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1
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Pierini S, Gabbasov R, Oliveira-Nunes MC, Qureshi R, Worth A, Huang S, Nagar K, Griffin C, Lian L, Yashiro-Ohtani Y, Ross K, Sloas C, Ball M, Schott B, Sonawane P, Cornell L, Blumenthal D, Chhum S, Minutolo N, Ciccaglione K, Shaw L, Zentner I, Levitsky H, Shestova O, Gill S, Varghese B, Cushing D, Ceeraz DeLong S, Abramson S, Condamine T, Klichinsky M. Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models. Nat Commun 2025; 16:706. [PMID: 39814734 PMCID: PMC11735936 DOI: 10.1038/s41467-024-55770-1] [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: 10/24/2024] [Accepted: 12/23/2024] [Indexed: 01/18/2025] Open
Abstract
We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.
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Affiliation(s)
| | | | | | | | | | - Shuo Huang
- Carisma Therapeutics Inc, Philadelphia, PA, USA
| | - Karan Nagar
- Carisma Therapeutics Inc, Philadelphia, PA, USA
| | | | - Lurong Lian
- Carisma Therapeutics Inc, Philadelphia, PA, USA
| | | | | | | | | | | | | | | | | | | | | | | | - Lauren Shaw
- Carisma Therapeutics Inc, Philadelphia, PA, USA
| | | | | | - Olga Shestova
- Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Saar Gill
- Center for Cellular Immunotherapies, Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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2
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VanderVeen BN, Cardaci TD, Bullard BM, Unger CA, Freeman JC, Enos RT, Shtutman M, Wyatt MD, Fan D, Murphy EA. The impact of diet-induced obesity on 5 fluorouracil-induced tumor and liver immune cell cytotoxicity. Am J Physiol Cell Physiol 2025; 328:C56-C77. [PMID: 39570672 PMCID: PMC11901352 DOI: 10.1152/ajpcell.00687.2024] [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: 09/18/2024] [Revised: 11/04/2024] [Accepted: 11/17/2024] [Indexed: 12/24/2024]
Abstract
Obesity increases the risk for developing several cancers, including colorectal cancer (CRC), and is associated with liver perturbations, which likely impacts treatment tolerance. 5 fluorouracil (5FU) remains a first line treatment for CRC, but efficacy is hampered by interpatient variable responsiveness and off-target toxicities. The current study examined the impact of diet-induced obesity (DIO) on 5FU cytopenia and efficacy using two established CRC models: MC38 (C57BL/6) and C26 (CD2F1). DIO increased tumor size in both MC38 and C26. DIO reduced liver dihydropyrimidine dehydrogenase (dpyd) expression, the enzyme that catalyzes 5FU's catabolism to become inactive, in MC38 mice, but not in C26. 5FU remained efficacious against early MC38 and C26 tumor growth; however, 5FU-induced tumor and liver immune cell death was exacerbated following three cycles of 5FU with MC38. DIO caused dramatic changes to liver Kupffer cells (KCs), wherein there were increased prometastatic, immunosuppressive KCs in Obese Control and MC38. 5FU, however, depleted these KCs and increased inflammatory KCs in both Lean and Obese MC38. DIO yielded a milder obesity phenotype in CD2F1 mice, and 5FU-induced cytopenia was not different between Lean and Obese. DIO increased total liver KCs; however, C26 tumors increased liver KCs, which were normalized with 5FU treatment, irrespective of DIO. Although 5FU remained efficacious in both models of CRC and did not reduce survival, multiple cycles of 5FU monotherapy increased liver and tumor immune cell death in DIO mice. Altogether, obesity was not protective but rather exacerbated chemotherapy-induced cytotoxicity and promoted a prometastatic liver environment.NEW & NOTEWORTHY The current study aimed to examine the impact of obesity on tumorigenesis and 5FU safety and efficacy with two established murine models of colorectal cancer. Diet-induced obesity increased tumor burden in both models, and 5FU's antitumor efficacy remained and extended survival with both tumor models. Obese mice demonstrated increased 5FU-induced immune cell cytotoxicity following multiple cycles of 5FU with distinct changes to liver macrophages, suggesting an increased propensity for liver metastasis.
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Affiliation(s)
- Brandon N VanderVeen
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Thomas D Cardaci
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Brooke M Bullard
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Christian A Unger
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Jeffrey C Freeman
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Reilly T Enos
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - Michael Shtutman
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States
| | - Michael D Wyatt
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States
| | - E Angela Murphy
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States
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3
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Santiago-Sánchez GS, Fabian KP, Hodge JW. A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance. Cancer Biol Ther 2024; 25:2308097. [PMID: 38306161 PMCID: PMC10841019 DOI: 10.1080/15384047.2024.2308097] [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: 08/31/2023] [Accepted: 01/17/2024] [Indexed: 02/03/2024] Open
Abstract
The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance). Here, we review the current FDA-approved ICI for the treatment of certain solid malignancies, evaluate the contrasting responses to checkpoint blockade in different cancer types, explore the known mechanisms associated with checkpoint blockade resistance (CBR), and assess current strategies in the field that seek to overcome these mechanisms. In order to improve current therapies and develop new ones, the immunotherapy field still has an unmet need in identifying other molecules that act as immune checkpoints, and uncovering other mechanisms that promote CBR.
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Affiliation(s)
- Ginette S. Santiago-Sánchez
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kellsye P. Fabian
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James W. Hodge
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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4
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Xie Q, Liu X, Liu R, Pan J, Liang J. Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer. Mol Cancer 2024; 23:252. [PMID: 39529058 PMCID: PMC11555832 DOI: 10.1186/s12943-024-02166-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.
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Affiliation(s)
- Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China
| | - Xiaolin Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China
| | - Rengyun Liu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jingxuan Pan
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China.
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5
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Lindeman SD, Booth OC, Tudi P, Schleinkofer TC, Moss JN, Kearney NB, Mukkamala R, Thompson LK, Modany MA, Srinivasarao M, Low PS. FAP Radioligand Linker Optimization Improves Tumor Dose and Tumor-to-Healthy Organ Ratios in 4T1 Syngeneic Model. J Med Chem 2024; 67:11827-11840. [PMID: 39013156 DOI: 10.1021/acs.jmedchem.4c00448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance. Seven FAP6 derivatives with different linkers or albumin binders were synthesized, radiolabeled, and investigated for their effects on binding and cellular uptake. The radioligands were then characterized in 4T1 tumor-bearing Balb/c mice using both single-photon emission computed tomography (SPECT) and ex vivo biodistribution analyses to identify the conjugate with the best tumor retention and tumor-to-healthy organ ratios. The results reveal an optimized FAP6 radioligand that exhibits efficacy and safety properties that potentially justify its translation into the clinic.
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Affiliation(s)
- Spencer D Lindeman
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
- MorphImmune, Inc., 1281 Win Hentschel Blvd, West Lafayette, Indiana 47906, United States
| | - Owen C Booth
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Pooja Tudi
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Taylor C Schleinkofer
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Jackson N Moss
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Nicholas B Kearney
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Ramesh Mukkamala
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Lauren K Thompson
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Mollie A Modany
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Madduri Srinivasarao
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
| | - Philip S Low
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States
- MorphImmune, Inc., 1281 Win Hentschel Blvd, West Lafayette, Indiana 47906, United States
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6
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Aubert C, Culty T, Zidane M, Bigot P, Lebdai S. Antibiotic therapy impact on intravesical BCG therapy efficacy for high-risk localized bladder cancer treatment. Front Oncol 2024; 13:1240378. [PMID: 38525411 PMCID: PMC10957779 DOI: 10.3389/fonc.2023.1240378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 12/29/2023] [Indexed: 03/26/2024] Open
Abstract
Intravesical Bacillus Calmettes-Guerin (BCG) instillations is the gold standard adjuvant treatment for high and very high-risk non-muscle-invasive bladder cancer (NMIBC). Antibiotics may be required to treat asymptomatic bacteriuria before instillations or to prevent side effects. By modifying the bladder microbiota and through its bactericidal action, it could modify the efficacy of BCG. This study evaluates the impact of antibiotics received during BCG-induction treatment on the oncological outcomes for high and very high risk NMIBC. We retrospectively included all patients who received a full induction regimen of BCG therapy between January 2017 and June 2022. Clinical and tumor characteristics as well as tolerability were collected. Recurrence-free survival (RFS) and progression-free survival (PFS) were compared according to the prescription of antibiotics, its type and duration. A total of 126 patients were included, 86.5% of the tumors were high risk and 13.5% very high risk. The median follow-up was 31 months (7-60). 36% of the patients received antibiotics during BCG-induction treatment (among which 44% received fluoroquinolones). 21.4% of patients had tumor recurrence. There was no difference in RFS (p=0.902) or PFS (p=0.88) according to the duration or the type of antibiotics received. The use of a prolonged antibiotic treatment (> 7 days) significantly increased the duration of the BCG-induction treatment from 35 to 41,5 days (p=0,049) and the median number of delayed treatments by 1,5 [0-4]. Neither the use of antibiotics nor their duration modified the risk of recurrence or the intensity of side effects in multivariate analysis. Antibiotics received during BCG-induction immunotherapy did not influence oncological short-term outcomes or intensity of side effects.
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Affiliation(s)
- Cécile Aubert
- Urology Department, University Hospital of Angers, Angers, France
| | - Thibaut Culty
- Urology Department, University Hospital of Angers, Angers, France
| | - Merzouka Zidane
- Pathology Department, University Hospital of Angers, Angers, France
| | - Pierre Bigot
- Urology Department, University Hospital of Angers, Angers, France
| | - Souhil Lebdai
- Urology Department, University Hospital of Angers, Angers, France
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7
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Yin T, Li X, Li Y, Zang X, Liu L, Du M. Macrophage plasticity and function in cancer and pregnancy. Front Immunol 2024; 14:1333549. [PMID: 38274812 PMCID: PMC10808357 DOI: 10.3389/fimmu.2023.1333549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.
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Affiliation(s)
- Tingxuan Yin
- Lab of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Xinyi Li
- Lab of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Yanhong Li
- Lab of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Lu Liu
- Lab of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
| | - Meirong Du
- Lab of Reproduction Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
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8
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Hikmet F, Rassy M, Backman M, Méar L, Mattsson JSM, Djureinovic D, Botling J, Brunnström H, Micke P, Lindskog C. Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer. Mol Oncol 2023; 17:2603-2617. [PMID: 37341056 DOI: 10.1002/1878-0261.13474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 05/15/2023] [Accepted: 06/19/2023] [Indexed: 06/22/2023] Open
Abstract
The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.
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Affiliation(s)
- Feria Hikmet
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | - Marc Rassy
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | - Max Backman
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | - Loren Méar
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | | | - Dijana Djureinovic
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
- Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA
| | - Johan Botling
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | - Hans Brunnström
- Division of Pathology, Department of Clinical Sciences Lund, Lund University, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden
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9
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Mihalik NE, Steinberger KJ, Stevens AM, Bobko AA, Hoblitzell EH, Tseytlin O, Akhter H, Dziadowicz SA, Wang L, O’Connell RC, Monaghan KL, Hu G, Mo X, Khramtsov VV, Tseytlin M, Driesschaert B, Wan EC, Eubank TD. Dose-Specific Intratumoral GM-CSF Modulates Breast Tumor Oxygenation and Antitumor Immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1589-1604. [PMID: 37756529 PMCID: PMC10656117 DOI: 10.4049/jimmunol.2300326] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023]
Abstract
GM-CSF has been employed as an adjuvant to cancer immunotherapy with mixed results based on dosage. We previously showed that GM-CSF regulated tumor angiogenesis by stimulating soluble vascular endothelial growth factor (VEGF) receptor-1 from monocytes/macrophages in a dose-dependent manner that neutralized free VEGF, and intratumoral injections of high-dose GM-CSF ablated blood vessels and worsened hypoxia in orthotopic polyoma middle T Ag (PyMT) triple-negative breast cancer (TNBC). In this study, we assessed both immunoregulatory and oxygen-regulatory components of low-dose versus high-dose GM-CSF to compare effects on tumor oxygen, vasculature, and antitumor immunity. We performed intratumoral injections of low-dose GM-CSF or saline controls for 3 wk in FVB/N PyMT TNBC. Low-dose GM-CSF uniquely reduced tumor hypoxia and normalized tumor vasculature by increasing NG2+ pericyte coverage on CD31+ endothelial cells. Priming of "cold," anti-PD1-resistant PyMT tumors with low-dose GM-CSF (hypoxia reduced) sensitized tumors to anti-PD1, whereas high-dose GM-CSF (hypoxia exacerbated) did not. Low-dose GM-CSF reduced hypoxic and inflammatory tumor-associated macrophage (TAM) transcriptional profiles; however, no phenotypic modulation of TAMs or tumor-infiltrating lymphocytes were observed by flow cytometry. In contrast, high-dose GM-CSF priming increased infiltration of TAMs lacking the MHC class IIhi phenotype or immunostimulatory marker expression, indicating an immunosuppressive phenotype under hypoxia. However, in anti-PD1 (programmed cell death 1)-susceptible BALB/c 4T1 tumors (considered hot versus PyMT), high-dose GM-CSF increased MHC class IIhi TAMs and immunostimulatory molecules, suggesting disparate effects of high-dose GM-CSF across PyMT versus 4T1 TNBC models. Our data demonstrate a (to our knowledge) novel role for low-dose GM-CSF in reducing tumor hypoxia for synergy with anti-PD1 and highlight why dosage and setting of GM-CSF in cancer immunotherapy regimens require careful consideration.
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Affiliation(s)
- Nicole E. Mihalik
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
| | - Kayla J. Steinberger
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
| | - Alyson M. Stevens
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
| | - Andrey A. Bobko
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
| | - E. Hannah Hoblitzell
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
| | - Oxana Tseytlin
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
| | - Halima Akhter
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- Bioinformatics Core, West Virginia University, Morgantown, WV 26506
- Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506
| | - Sebastian A. Dziadowicz
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- Bioinformatics Core, West Virginia University, Morgantown, WV 26506
| | - Lei Wang
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- Bioinformatics Core, West Virginia University, Morgantown, WV 26506
| | - Ryan C. O’Connell
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
| | - Kelly L. Monaghan
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
| | - Gangqing Hu
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- Bioinformatics Core, West Virginia University, Morgantown, WV 26506
| | - Xiaokui Mo
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, 1585 Neil Ave, Columbus, OH 43210, USA
| | - Valery V. Khramtsov
- West Virginia Clinical and Translational Science Institute, West Virginia University, Morgantown WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
| | - Mark Tseytlin
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
| | - Benoit Driesschaert
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506
- West Virginia Clinical and Translational Science Institute, West Virginia University, Morgantown WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
- C. Eugene Bennet Department of Chemistry, West Virginia University, Morgantown, WV, 26505, United States
| | - Edwin C.K. Wan
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- Department of Neuroscience, West Virginia University, Morgantown, WV, 26505
| | - Timothy D. Eubank
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506
- West Virginia Clinical and Translational Science Institute, West Virginia University, Morgantown WV 26506
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26505
- In vivo Multifunctional Magnetic Resonance (IMMR) center, West Virginia University, Morgantown, WV 26506
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10
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Koh CH, Lee S, Kwak M, Kim BS, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med 2023; 55:2287-2299. [PMID: 37907738 PMCID: PMC10689838 DOI: 10.1038/s12276-023-01105-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 11/02/2023] Open
Abstract
CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Suyoung Lee
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Minkyeong Kwak
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Gangwon, 25159, Republic of Korea.
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11
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Cody JW, Ellis-Connell AL, O’Connor SL, Pienaar E. Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load. PLoS Comput Biol 2023; 19:e1011425. [PMID: 37616311 PMCID: PMC10482305 DOI: 10.1371/journal.pcbi.1011425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 09/06/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes.
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Affiliation(s)
- Jonathan W. Cody
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America
| | - Amy L. Ellis-Connell
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Shelby L. O’Connor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Elsje Pienaar
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, United States of America
- Regenstrief Center for Healthcare Engineering, Purdue University, West Lafayette, Indiana, United States of America
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12
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Redmond WL. Challenges and opportunities in the development of combination immunotherapy with OX40 agonists. Expert Opin Biol Ther 2023; 23:901-912. [PMID: 37587644 PMCID: PMC10530613 DOI: 10.1080/14712598.2023.2249396] [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: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 08/18/2023]
Abstract
INTRODUCTION Costimulatory members of the tumor necrosis factor receptor family, such as OX40 (CD134), provide essential survival and differentiation signals that enhance T cell function. Specifically, OX40 (CD134) agonists stimulate potent anti-tumor immunity in a variety of preclinical models but their therapeutic impact in patients with advanced malignancies has been limited thus far. AREAS COVERED In this review, we discuss the current state of combination immunotherapy with OX40 agonists including preclinical studies and recent clinical trials. We also discuss the strengths and limitations of these approaches and provide insight into alternatives that may help enhance the efficacy of combination OX40 agonist immunotherapy. EXPERT OPINION OX40 agonist immunotherapy has not yet demonstrated significant clinical activity as a monotherapy or in combination with immune checkpoint blockade (ICB), likely due to several factors including the timing of administration, drug potency, and selection of agents for combination therapy clinical trials. We believe that careful consideration of the biological mechanisms regulating OX40 expression and function may help inform new approaches, particularly in combination with novel agents, capable of increasing the therapeutic efficacy of this approach.
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Affiliation(s)
- William L Redmond
- Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan St., 2N35, Portland, OR, 97213
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13
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Wu L, Bai S, Huang J, Cui G, Li Q, Wang J, Du X, Fu W, Li C, Wei W, Lin H, Luo ML. Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer. Cancers (Basel) 2023; 15:3221. [PMID: 37370831 PMCID: PMC10296105 DOI: 10.3390/cancers15123221] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/04/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.
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Affiliation(s)
- Lisha Wu
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Shoumin Bai
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jing Huang
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Guohui Cui
- South China National Bio-Safety Laboratory, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510600, China
| | - Qingjian Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jingshu Wang
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xin Du
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Wenkui Fu
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Chuping Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Wei Wei
- Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Huan Lin
- Department of Breast Oncology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Man-Li Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, China
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Lui G, Minnar CM, Soon-Shiong P, Schlom J, Gameiro SR. Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies. Cells 2023; 12:1611. [PMID: 37371081 DOI: 10.3390/cells12121611] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/13/2023] [Accepted: 05/15/2023] [Indexed: 06/29/2023] Open
Abstract
Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette-Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803.
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Affiliation(s)
- Grace Lui
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Christine M Minnar
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Jeffrey Schlom
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sofia R Gameiro
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Ma SX, Li L, Cai H, Guo TK, Zhang LS. Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review. World J Clin Oncol 2023; 14:81-88. [PMID: 36908678 PMCID: PMC9993140 DOI: 10.5306/wjco.v14.i2.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/13/2022] [Accepted: 02/07/2023] [Indexed: 02/21/2023] Open
Abstract
Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response. There may be three reasons. First, the complex tumor microenvironment of cold colorectal cancer (CRC) leads to tolerance and clearance of immunotherapy. Second, the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption. Finally, the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy. Therefore, we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.
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Affiliation(s)
- Shi-Xun Ma
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Li Li
- Scientific Research Division, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Tian-Kang Guo
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
| | - Lei-Sheng Zhang
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 73000, Gansu Province, China
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui Province, China
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16
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Sánchez Y, Concepción ML, Amador Y, Piriz A, Rabassa R, Leyva A, Arguelles O, Leblanch L, Moret S, Rivero G, Vasallo AL, Martorell B, Guerra PP, Valls AR, Sánchez L, Saumell Y. Nimotuzumab Concurrent with Gemcitabine as First-Line Treatment of Locally Advanced or Metastatic Pancreatic Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2023; 2023:1496072. [PMID: 37152586 PMCID: PMC10162878 DOI: 10.1155/2023/1496072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 02/11/2023] [Accepted: 02/15/2023] [Indexed: 05/09/2023]
Abstract
Background Nimotuzumab exerts its antitumor effect (mainly antiproliferative, proapoptotic, and antiangiogenic) by blocking the epidermal growth factor receptor overexpressing between 30 and 95% in pancreatic tumors cells. Methods A prospective, nonrandomized, uncontrolled, open-label, and multicenter clinical trial was conducted to evaluate the safety and effectiveness of nimotuzumab combined with gemcitabine as first-line treatment in unresectable locally advanced or metastatic pancreatic tumors in a real-world condition. Adverse events, their intensity, severity, and causality were determined using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Median overall survival, median progression-free survival, and 1- and 2-year survival rates were determined by using the Kaplan-Meier. Results 69 patients were included. The proportion of related serious adverse events was 1.2%. The most frequent adverse events were nausea (10%), anemia (8%), and abdominal pain (8%). Objective response was achieved in 18.5% of the patients and disease control in 43.1%. Patients with locally advanced disease achieved a median overall survival of 16.36 months (95% CI; 14.35-18.38); 1- and 2-year survival rates of 72.2 and 29.2 months, respectively; a median progression-free survival of 9.6 months (95% CI; 4.91-14.20); and a 1-year progression-free survival rate of 39%. Patients with metastatic disease achieved a median survival of 6.23 months (95% CI; 4.32-8.13); 1- and 2-year survival rates of 18.1 and 3.0 months, respectively; a median progression-free survival of 7.6 months (95% CI; 6.08-9.90); and 1- and 2-year PFS rates of 20.5 and 5.1 months, respectively. Conclusions Nimotuzumab combined with gemcitabine represents a safe and effective first-line treatment option for patients with advanced pancreatic adenocarcinoma in real-world conditions. Survival benefits were increased in those patients who received 8 or more doses of nimotuzumab. This trial is registered with RPCEC00000245 in the Cuban Registry of Clinical Trials, part of the World Health Organization's International Clinical Trials Registry Platform (ICTRP).
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Affiliation(s)
- Yamirka Sánchez
- Oncology Department, III Congreso Hospital, Pinar del Río 20100, Cuba
| | | | - Yohan Amador
- Oncology Department, Faustino Pérez Hospital, Matanzas 40100, Cuba
| | - Angel Piriz
- Oncology Department, Agostinho Neto Hospital, Guantánamo 85100, Cuba
| | - René Rabassa
- Oncology Department, Manuel Ascunce Domenech Hospital, Camagüey 70100, Cuba
| | - Ariel Leyva
- Oncology Department, Vladimir Ilich Lenin Hospital, Holguín 80100, Cuba
| | - Odalys Arguelles
- Oncology Department, Antonio Luaces Iraola Hospital, Ciego de Ávila 65200, Cuba
| | - Lisett Leblanch
- Oncology Department, Carlos Manuel de Céspedes Hospital, Granma 85100, Cuba
| | - Sheyla Moret
- Oncology Department, Medical and Surgical Research Center, Havana 11600, Cuba
| | - Gilberto Rivero
- Oncology Department, Ernesto Guevara de la Serna Hospital, Las Tunas 75100, Cuba
| | - Ana L. Vasallo
- Oncology Department, Gustavo Aldereguía Lima Hospital, Cienfuegos 55100, Cuba
| | - Beatriz Martorell
- Oncology Department, Saturnino Lora Hospital, Santiago de Cuba 90500, Cuba
| | - Pedro P. Guerra
- Clinical Trial Department, National Coordinating Center of Clinical Trials, Havana 11600, Cuba
| | - Ana R. Valls
- Clinical Trial Department, Center of Molecular Immunology, Havana 11600, Cuba
| | - Lisset Sánchez
- Clinical Trial Department, Center of Molecular Immunology, Havana 11600, Cuba
| | - Yaimarelis Saumell
- Clinical Trial Department, Center of Molecular Immunology, Havana 11600, Cuba
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17
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Sha Y, Mao AQ, Liu YJ, Li JP, Gong YT, Xiao D, Huang J, Gao YW, Wu MY, Shen H. Nidogen-2 (NID2) is a Key Factor in Collagen Causing Poor Response to Immunotherapy in Melanoma. Pharmgenomics Pers Med 2023; 16:153-172. [PMID: 36908806 PMCID: PMC9994630 DOI: 10.2147/pgpm.s399886] [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: 12/08/2022] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Background The incidence of cutaneous melanoma continues to rise rapidly and has an extremely poor prognosis. Immunotherapy strategies are the most effective approach for patients who have developed metastases, but not all cases have been successful due to the complex and variable mechanisms of melanoma response to immune checkpoint inhibition. Methods We synthesized collagen-coding gene expression data (second-generation and single-cell sequencing) from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as Metascape database, Gene Set Cancer Analysis (GSCA) database, and Cytoscape software, etc., to investigate the biological mechanisms that may be related with collagens. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of Nidogen-2 (NID2). Results Melanoma patients can be divided into two collagen clusters. Patients with high collagen levels (C1) had a shorter survival than those with low collagen levels (C2) and were less likely to benefit from immunotherapy. We demonstrated that NID2 is a potential key factor in the collagen phenotype, is involved in fibroblast activation in melanoma, and forms a barrier to limit the proximity of CD8+ T cells to tumor cells. Conclusion We clarified the adverse effects of collagen on melanoma patients and identified NID2 as a potential therapeutic target.
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Affiliation(s)
- Yan Sha
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - An-Qi Mao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Yuan-Jie Liu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China
| | - Jie-Pin Li
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China
| | - Ya-Ting Gong
- Departments of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Dong Xiao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Jun Huang
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Yan-Wei Gao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Mu-Yao Wu
- Departments of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Hui Shen
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
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18
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Kowalczyk JT, Fabian KP, Padget MR, Lopez DC, Hoke ATK, Allen CT, Hermsen M, London, NR, Hodge JW. Exploiting the immunogenic potential of standard of care radiation or cisplatin therapy in preclinical models of HPV-associated malignancies. J Immunother Cancer 2022; 10:jitc-2022-005752. [PMID: 36564129 PMCID: PMC9791467 DOI: 10.1136/jitc-2022-005752] [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] [Accepted: 11/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND While radiation and chemotherapy are primarily purposed for their cytotoxic effects, a growing body of preclinical and clinical evidence demonstrates an immunogenic potential for these standard therapies. Accordingly, we sought to characterize the immunogenic potential of radiation and cisplatin in human tumor models of HPV-associated malignancies. These studies may inform rational combination immuno-oncology (IO) strategies to be employed in the clinic on the backbone of standard of care, and in so doing exploit the immunogenic potential of standard of care to improve durable responses in HPV-associated malignancies. METHODS Retroviral transduction with HPV16 E7 established a novel HPV-associated sinonasal squamous cell carcinoma (SNSCC) cell line. Three established HPV16-positive cell lines were also studied (cervical carcinoma and head and neck squamous cell carcinoma). Following determination of sensitivities to standard therapies using MTT assays, flow cytometry was used to characterize induction of immunogenic cell stress following sublethal exposure to radiation or cisplatin, and the functional consequence of this induction was determined using impedance-based real time cell analysis cytotoxicity assays employing HPV16 E7-specific cytotoxic lymphocytes (CTLs) with or without N803 (IL-15/IL-15-Rα superagonist) or exogenous death receptor ligands. In vitro observations were translated using an in vivo xenograft NSG mouse model of human cervical carcinoma evaluating cisplatin in combination with CTL adoptive cell transfer. RESULTS We showed that subpopulations surviving clinically relevant doses of radiation or cisplatin therapy were more susceptible to CTL-mediated lysis in four of four tumor models of HPV-associated malignancies, serving as a model for HPV therapeutic vaccine or T-cell receptor adoptive cell transfer. This increased killing was further amplified by IL-15 agonism employing N803. We further characterized that radiation or cisplatin induced immunogenic cell stress in three of three cell lines, and consequently demonstrated that upregulated surface expression of Fas and TRAIL-R2 death receptors at least in part mediated enhanced CTL-mediated lysis. In vivo, cisplatin-induced immunogenic cell stress synergistically potentiated CTL-mediated tumor control in a human model of HPV-associated malignancy. CONCLUSION Standard of care radiation or cisplatin therapy induced immunogenic cell stress in preclinical models of HPV-associated malignancies, presenting an opportunity poised for exploitation by employing IO strategies in combination with standard of care.
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Affiliation(s)
- Joshua T Kowalczyk
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Kellsye P Fabian
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Michelle R Padget
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Diana C Lopez
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Austin TK Hoke
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Clint T Allen
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Mario Hermsen
- Department Head and Neck Cancer, Centro de Investigación Biomédica en Red, Madrid, Spain
| | - Nyall R London,
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA,Sinonasal and Skull Base Tumor Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA,Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - James W Hodge
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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19
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Sánchez J, Nicolini V, Fahrni L, Waldhauer I, Walz AC, Jamois C, Fowler S, Simon S, Klein C, Umaña P, Friberg L, Frances N. Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1. AAPS J 2022; 24:106. [PMID: 36207642 DOI: 10.1208/s12248-022-00755-5] [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: 06/23/2022] [Accepted: 09/20/2022] [Indexed: 11/07/2022] Open
Abstract
TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.
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Affiliation(s)
- Javier Sánchez
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland. .,Department of Pharmacy, Uppsala University, Uppsala, Sweden.
| | - Valeria Nicolini
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Linda Fahrni
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Inja Waldhauer
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Antje-Christine Walz
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Candice Jamois
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Stephen Fowler
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Silke Simon
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Christian Klein
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Pablo Umaña
- Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
| | - Lena Friberg
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Nicolas Frances
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
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20
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Santiago-Sánchez GS, Hodge JW, Fabian KP. Tipping the scales: Immunotherapeutic strategies that disrupt immunosuppression and promote immune activation. Front Immunol 2022; 13:993624. [PMID: 36159809 PMCID: PMC9492957 DOI: 10.3389/fimmu.2022.993624] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy has emerged as an effective therapeutic approach for several cancer types. However, only a subset of patients exhibits a durable response due in part to immunosuppressive mechanisms that allow tumor cells to evade destruction by immune cells. One of the hallmarks of immune suppression is the paucity of tumor-infiltrating lymphocytes (TILs), characterized by low numbers of effector CD4+ and CD8+ T cells in the tumor microenvironment (TME). Additionally, the proper activation and function of lymphocytes that successfully infiltrate the tumor are hampered by the lack of co-stimulatory molecules and the increase in inhibitory factors. These contribute to the imbalance of effector functions by natural killer (NK) and T cells and the immunosuppressive functions by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the TME, resulting in a dysfunctional anti-tumor immune response. Therefore, therapeutic regimens that elicit immune responses and reverse immune dysfunction are required to counter immune suppression in the TME and allow for the re-establishment of proper immune surveillance. Immuno-oncology (IO) agents, such as immune checkpoint blockade and TGF-β trapping molecules, have been developed to decrease or block suppressive factors to enable the activity of effector cells in the TME. Therapeutic agents that target immunosuppressive cells, either by direct lysis or altering their functions, have also been demonstrated to decrease the barrier to effective immune response. Other therapies, such as tumor antigen-specific vaccines and immunocytokines, have been shown to activate and improve the recruitment of CD4+ and CD8+ T cells to the tumor, resulting in improved T effector to Treg ratio. The preclinical data on these diverse IO agents have led to the development of ongoing phase I and II clinical trials. This review aims to provide an overview of select therapeutic strategies that tip the balance from immunosuppression to immune activity in the TME.
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21
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Borgovan T, Yanamandra N, Schmidt H. INNATE IMMUNITY AS A TARGET FOR NOVEL THERAPEUTICS IN TRIPLE NEGATIVE BREAST CANCER. Expert Opin Investig Drugs 2022; 31:781-794. [DOI: 10.1080/13543784.2022.2096005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Theo Borgovan
- Oncology Research and DevelopmentGlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426,
| | - Niranjan Yanamandra
- Immuno-Oncology & Combinations Research Unit.GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426,
| | - Hank Schmidt
- Oncology Research and DevelopmentGlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426,
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22
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Du X, Wu J, Zhao Y, Wang B, Ding X, Lin Q, Chen Y, Zhao J, Liu L, Mao X, Fang Z, Zhang C, Li W. Optimization of whole-cell vaccines with CpG/αOX40/cGAMP to strengthen the anti-tumor response of CD4 + T cells in melanomas. J Cancer Res Clin Oncol 2022; 148:3337-3350. [PMID: 35748951 PMCID: PMC9587117 DOI: 10.1007/s00432-022-04117-8] [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: 04/17/2022] [Accepted: 06/06/2022] [Indexed: 11/04/2022]
Abstract
Methods In this study, we developed a strategy for the prevention and therapy of melanoma using a whole-cell vaccine combined with a CpG/αOX40/cGAMP triple adjuvant. The CpG/αOX40/cGAMP triple adjuvant was used to co-culture melanoma cells in vitro to induce immunogenic death of tumor cells. The mixture of inactivated tumor cells and the triple drug was an optimized tumor whole-cell vaccine, which was injected subcutaneously into mice for tumor prevention and therapy. Furthermore, we analyzed the changes of immune cells in spleen and tumor by flow cytometry and immunohistochemistry, and detected the changes of cytokines after vaccine application by cytometric bead array to explore the specific mechanism of vaccine. Results In vaccine prevention and therapy experiments, it was observed that the tumor growth was significantly inhibited in the whole-cell vaccine group, and the survival time of mice was significantly prolonged. Flow cytometry results showed that the proportion of CD4+ T cells and CD8+ T cells in tumor of mice in vaccine group was higher than that in control group, especially the CD4+ T cells. Conclusion The optimized vaccine has the unique ability to amplify tumor-specific CD4+ T cells, which improves antitumor sensitivity, and has a significant effect on the prevention and therapy of melanoma mice. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-022-04117-8.
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Affiliation(s)
- Xuedan Du
- Department of Oncology, Lishui Central Hospital, Lishui, Zhejiang, People's Republic of China
| | - Jinting Wu
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Ye Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Bin Wang
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Xiaobo Ding
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Qiuyan Lin
- Department of Oncology, Ruian City People's Hospital, Wenzhou, Zhejiang, People's Republic of China
| | - Yingyu Chen
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Jinduo Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Lixiao Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaolu Mao
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Zhen Fang
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Chunhong Zhang
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Wenfeng Li
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, 325000, Zhejiang, People's Republic of China.
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23
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Jeong M, Kim H, Yoon J, Kim DH, Park JH. Co-immunomodulation of tumor and tumor-draining lymph node during in situ vaccination promotes antitumor immunity. JCI Insight 2022; 7:146608. [PMID: 35579961 PMCID: PMC9309043 DOI: 10.1172/jci.insight.146608] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/13/2022] [Indexed: 11/17/2022] Open
Abstract
In situ vaccination has demonstrated the feasibility of priming local immunity for systemic antitumor responses. Although direct intratumoral delivery of adjuvant is the mainstay, tumor-draining lymph nodes (TDLNs) also play essential roles in antitumor immunity. We report that directing an adjuvant to both tumors and TDLNs during in situ vaccination can induce robust antitumor responses. Conventional intratumoral dosing leads to tumor-limited delivery of agents; however, delivery to both tumors and TDLNs can be ensured through a micellar formation. The peritumoral delivery of micellar MEDI9197 (mcMEDI), a toll-like receptor 7/8 agonist, induced significantly stronger innate and adaptive immune responses than those on conventional dosing. Optimal dosing was crucial because excessive or insufficient accumulation of the adjuvant in the TDLNs compromised therapeutic efficacy. The combination of local mcMEDI therapy significantly improved the efficacy of systemic anti-programmed death receptor-1 therapy. These data suggest that rerouting adjuvants to tumors and TDLNs can augment the therapeutic efficacy of in situ vaccination.
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Affiliation(s)
- Moonkyoung Jeong
- Department of Bio and Brain Engineering, KAIST (Korea Advanced Institute of Science and Technology), Daejeon, Korea, Republic of
| | - Heegon Kim
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
| | - Junyong Yoon
- Department of Bio and Brain Engineering, KAIST (Korea Advanced Institute of Science and Technology), Daejeon, Korea, Republic of
| | - Dong-Hyun Kim
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
| | - Ji-Ho Park
- Department of Bio and Brain Engineering, KAIST (Korea Advanced Institute of Science and Technology), Daejeon, Korea, Republic of
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24
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Shang L, Jiang X, Yang T, Xu H, Xie Q, Hu M, Yang C, Kong L, Zhang Z. Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment. Acta Pharm Sin B 2022; 12:2550-2567. [PMID: 35646526 PMCID: PMC9136611 DOI: 10.1016/j.apsb.2021.11.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/15/2021] [Accepted: 10/18/2021] [Indexed: 12/13/2022] Open
Abstract
In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).
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Affiliation(s)
- Lihuan Shang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xue Jiang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Ting Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hongbo Xu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qi Xie
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Mei Hu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Conglian Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Kong
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- Corresponding authors. Tel./fax: +86 27 83692762.
| | - Zhiping Zhang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Engineering Research Centre for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, China
- Corresponding authors. Tel./fax: +86 27 83692762.
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25
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Doshi AS, Cantin S, Prickett LB, Mele DA, Amiji M. Systemic nano-delivery of low-dose STING agonist targeted to CD103+ dendritic cells for cancer immunotherapy. J Control Release 2022; 345:721-733. [PMID: 35378213 DOI: 10.1016/j.jconrel.2022.03.054] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/14/2022] [Accepted: 03/28/2022] [Indexed: 10/18/2022]
Abstract
Current methods of STING activation based on intra-tumoral injections of cyclic dinucleotides (CDNs) are not suitable for addressing tumor heterogeneity or for inaccessible, metastatic and abscopal tumors. In this study, we developed systemically administered CD103+ dendritic cell (DCs) targeted liposomal formulations and evaluated the anti-tumor efficacy with low dose. Liposomal CDN formulations were prepared using Clec9a targeting peptide and evaluated therapeutic efficacy in vitro and in vivo in subcutaneous MC38 and B16F10 tumor models. Targeted delivery of CDNs is expected to enhance anti-tumor immune response as well as reduce off-target toxicities. With intravenous 0.1 mg/kg systemic CDN dose of the targeted liposomal formulation, our results showed robust immune response with significant antitumor efficacy both as a monotherapy and in combination with anti-PD-L1 antibody. These results show that a CD103+ DC targeted CDN formulation can lead to potent immune stimulation upon systemic administration even in relatively "cold" tumors such as B16F10.
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Affiliation(s)
- Aatman S Doshi
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, United States of America; Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 360 Huntington Ave, Boston, MA 02115, United States of America
| | - Susan Cantin
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, United States of America
| | - Laura B Prickett
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, United States of America
| | - Deanna A Mele
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, United States of America
| | - Mansoor Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 360 Huntington Ave, Boston, MA 02115, United States of America; Department of Chemical Engineering, College of Engineering, Northeastern University, 360 Huntington Ave, Boston, MA 02115, United States of America.
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26
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Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response. Transl Oncol 2022; 20:101405. [PMID: 35339889 PMCID: PMC8961218 DOI: 10.1016/j.tranon.2022.101405] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/04/2022] [Accepted: 03/20/2022] [Indexed: 12/12/2022] Open
Abstract
Anti-PD-1 and anti-CTLA-4 induced anti-tumor response in breast cancer mouse model. Anti-PD-1 and anti-CTLA-4 induced anti-tumor response in colon cancer mouse model. Anti-CTLA-4 reduced colon cancer–derived lung metastasis formation in a mouse model. We identified specific T cell response between anti-PD-1 and anti-CTLA-4. The recent development of immunotherapy represents a significant breakthrough in cancer therapy. Several immunotherapies provide robust efficacy gains in a wide variety of cancers. However, in some patients the immune checkpoint blockade remains ineffective due to poor therapeutic response and tumor relapse. An improved understanding of the mechanisms underlying tumor-immune system interactions can improve clinical management of cancer. Here, we report preclinical data evaluating two murine antibodies corresponding to recent FDA-approved antibodies for human therapy, e.g. anti-CTLA-4 and anti-PD-1. We demonstrated in two mouse syngeneic grafting models of triple negative breast or colon cancer that the two antibodies displayed an efficient anticancer activity, which is enhanced by combination treatment in the breast cancer model. We also demonstrated that CTLA-4 targeting reduced metastasis formation in the colon cancer metastasis model. In addition, using cytometry-based multiplex analysis, we showed that anti-CTLA-4 and anti-PD-1 affected the tumor immune microenvironment differently and in particular the tumor immune infiltration. This work demonstrated anti-cancer effect of CTLA-4 or PD-1 blockade on mouse colon and triple negative breast and on tumor-infiltrating immune cell subpopulations that could improve our knowledge and benefit the breast and colon cancer tumor research community.
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27
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Audenet F, Sotto A, Roumiguié M, Allory Y, Andrejak C, Leon P, Loriot Y, Masson-Lecomte A, Pradère B, Seisen T, Traxer O, Xylinas E, Bruyère F, Roupret M, Saint F, Neuzillet Y. Recommandations des Comités de cancérologie (CC-AFU) et d’infectiologie (CI-AFU) de l’Association française d’urologie pour la prise en charge effets indésirables et complications du BCG. Prog Urol 2022; 32:165-176. [DOI: 10.1016/j.purol.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/02/2022] [Accepted: 01/10/2022] [Indexed: 12/01/2022]
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28
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Han X, Wei Q, Lv Y, Weng L, Huang H, Wei Q, Li M, Mao Y, Hua D, Cai X, Cao M, Cao P. Ginseng-derived nanoparticles potentiate immune checkpoint antibody efficacy by reprogramming the cold tumor microenvironment. Mol Ther 2022; 30:327-340. [PMID: 34450250 PMCID: PMC8753455 DOI: 10.1016/j.ymthe.2021.08.028] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/08/2021] [Accepted: 08/20/2021] [Indexed: 01/07/2023] Open
Abstract
Cold tumor microenvironment (TME) marked with low effector T cell infiltration leads to weak response to immune checkpoint inhibitor (ICI) treatment. Thus, switching cold to hot TME is critical to improve potent ICI therapy. Previously, we reported extracellular vesicle (EV)-like ginseng-derived nanoparticles (GDNPs) that were isolated from Panax ginseng C.A. Mey and can alter M2 polarization to delay the hot tumor B16F10 progression. However, the cold tumor is more common and challenging in the real world. Here, we explored a combinatorial strategy with both GDNPs and PD-1 (programmed cell death protein-1) monoclonal antibody (mAb), which exhibited the ability to alter cold TME and subsequently induce a durable systemic anti-tumor immunity in multiple murine tumor models. GDNPs enhanced PD-1 mAb anti-tumor efficacy in activating tumor-infiltrated T lymphocytes. Our results demonstrated that GDNPs could reprogram tumor-associated macrophages (TAMs) to increase CCL5 and CXCL9 secretion for recruiting CD8+ T cells into the tumor bed, which have the synergism to PD-1 mAb therapy with no detected systemic toxicity. In situ activation of TAMs by GDNPs may broadly serve as a facile platform to modulate the suppressive cold TME and optimize the PD-1 mAb immunotherapy in future clinical application.
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Affiliation(s)
- Xuan Han
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qin Wei
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yan Lv
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ling Weng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Haoying Huang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qingyun Wei
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Mengyuan Li
- College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Rd., Nanjing, Jiangsu 210023, China
| | - Yujie Mao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Di Hua
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xueting Cai
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Meng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,Corresponding author: Meng Cao, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China,College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Rd., Nanjing, Jiangsu 210023, China,Collaborative Innovation Centre for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, China,Corresponding author: Peng Cao, College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Rd., Nanjing, Jiangsu 210023, China.
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29
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Sawada L, Vallinoto ACR, Brasil-Costa I. Regulation of the Immune Checkpoint Indoleamine 2,3-Dioxygenase Expression by Epstein-Barr Virus. Biomolecules 2021; 11:1792. [PMID: 34944437 PMCID: PMC8699098 DOI: 10.3390/biom11121792] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 12/16/2022] Open
Abstract
Epstein-Barr virus (EBV) is an oncovirus ubiquitously distributed and associated with different types of cancer. The reason why only a group of infected people develop cancer is still unknown. EBV-associated cancers represent about 1.8% of all cancer deaths worldwide, with more than 150,000 new cases of cancer being reported annually. Since EBV-associated cancers are described as more aggressive and more resistant to the usual treatment compared to EBV-negative ones, the recent introduction of monoclonal antibodies (mAbs) targeting immune checkpoints (ICs) in the treatment of cancer patients represents a possible therapy for EBV-associated diseases. However, the current mAb therapies available still need improvement, since a group of patients do not respond well to treatment. Therefore, the main objective of this review is to summarize the progress made regarding the contribution of EBV infection to the expression of the IC indoleamine 2,3-dioxygenase (IDO) thus far. This IC has the potential to be used as a target in new immune therapies, such as mAbs. We hope that this work helps the development of future immunotherapies, improving the prognosis of EBV-associated cancer patients.
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Affiliation(s)
- Leila Sawada
- Immunology Laboratory, Virology Section, Evandro Chagas Institute, Ananindeua, Pará 67030-000, Brazil;
- Postgraduate Program in Virology (PPGV), Evandro Chagas Institute, Ananindeua, Pará 67030-000, Brazil
| | | | - Igor Brasil-Costa
- Immunology Laboratory, Virology Section, Evandro Chagas Institute, Ananindeua, Pará 67030-000, Brazil;
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Gong TJ, Tang F, Zheng CX, Wang J, Wang YT, Zhang YH, Luo Y, Zhou Y, Min L, Tu CQ. Case Report: Pulmonary Metastases From Epithelioid Sarcoma in Extremity Favourably Responding to Immunotherapy With Camrelizumab. Front Oncol 2021; 11:728437. [PMID: 34692503 PMCID: PMC8526861 DOI: 10.3389/fonc.2021.728437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/20/2021] [Indexed: 02/05/2023] Open
Abstract
Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.
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Affiliation(s)
- Tao-Jun Gong
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Fan Tang
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chuan-Xi Zheng
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Wang
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Yi-Tian Wang
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Ya-Han Zhang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Luo
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zhou
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Li Min
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
| | - Chong-Qi Tu
- Department of Orthopeadics, West China Hospital, Sichuan University, Chengdu, China
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Fabian KP, Wolfson B, Hodge JW. From Immunogenic Cell Death to Immunogenic Modulation: Select Chemotherapy Regimens Induce a Spectrum of Immune-Enhancing Activities in the Tumor Microenvironment. Front Oncol 2021; 11:728018. [PMID: 34497771 PMCID: PMC8419351 DOI: 10.3389/fonc.2021.728018] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/29/2021] [Indexed: 12/22/2022] Open
Abstract
Cancer treatment has rapidly entered the age of immunotherapy, and it is becoming clear that the effective therapy of established tumors necessitates rational multi-combination immunotherapy strategies. But even in the advent of immunotherapy, the clinical role of standard-of-care chemotherapy regimens still remains significant and may be complementary to emerging immunotherapeutic approaches. Depending on dose, schedule, and agent, chemotherapy can induce immunogenic cell death, resulting in the release of tumor antigens to stimulate an immune response, or immunogenic modulation, sensitizing surviving tumor cells to immune cell killing. While these have been previously defined as distinct processes, in this review we examine the published mechanisms supporting both immunogenic cell death and immunogenic modulation and propose they be reclassified as similar effects termed "immunogenic cell stress." Treatment-induced immunogenic cell stress is an important result of cytotoxic chemotherapy and future research should consider immunogenic cell stress as a whole rather than just immunogenic cell death or immunogenic modulation. Cancer treatment strategies should be designed specifically to take advantage of these effects in combination immunotherapy, and novel chemotherapy regimens should be designed and investigated to potentially induce all aspects of immunogenic cell stress.
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Affiliation(s)
| | | | - James W. Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
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Wolfson B, Franks SE, Hodge JW. Stay on Target: Reengaging Cancer Vaccines in Combination Immunotherapy. Vaccines (Basel) 2021; 9:vaccines9050509. [PMID: 34063388 PMCID: PMC8156017 DOI: 10.3390/vaccines9050509] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors.
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