression of CD47 on healthy cells poses potential limitations for such therapies. In contrast, CD123 is a well-known LSC-specific surface marker utilized as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of CD47/SIRPα signalling to AML while specifically enhancing LSC clearance. Methods SIRPα-αCD123 antibodies were generated by fusing the extracellular domain of SIRPα to an αCD123 antibody. The binding properties of the antibodies were analysed by flow cytometry and surface plasmon resonance. The functional characteristics of the fusion antibodies were determined by antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays using primary AML patient cells. Finally, an in vivo engraftment assay was utilized to assess LSC targeting. Results SIRPα-αCD123 fusion antibodies exhibited increased binding and preferential targeting of CD123+ CD47+ AML cells even in the presence of CD47+ healthy cells. Furthermore, SIRPα-αCD123 fusion antibodies confined disruption of the CD47-SIRPα axis locally to AML cells. In vitro experiments demonstrated that SIRPα-αCD123 antibodies greatly enhanced AML cell phagocytosis mediated by allogeneic and autologous macrophages. Moreover, SIRPα-αCD123 fusion antibodies efficiently targeted LSCs with in vivo engraftment potential. Conclusions SIRPα-αCD123 antibodies combine local CD47 blockade with specific LSC targeting in a single molecule, minimize the risk of targeting healthy cells and efficiently eliminate AML LSCs. These results validate SIRPα-αCD123 antibodies as promising therapeutic interventions for AML. Supplementary Information The online version contains supplementary material available at 10.1186/s13045-021-01163-6.
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Affiliation(s)
- Siret Tahk
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany
| | - Binje Vick
- Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Björn Hiller
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany
| | - Saskia Schmitt
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany
| | - Anetta Marcinek
- Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Enrico D Perini
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany
| | - Alexandra Leutbecher
- Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Christian Augsberger
- Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Anna Reischer
- Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Benjamin Tast
- Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Andreas Humpe
- Department of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, University Hospital, LMU Munich, Munich, Germany
| | - Irmela Jeremias
- Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.,Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany
| | - Marion Subklewe
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.,Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.,Department of Hematology and Oncology, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Nadja C Fenn
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany.
| | - Karl-Peter Hopfner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany.
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Gorshkova O, Cappaï J, Maillot L, Sergé A. Analyzing normal and disrupted leukemic stem cell adhesion to bone marrow stromal cells by single-molecule tracking nanoscopy. J Cell Sci 2021; 134:271951. [PMID: 34435622 DOI: 10.1242/jcs.258736] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/02/2021] [Indexed: 01/02/2023] Open
Abstract
Leukemic stem cells (LSCs) adhere to bone niches through adhesion molecules. These interactions, which are deeply reorganized in tumors, contribute to LSC resistance to chemotherapy and leukemia relapse. However, LSC adhesion mechanisms and potential therapeutic disruption using blocking antibodies remain largely unknown. Junctional adhesion molecule C (JAM-C, also known as JAM3) overexpression by LSCs correlates with increased leukemia severity, and thus constitutes a putative therapeutic target. Here, we took advantage of the ability of nanoscopy to detect single molecules with nanometric accuracy to characterize junctional adhesion molecule (JAM) dynamics at leuko-stromal contacts. Videonanoscopy trajectories were reconstructed using our dedicated multi-target tracing algorithm, pipelined with dual-color analyses (MTT2col). JAM-C expressed by LSCs engaged in transient interactions with JAM-B (also known as JAM2) expressed by stromal cells. JAM recruitment and colocalization at cell contacts were proportional to JAM-C level and reduced by a blocking anti-JAM-C antibody. MTT2col revealed, at single-molecule resolution, the ability of blocking antibodies to destabilize LSC binding to their niches, opening opportunities for disrupting LSC resistance mechanisms.
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Affiliation(s)
- Oksana Gorshkova
- Centre de recherche en cancérologie de Marseille (CRCM), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (Inserm), Institut Paoli-Calmettes (IPC), Aix-Marseille Université, F-13273 Marseille, France
| | - Jessica Cappaï
- Centre de recherche en cancérologie de Marseille (CRCM), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (Inserm), Institut Paoli-Calmettes (IPC), Aix-Marseille Université, F-13273 Marseille, France
| | - Loriane Maillot
- Laboratoire adhésion inflammation (LAI), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (Inserm), Aix-Marseille Université, F-13288 Marseille, France
| | - Arnauld Sergé
- Centre de recherche en cancérologie de Marseille (CRCM), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (Inserm), Institut Paoli-Calmettes (IPC), Aix-Marseille Université, F-13273 Marseille, France.,Laboratoire adhésion inflammation (LAI), Centre national de la recherche scientifique (CNRS), Institut national de la santé et de la recherche médicale (Inserm), Aix-Marseille Université, F-13288 Marseille, France
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49
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Bonnevaux H, Guerif S, Albrecht J, Jouannot E, De Gallier T, Beil C, Lange C, Leuschner WD, Schneider M, Lemoine C, Caron A, Amara C, Barrière C, Siavellis J, Bardet V, Luna E, Agrawal P, Drake DR, Rao E, Wonerow P, Carrez C, Blanc V, Hsu K, Wiederschain D, Fraenkel PG, Virone-Oddos A. Pre-clinical development of a novel CD3-CD123 bispecific T-cell engager using cross-over dual-variable domain (CODV) format for acute myeloid leukemia (AML) treatment. Oncoimmunology 2021; 10:1945803. [PMID: 34484869 PMCID: PMC8409758 DOI: 10.1080/2162402x.2021.1945803] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Novel therapies are needed for effective treatment of AML. In the relapsed setting, prognosis is very poor despite salvage treatment with chemotherapy. Evidence suggests that leukemic stem cells (LSCs) cause relapse. The cell surface receptor CD123 is highly expressed in blast cells and LSCs from AML patients and is a potential therapeutic target. CD123 cross-over dual-variable domain T-cell engager (CD123-CODV-TCE) is a bispecific antibody with an innovative format. One arm targets the CD3εδ subunit of T-cell co-receptors on the surface of T cells, while the other targets CD123 on malignant cells, leading to cell-specific cytotoxic activity. Here, we describe the preclinical activity of CD123-CODV-TCE. CD123-CODV-TCE effectively binds to human and cynomolgus monkey CD3 and CD123 and is a highly potent T-cell engager. It mediates T-cell activation and T-cell-directed killing of AML cells in vitro. In vivo, CD123-CODV-TCE suppresses AML tumor growth in leukemia xenograft mouse models, where it achieves an effective half-life of 3.2 days, which is a significantly longer half-life compared to other bispecific antibodies with no associated Fc fragment. The in vitro safety profile is as expected for compounds with similar modes of action. These results suggest that CD123-CODV-TCE may be a promising therapy for patients with relapsed/refractory AML.
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Affiliation(s)
- Hélène Bonnevaux
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Stephane Guerif
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Jana Albrecht
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Erwan Jouannot
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Thibaud De Gallier
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Christian Beil
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Christian Lange
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Wulf Dirk Leuschner
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Marion Schneider
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Cendrine Lemoine
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Anne Caron
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Céline Amara
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Cédric Barrière
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Justine Siavellis
- Hopitaux Universitaires Paris Ile De France Ouest, Université Versailles Saint Quentin, Paris, France
| | - Valérie Bardet
- Hopitaux Universitaires Paris Ile De France Ouest, Université Versailles Saint Quentin, Paris, France
| | | | | | | | - Ercole Rao
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Peter Wonerow
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Chantal Carrez
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Véronique Blanc
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Karl Hsu
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Dmitri Wiederschain
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Paula G Fraenkel
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
| | - Angéla Virone-Oddos
- Sanofi R&D, Vitry-sur-Seine, France; Frankfurt, Germany; and Cambridge, MA, USA
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Uckun FM, Lin TL, Mims AS, Patel P, Lee C, Shahidzadeh A, Shami PJ, Cull E, Cogle CR, Watts J. A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome. Cancers (Basel) 2021; 13:4113. [PMID: 34439266 PMCID: PMC8394899 DOI: 10.3390/cancers13164113] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 01/06/2023] Open
Abstract
APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1-8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.
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Affiliation(s)
- Fatih M. Uckun
- Aptevo Therapeutics, Seattle, WA 98121, USA; (C.L.); (A.S.)
- Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN 55110, USA
| | - Tara L. Lin
- University of Kansas Cancer Center and Medical Pavillon, University of Kansas, Westwood, KS 66205, USA;
| | - Alice S. Mims
- Wexner Medical Center, James Cancer Hospital, The Ohio State University, Columbus, OH 43210, USA;
| | - Prapti Patel
- Southwestern Medical Center, University of Texas, Dallas, TX 75390, USA;
| | - Cynthia Lee
- Aptevo Therapeutics, Seattle, WA 98121, USA; (C.L.); (A.S.)
| | | | - Paul J. Shami
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA;
| | - Elizabeth Cull
- Institute for Translational Oncology Research, Greenville Health System, Greenville, SC 29605, USA;
| | - Christopher R. Cogle
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Justin Watts
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
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