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Zhu J, Zhou J, Liang X, An F, Ding Y, Jiao X, Xiao M, Wu F, Li Y, Xiao H, Pan Y, Wang H, Zhai Z. Elevated CD10 - neutrophils correlate with non-response and poor prognosis of CD19 CAR T-cell therapy for B-cell acute lymphoblastic leukemia. BMC Med 2025; 23:138. [PMID: 40038688 PMCID: PMC11881286 DOI: 10.1186/s12916-025-03968-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 02/25/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND The primary challenges in CD19-specific chimeric antigen receptor T-cell (CD19 CAR T) therapy for patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL) are non-response and relapse; it is urgent to reveal these mechanisms. Neutrophils play a critical role in the immunosuppressive tumor microenvironment (TME), which can hinder CAR T efficacy. Our previous research identified a subset of immunosuppressive neutrophils with a special phenotype (CD14-CD10-CD45-HLA-DR-SSC++, termed CD10- neuts), which suppress T cell function. Therefore, we speculate that CD10- neuts may also influence CAR T efficacy, and this study aims to clinically validate this hypothesis. METHODS We enrolled 44 patients with r/r B-ALL undergoing CD19 CAR T therapy and 47 healthy controls (HCs). Peripheral blood samples were obtained prior to CAR T infusion to detect CD10- neuts levels by flow cytometry. Key parameters included the percentage of CD10- neuts in neutrophils (CD10- neuts/neutrophils), in all nucleated cells (CD10- neuts/nucleated cells), and the absolute count of CD10- neuts. We analyzed the correlations between these indicators and therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cell persistence time. RESULTS CD10- neuts levels were significantly elevated in patients with r/r B-ALL compared to HCs. Additionally, non-responding patients exhibited higher CD10- neuts levels than those in remission. Specifically, CD10- neuts/neutrophils, CD10- neuts/nucleated cells, and absolute CD10- neuts count were 64.44% vs. 25.43% (p = 0.004), 28.61% vs. 9.81% (p = 0.018), and 766.1/μL vs. 152.9/μL (p = 0.04), respectively. Among these indices, only CD10- neuts/neutrophils emerged as an independent risk factor for CAR T response (OR = 19.8, p = 0.013), relapse (HR = 4.704, p = 0.004), and survival (HR = 6.417, p = 0.001). Patients with CD10- neuts/neutrophils ≥ 21.57% demonstrated significantly shorter RFS and OS compared to those with lower levels (p = 0.001; p = 0.0002). Furthermore, CD10- neuts/neutrophils were negatively correlated with the persistence time of CAR T cells. CONCLUSIONS As one of the key factors in the TME, abnormally elevated CD10- neuts correlate with CAR T therapy resistance. Targeting these neutrophils could enhance the effectiveness of CAR T treatment.
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Affiliation(s)
- Jinli Zhu
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Ji Zhou
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- School of Nursing, Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Xue Liang
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Furun An
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Yangyang Ding
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Xunyi Jiao
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Meng Xiao
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Fan Wu
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Yingwei Li
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Hao Xiao
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Ying Pan
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China
| | - Huiping Wang
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
| | - Zhimin Zhai
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
- Hematology Diagnosis and Treatment Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
- Center of Hematology Research, Anhui Medical University, Hefei, Anhui, 230000, People's Republic of China.
- Institute of Hematology and Clinical Immunology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
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Cardle II, Scherer DR, Jensen MC, Pun SH, Sellers DL. In Situ Bioconjugation of Synthetic Peptides onto Universal Chimeric Antigen Receptor T Cells for Targeted Cancer Immunotherapies. ACS NANO 2025; 19:5750-5768. [PMID: 39869930 DOI: 10.1021/acsnano.4c16824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
The recent development of modular universal chimeric antigen receptor (CAR) T-cell platforms that use bifunctional adaptor intermediates to redirect engineered T-cell effector function has greatly expanded the capabilities of adoptive T-cell therapy, enabling safer and more comprehensive cancer treatment. However, universal CAR receptor systems rely on unstable transient recognition of tag-coupled intermediates for T-cell activation, and the array of targeting intermediates has been limited to antibodies and small molecules. Addressing these shortcomings, we engineered universal CAR T-cell receptors that can be covalently modified with synthetic biomaterials in vivo by accelerated SpyCatcher003-SpyTag003 chemistry for cancer-cell targeting. SpyCatcher003-modified CARs, nicknamed DB5 CARs, displayed fast, low-nanomolar reaction kinetics with a synthetic αvβ6-binding peptide that incorporates a SpyTag003 peptide via branched peptide synthesis to comprise a bifunctional intermediate. Prearming DB5 CAR T cells or prelabeling target cells with the bifunctional peptide produced selective CD4+ and CD8+ CAR T-cell responses against αvβ6+ cancer cells in vitro. Furthermore, the synthetic targeting intermediate showed robust DB5 CAR T-cell arming in vivo and selectively reduced αvβ6+ tumor progression in a dual flank xenograft model. We demonstrate the versatility and therapeutic potential of "Cyborg" CAR T-cell therapies that utilize synthetic biomaterials to direct CAR T-cell activity via highly selective bioconjugation that occurs in vivo.
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Affiliation(s)
- Ian I Cardle
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
- Seattle Children's Therapeutics, Seattle, Washington 98101, United States
| | - Dylan R Scherer
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
| | - Michael C Jensen
- Seattle Children's Therapeutics, Seattle, Washington 98101, United States
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States
| | - Suzie H Pun
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
| | - Drew L Sellers
- Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States
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Sherpally D, Manne A. Advancing Immunotherapy in Pancreatic Cancer: A Brief Review of Emerging Adoptive Cell Therapies. Cancers (Basel) 2025; 17:589. [PMID: 40002184 PMCID: PMC11853216 DOI: 10.3390/cancers17040589] [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: 12/24/2024] [Revised: 01/28/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Pancreatic cancer has the lowest 5-year survival rate (13%) among major cancers and is the third leading cause of cancer-related deaths in the United States. The high lethality of this cancer is attributed to its insidious onset, late-stage diagnosis, rapid progression, and limited treatment options. Addressing these challenges requires a deeper understanding of the complex tumor microenvironment to identify novel therapeutic targets. Newer approaches like adoptive cell therapy have shown remarkable success in treating hematological malignancies, but their application in solid tumors, particularly pancreatic cancer, is still in the early stages of development. ACT broadly involves isolating immune cells (T lymphocytes, Natural Killer cells, and macrophages) from the patient, followed by genetic engineering to enhance and mount a specific anti-tumor response. Various ACT modalities are under investigation for pancreatic cancer, including chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor NK cells (CAR-NK), tumor-infiltrating lymphocytes (TIL), T-cell receptor (TCR)-engineered T cells, and cytokine-induced killer cells (CIK). Major hurdles have been identifying actionable tumor antigens and delivering focused cellular therapies to overcome the immunosuppressive and dense fibrotic stroma surrounding the pancreatic cancer. Further studies are needed to explore the limitations faced by cellular therapy in pancreatic cancer and identify novel combination treatment approaches in order to improve clinical outcomes.
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Affiliation(s)
- Deepak Sherpally
- Department of Internal Medicine, New York Medical College, Metropolitan, New York, NY 10029, USA
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
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Papadaki GF, Li Y, Monos DS, Bhoj VG. Cars pick up another passenger: Organ transplantation. Hum Immunol 2025; 86:111180. [PMID: 39591915 DOI: 10.1016/j.humimm.2024.111180] [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: 07/17/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024]
Abstract
With over 30,000 patients having received CAR T cells as a treatment for malignancy, our experience in oncology has facilitated numerous efforts to adapt the CAR therapeutic platform for diseases and conditions beyond cancer. Recognition of their efficacy, where traditional small molecule or biologic therapies fail, has spurred multiple efforts leveraging CAR T cells for immune modulation in the setting of organ/tissue transplantation. In the present review, we discuss CAR T cell approaches that are currently under development, to target both humoral and cellular alloimmunity. These include CAR T platforms repurposed from oncology and autoimmune diseases, as well as ones designed specifically to target alloimmunity in transplant. We also present important challenges and application considerations that will need to be addressed before we can expect successful clinical translation. Finally, we highlight a few of the exciting advances currently in development that are likely to pave a smoother path to translating CAR T cell therapies into transplant patients.
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MESH Headings
- Humans
- Organ Transplantation
- Immunotherapy, Adoptive/methods
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/transplantation
- Animals
- Graft Rejection/immunology
- Graft Rejection/prevention & control
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Neoplasms/therapy
- Neoplasms/immunology
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Affiliation(s)
- Georgia F Papadaki
- Department of Pathology & Laboratory Medicine, Immunogenetics Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Yang Li
- Department of Pathology & Laboratory Medicine, Immunogenetics Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Dimitri S Monos
- Department of Pathology & Laboratory Medicine, Immunogenetics Laboratory, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Vijay G Bhoj
- Department of Pathology & Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Mohammad A, Yurina A, Simonyan T, Chistyakov D, Salman R, Zornikova K, Minina E, Bogolyubova A. Modular (universal) CAR-T platforms in vivo: a comprehensive systematic review. Front Immunol 2024; 15:1409665. [PMID: 39712013 PMCID: PMC11659234 DOI: 10.3389/fimmu.2024.1409665] [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: 03/30/2024] [Accepted: 11/14/2024] [Indexed: 12/24/2024] Open
Abstract
Background Modular (universal) CAR T-platforms were developed to combat the limitations of traditional CAR-T therapy, allowing for multiple targeting of tumor-associated antigens and the ability to control CAR-T cell activity. The modular CAR-T platform consists of a universal receptor (signaling module) that recognizes an adapter molecule on the soluble module, which is responsible for antigen recognition. Multiple platforms have been developed over the last 12 years, and some of them have entered the clinical trial phase. This systematic review seeks to evaluate the different parameters of modular CAR-T platforms performance in animal models. Methods A systematic search of literature in the PubMed database and in Google Scholar and BASE (Bielefeld Academic Search Engine) search engines was performed according to predefined eligibility criteria. All studies conducted on xenograft mouse models with any variant of modular CAR-T platforms were included. Forest plots were generated for visual presentation of the extracted quantitative findings (standardized mean difference (SMD) and median survival rate (MSR)). Results A total of 33 studies employing 15 different modular CAR-T platforms were included. The platforms varied in terms of CAR-T cells, soluble module doses, and their frequency of administration. The studies showed a reduction in tumor burden and in tumor volume compared to the combined negative group. In comparison with the positive control group, there was no significant change in tumor burden or volume. In all the included studies the experimental group had a higher survival probability compared to the combined negative group at the study endpoint, with no significant difference in survival rate compared to the positive control group. Conclusion The modular CAR-T platforms are generally effective and are a valuable addition to the arsenal of CAR therapy. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42023443984.
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Cheever A, Kang CC, O’Neill KL, Weber KS. Application of novel CAR technologies to improve treatment of autoimmune disease. Front Immunol 2024; 15:1465191. [PMID: 39445021 PMCID: PMC11496059 DOI: 10.3389/fimmu.2024.1465191] [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: 07/15/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success has spurred research into CAR T cell therapies for other diseases, including solid tumor cancers and autoimmune diseases. Notably, the development of CAR-based treatments for autoimmune diseases has shown great progress recently. Clinical trials for anti-CD19 and anti-BCMA CAR T cells in treating severe B cell-mediated autoimmune diseases, like systemic lupus erythematosus (SLE), have shown lasting remission thus far. CAR T cells targeting autoreactive T cells are beginning clinical trials for treating T cell mediated autoimmune diseases. Chimeric autoantigen receptor (CAAR) T cells specifically target and eliminate only autoreactive B cells, and they have shown promise in treating mucosal pemphigus vulgaris and MuSK myasthenia gravis. Regulatory CAR T cells have also been developed, which show potential in altering autoimmune affected areas by creating a protective barrier as well as helping decrease inflammation. These new treatments are only the beginning of potential CAR T cell applications in treating autoimmune disease. Novel CAR technologies have been developed that increase the safety, potency, specificity, and efficacy of CAR T cell therapy. Applying these novel modifications to autoimmune CARs has the potential to enhance the efficacy and applicability of CAR therapies to autoimmune disease. This review will detail several recently developed CAR technologies and discuss how their application to autoimmune disease will improve this emerging field. These include logic-gated CARs, soluble protein-secreting CARs, and modular CARs that enable CAR T cell therapies to be more specific, reach a wider span of target cells, be safer for patients, and give a more potent cytotoxic response. Applying these novel CAR technologies to the treatment of autoimmune diseases has the potential to revolutionize this growing application of CAR T cell therapies.
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Ali FEM, Ibrahim IM, Althagafy HS, Hassanein EHM. Role of immunotherapies and stem cell therapy in the management of liver cancer: A comprehensive review. Int Immunopharmacol 2024; 132:112011. [PMID: 38581991 DOI: 10.1016/j.intimp.2024.112011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/08/2024]
Abstract
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan.
| | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
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Zhu B, Yin H, Zhang D, Zhang M, Chao X, Scimeca L, Wu MR. Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy. Cell Mol Immunol 2024; 21:436-447. [PMID: 38605087 PMCID: PMC11061174 DOI: 10.1038/s41423-024-01153-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 03/03/2024] [Indexed: 04/13/2024] Open
Abstract
Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.
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Affiliation(s)
- Bo Zhu
- Department of Liver Surgery, Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Hang Yin
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA
| | - Di Zhang
- Drug Safety Research & Evaluation, Takeda Pharmaceuticals International Company, Cambridge, MA, 02139, USA
| | - Meiling Zhang
- Medical Research Institute, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Xiaojuan Chao
- Department of Liver Surgery, Center of Hepato-Pancreato-Biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Luca Scimeca
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA
| | - Ming-Ru Wu
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA.
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Amorós-Pérez B, Rivas-Pardo B, Gómez del Moral M, Subiza JL, Martínez-Naves E. State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future? Cells 2024; 13:725. [PMID: 38727261 PMCID: PMC11083689 DOI: 10.3390/cells13090725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 05/13/2024] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved. There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells. Strategies being developed to improve CAR-T-based therapy for solid tumors include the use of new-generation CARs such as TRUCKs or bi-specific CARs, the combination of CAR therapy with chemo- or radiotherapy, the use of checkpoint inhibitors, and the use of oncolytic viruses. Furthermore, despite the scarcity of targets, a growing number of phase I/II clinical trials are exploring new solid-tumor-associated antigens. Most of these antigens are of a protein nature; however, there is a clear potential in identifying carbohydrate-type antigens associated with tumors, or carbohydrate and proteoglycan antigens that emerge because of aberrant glycosylations occurring in the context of tumor transformation.
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Affiliation(s)
- Beatriz Amorós-Pérez
- Department of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), 28040 Madrid, Spain; (B.A.-P.); (B.R.-P.)
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Inmunotek S.L., 28805 Madrid, Spain;
| | - Benigno Rivas-Pardo
- Department of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), 28040 Madrid, Spain; (B.A.-P.); (B.R.-P.)
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Manuel Gómez del Moral
- Department of Cellular Biology, School of Medicine, Universidad Complutense of Madrid (UCM), 28040 Madrid, Spain;
| | | | - Eduardo Martínez-Naves
- Department of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), 28040 Madrid, Spain; (B.A.-P.); (B.R.-P.)
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
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Mishra A, Maiti R, Mohan P, Gupta P. Antigen loss following CAR-T cell therapy: Mechanisms, implications, and potential solutions. Eur J Haematol 2024; 112:211-222. [PMID: 37705357 DOI: 10.1111/ejh.14101] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR-T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%-70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T-cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR-T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR-T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem.
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Affiliation(s)
- Archana Mishra
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Rituparna Maiti
- Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Prafull Mohan
- Clinical Pharmacologist, Armed Forces Medical Services, Guwahati, India
| | - Pooja Gupta
- Department of Pharmacology, All India Institute of Medical Sciences, Delhi, India
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Mannan A, Kakkar C, Dhiman S, Singh TG. Advancing the frontiers of adaptive cell therapy: A transformative mechanistic journey from preclinical to clinical settings. Int Immunopharmacol 2023; 125:111095. [PMID: 37875038 DOI: 10.1016/j.intimp.2023.111095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/08/2023] [Accepted: 10/17/2023] [Indexed: 10/26/2023]
Abstract
Although the concept of using the patient's immune system to combat cancer has been around for a while, it is only in recent times that substantial progress has been achieved in this field. Over the last ten years, there has been a significant advancement in the treatment of cancer through immune checkpoint blockade. This treatment has been approved for multiple types of tumors. Another approach to modifying the immune system to detect tumor cells and fight them off is adaptive cell therapy (ACT). This therapy involves using T cells that have been modified with either T cell receptors (TCR) or chimeric antigen receptors (CAR) to target the tumor cells. ACT has demonstrated encouraging outcomes in different types of tumors, and clinical trials are currently underway worldwide to enhance this form of treatment. This review focuses on the advancements that have been made in ACT from preclinical to clinical settings till now.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Chirag Kakkar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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12
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Celichowski P, Turi M, Charvátová S, Radhakrishnan D, Feizi N, Chyra Z, Šimíček M, Jelínek T, Bago JR, Hájek R, Hrdinka M. Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility. J Transl Med 2023; 21:197. [PMID: 36922828 PMCID: PMC10015723 DOI: 10.1186/s12967-023-04041-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility.
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Affiliation(s)
- Piotr Celichowski
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Marcello Turi
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Faculty of Science, University of Ostrava, Ostrava, Czech Republic
| | - Sandra Charvátová
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Faculty of Science, University of Ostrava, Ostrava, Czech Republic
| | - Dhwani Radhakrishnan
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
- Faculty of Science, University of Ostrava, Ostrava, Czech Republic
| | - Neda Feizi
- Department of Internal Clinical Sciences, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Zuzana Chyra
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Michal Šimíček
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Tomáš Jelínek
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Juli Rodriguez Bago
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Roman Hájek
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Matouš Hrdinka
- Department of Haematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic.
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13
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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14
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Hepatocellular Carcinoma: Current Therapeutic Algorithm for Localized and Advanced Disease. JOURNAL OF ONCOLOGY 2022; 2022:3817724. [PMID: 36624801 PMCID: PMC9825221 DOI: 10.1155/2022/3817724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer in patients with liver cirrhosis of various etiologies. In recent years, there has been an advance in the knowledge of molecular mechanisms and a better staging definition of patients which has allowed the development of new therapies that have entered the therapeutic workup of these patients. Deep information on molecular drivers of HCC contributed to the development of targeted therapies with remarkable benefits. The novel strategies of targeting immune evasion using immune checkpoint inhibitors and CAR-T and TCR-T therapeutics have also shown promising results. For advanced diseases, the therapeutic algorithm has been recently updated, thanks to the efficacy of combining immunotherapy and antiangiogenic therapy in the first-line setting, and new drugs, both as single-agents or combinations, are currently under investigation.
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15
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Liu L, Qu Y, Cheng L, Yoon CW, He P, Monther A, Guo T, Chittle S, Wang Y. Engineering chimeric antigen receptor T cells for solid tumour therapy. Clin Transl Med 2022; 12:e1141. [PMID: 36495108 PMCID: PMC9736813 DOI: 10.1002/ctm2.1141] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/22/2022] [Accepted: 11/26/2022] [Indexed: 12/13/2022] Open
Abstract
Cell-based immunotherapy, for example, chimeric antigen receptor T (CAR-T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR-based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR-T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR-T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR-T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME-associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME-associated factors. Lastly, the future directions for engineering efficient CAR-T cells for solid tumour therapy will be discussed.
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Affiliation(s)
- Longwei Liu
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Yunjia Qu
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Leonardo Cheng
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Chi Woo Yoon
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Peixiang He
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Abdula Monther
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Tianze Guo
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Sarah Chittle
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
| | - Yingxiao Wang
- Department of BioengineeringInstitute of Engineering in MedicineUniversity of CaliforniaLa JollaCaliforniaUSA
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16
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Immunotherapy for hepatocellular carcinoma. Clin Exp Med 2022:10.1007/s10238-022-00874-5. [PMID: 36001163 DOI: 10.1007/s10238-022-00874-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/08/2022] [Indexed: 11/03/2022]
Abstract
Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is a threat to the health of all humans as a prevalent malignancy and is the sixth most common cancer worldwide. It is difficult to diagnose because symptoms do not show up until late in the disease, and patients often progress to the point where transplantation, resection, or even local treatment cannot be performed. The progression of HCC is regulated by the immune system, and immunotherapy enables the body's immune system's defenses to target liver cancer cells; therefore, immunotherapy has brought a new hope for the treatment of HCC. Currently, the main types of immunotherapies for liver cancer are: immune checkpoint inhibitors, liver cancer vaccines and cellular therapies. In this review, the progress of immunotherapy for the treatment of HCC is summarized.
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17
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Yao M, Yang JL, Wang DF, Wang L, Chen Y, Yao DF. Encouraging specific biomarkers-based therapeutic strategies for hepatocellular carcinoma. World J Clin Cases 2022; 10:3321-3333. [PMID: 35611205 PMCID: PMC9048543 DOI: 10.12998/wjcc.v10.i11.3321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
The prevention, early discovery and effective treatment of patients with hepatocellular carcinoma (HCC) remain a global medical challenge. At present, HCC is still mainly treated by surgery, supplemented by vascular embolization, radio frequency, radiotherapy, chemotherapy and biotherapy. The application of multikinase inhibitor sorafenib, chimeric antigen receptor T cells, or PD-1/PD-L1 inhibitors can prolong the median survival of HCC patients. However, the treatment efficacy is still unsatisfactory due to HCC metastasis and postoperative recurrence. During the process of hepatocyte malignant transformation, HCC tissues can express and secrete many types of specific biomarkers, or oncogenic antigen molecules into blood, for example, alpha-fetoprotein, glypican-3, Wnt3a (one of the key signaling molecules in the Wnt/β-catenin pathway), insulin-like growth factor (IGF)-II or IGF-I receptor, vascular endothelial growth factor, secretory clusterin and so on. In addition, combining immunotherapy with non-coding RNAs might improve anti-cancer efficacy. These biomarkers not only contribute to HCC diagnosis or prognosis, but may also become molecular targets for HCC therapy under developing or clinical trials. This article reviews the progress in emerging biomarkers in basic research or clinical trials for HCC immunotherapy.
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Affiliation(s)
- Min Yao
- Research Center of Clinical Medicine & Department of Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Jun-Ling Yang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - De-Feng Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ying Chen
- Department of Oncology, Affiliated Second Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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18
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Gumber D, Wang LD. Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion. EBioMedicine 2022; 77:103941. [PMID: 35301179 PMCID: PMC8927848 DOI: 10.1016/j.ebiom.2022.103941] [Citation(s) in RCA: 201] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/15/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of hematological malignancies. However, CAR T cell exhaustion is a major limitation to their efficacy, particularly in the application of CAR T cells to solid tumors. CAR T cell exhaustion is thought to be due to persistent antigen stimulation, as well as an immunosuppressive tumor microenvironment, and mitigating exhaustion to maintain CAR T cell effector function and persistence and achieve clinical potency remains a central challenge. Here, we review the underlying mechanisms of exhaustion and discuss emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. Additionally, we discuss the potential of these strategies for improving clinical outcomes of CAR T cell therapy.
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Affiliation(s)
- Diana Gumber
- Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Beckman Research Institute, Duarte CA, United States; Department of Immunooncology, City of Hope National Medical Center, Beckman Research Institute, Duarte, CA, United States
| | - Leo D Wang
- Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Beckman Research Institute, Duarte CA, United States; Department of Immunooncology, City of Hope National Medical Center, Beckman Research Institute, Duarte, CA, United States; Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, United States.
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19
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Hanssens H, Meeus F, De Veirman K, Breckpot K, Devoogdt N. The antigen-binding moiety in the driver's seat of CARs. Med Res Rev 2022; 42:306-342. [PMID: 34028069 PMCID: PMC9292017 DOI: 10.1002/med.21818] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 02/17/2021] [Accepted: 04/21/2021] [Indexed: 12/16/2022]
Abstract
Immuno-oncology has been at the forefront of cancer treatment in recent decades. In particular immune checkpoint and chimeric antigen receptor (CAR)-T cell therapy have achieved spectacular results. Over the years, CAR-T cell development has followed a steady evolutionary path, focusing on increasing T cell potency and sustainability, which has given rise to different CAR generations. However, there was less focus on the mode of interaction between the CAR-T cell and the cancer cell; more specifically on the targeting moiety used in the CAR and its specific properties. Recently, the importance of optimizing this domain has been recognized and the possibilities have been exploited. Over the last 10 years-in addition to the classical scFv-based CARs-single domain CARs, natural receptor-ligand CARs, universal CARs and CARs targeting more than one antigen have emerged. In addition, the specific parameters of the targeting domain and their influence on T cell activation are being examined. In this review, we concisely present the history of CAR-T cell therapy, and then expand on various developments in the CAR ectodomain. We discuss different formats, each with their own advantages and disadvantages, as well as the developments in affinity tuning, avidity effects, epitope location, and influence of the extracellular spacer.
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Affiliation(s)
- Heleen Hanssens
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
- Laboratory of Hematology and ImmunologyVrije Universiteit BrusselBrusselsBelgium
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Fien Meeus
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Kim De Veirman
- Laboratory of Hematology and ImmunologyVrije Universiteit BrusselBrusselsBelgium
| | - Karine Breckpot
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Nick Devoogdt
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
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20
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Immunotherapy for Hepatocellular Carcinoma: New Prospects for the Cancer Therapy. Life (Basel) 2021; 11:life11121355. [PMID: 34947886 PMCID: PMC8704694 DOI: 10.3390/life11121355] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/29/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. HCC patients may benefit from liver transplantation, hepatic resection, radiofrequency ablation, transcatheter arterial chemoembolization, and targeted therapies. The increased infiltration of immunosuppressive immune cells and the elevated expression of immunosuppressive factors in the HCC microenvironment are the main culprits of the immunosuppressive nature of the HCC milieu. The immunosuppressive tumor microenvironment can substantially attenuate antitumoral immune responses and facilitate the immune evasion of tumoral cells. Immunotherapy is an innovative treatment method that has been promising in treating HCC. Immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and cell-based (primarily dendritic cells) and non-cell-based vaccines are the most common immunotherapeutic approaches for HCC treatment. However, these therapeutic approaches have not generally induced robust antitumoral responses in clinical settings. To answer to this, growing evidence has characterized immune cell populations and delineated intercellular cross-talk using single-cell RNA sequencing (scRNA-seq) technologies. This review aims to discuss the various types of tumor-infiltrating immune cells and highlight their roles in HCC development. Besides, we discuss the recent advances in immunotherapeutic approaches for treating HCC, e.g., ICIs, dendritic cell (DC)-based vaccines, non-cell-based vaccines, oncolytic viruses (OVs), and ACT. Finally, we discuss the potentiality of scRNA-seq to improve the response rate of HCC patients to immunotherapeutic approaches.
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21
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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22
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Zheng Y, Li Y, Feng J, Li J, Ji J, Wu L, Yu Q, Dai W, Wu J, Zhou Y, Guo C. Cellular based immunotherapy for primary liver cancer. J Exp Clin Cancer Res 2021; 40:250. [PMID: 34372912 PMCID: PMC8351445 DOI: 10.1186/s13046-021-02030-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.
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Affiliation(s)
- Yuanyuan Zheng
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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23
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Ni H, Xue J, Wang F, Sun X, Niu M. Nanomedicine Approach to Immunotherapy of Hepatocellular Carcinoma. J Biomed Nanotechnol 2021; 17:771-792. [PMID: 34082866 DOI: 10.1166/jbn.2021.3055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In recent years, the growing studies focused on the immunotherapy of hepatocellular carcinoma and proved the preclinical and clinical promises of host antitumor immune response. However, there were still various obstacles in meeting satisfactory clinic need, such as low response rate, primary resistance and secondary resistance to immunotherapy. Tackling these barriers required a deeper understanding of immune underpinnings and a broader understanding of advanced technology. This review described immune microenvironment of liver and HCC which naturally decided the complexity of immunotherapy, and summarized recent immunotherapy focusing on different points. The ever-growing clues indicated that the instant killing of tumor cell and the subsequent relive of immunosuppressive microenvironment were both indis- pensables. The nanotechnology applied in immunotherapy and the combination with intervention technology was also discussed.
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Affiliation(s)
- Hongbo Ni
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Jian Xue
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Fan Wang
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Xiaohan Sun
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Meng Niu
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
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Damiris K, Abbad H, Pyrsopoulos N. Cellular based treatment modalities for unresectable hepatocellular carcinoma. World J Clin Oncol 2021; 12:290-308. [PMID: 34131562 PMCID: PMC8173328 DOI: 10.5306/wjco.v12.i5.290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/19/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is unfortunately associated with an overall poor prognosis and high mortality. Early and intermediate stages of HCC allow for treatment with surgical resection, ablation and even liver transplantation, however disease progression warrants conventional systemic therapy. For years treatment options were limited to molecular-targeting medications, of which sorafenib remains the standard of care. The recent development and success of immune checkpoint inhibitors has proven to be a breakthrough in the treatment of HCC, but there is an urgent need for the development of further novel therapeutic treatments that prolong overall survival and minimize recurrence. Current investigation is focused on adoptive cell therapy including chimeric antigen receptor-T cells (CAR-T cells), T cell receptor (TCR) engineered T cells, dendritic cells, natural killer cells, and tumor infiltrating lymphocyte cells, which have shown remarkable success in the treatment of hematological and solid tumor malignancies. In this review we briefly introduce readers to the currently approved systemic treatment options and present clinical and experimental evidence of HCC immunotherapeutic treatments that will hopefully one day allow for revolutionary change in the treatment modalities used for unresectable HCC. We also provide an up-to-date compilation of ongoing clinical trials investigating CAR-T cells, TCR engineered T cells, cancer vaccines and oncolytic viruses, while discussing strategies that can help overcome commonly faced challenges when utilizing cellular based treatments.
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Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Hamza Abbad
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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Leone P, Solimando AG, Fasano R, Argentiero A, Malerba E, Buonavoglia A, Lupo LG, De Re V, Silvestris N, Racanelli V. The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment. Vaccines (Basel) 2021; 9:vaccines9050532. [PMID: 34065489 PMCID: PMC8160723 DOI: 10.3390/vaccines9050532] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/19/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.
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Affiliation(s)
- Patrizia Leone
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
| | - Antonio Giovanni Solimando
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Rossella Fasano
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | | | - Eleonora Malerba
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- Department of Experimental Diagnostic and Specialty Medicine, “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Alessio Buonavoglia
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
| | - Luigi Giovanni Lupo
- Department of General Surgery and Liver Transplantation, University of Bari, 70124 Bari, Italy;
| | - Valli De Re
- Immunopathology and Cancer Biomarkers—Bio-Proteomics Facility, CRO Aviano National Cancer Institute, 33081 Aviano, Italy;
| | - Nicola Silvestris
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Vito Racanelli
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- Correspondence: ; Tel.: +39-080-5478050
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Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. Cancers (Basel) 2021; 13:cancers13020271. [PMID: 33450845 PMCID: PMC7828372 DOI: 10.3390/cancers13020271] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.
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Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome. Adv Cancer Res 2020; 149:171-255. [PMID: 33579424 DOI: 10.1016/bs.acr.2020.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Much recent research has delved into understanding the underlying molecular mechanisms of HCC pathogenesis, which has revealed to be heterogenous and complex. Two major hallmarks of HCC include: (i) a hijacked immunometabolism and (ii) a reprogramming in metabolic processes. We posit that the gut microbiota is a third component in an entanglement triangle contributing to HCC progression. Besides metagenomic studies highlighting the diagnostic potential in the gut microbiota profile, recent research is pinpointing the gut microbiota as an instigator, not just a mere bystander, in HCC. In this chapter, we discuss mechanistic insights on atypical immunometabolism and metabolic reprogramming in HCC, including the examination of tumor-associated macrophages and neutrophils, tumor-infiltrating lymphocytes (e.g., T-cell exhaustion, regulatory T-cells, natural killer T-cells), the Warburg effect, rewiring of the tricarboxylic acid cycle, and glutamine addiction. We further discuss the potential involvement of the gut microbiota in these characteristics of hepatocarcinogenesis. An immediate highlight is that microbiota metabolites (e.g., short chain fatty acids, secondary bile acids) can impair anti-tumor responses, which aggravates HCC. Lastly, we describe the rising 'new era' of immunotherapies (e.g., immune checkpoint inhibitors, adoptive T-cell transfer) and discuss for the potential incorporation of gut microbiota targeted therapeutics (e.g., probiotics, fecal microbiota transplantation) to alleviate HCC. Altogether, this chapter invigorates for continuous research to decipher the role of gut microbiome in HCC from its influence on immunometabolism and metabolic reprogramming.
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Kole C, Charalampakis N, Tsakatikas S, Vailas M, Moris D, Gkotsis E, Kykalos S, Karamouzis MV, Schizas D. Immunotherapy for Hepatocellular Carcinoma: A 2021 Update. Cancers (Basel) 2020; 12:2859. [PMID: 33020428 PMCID: PMC7600093 DOI: 10.3390/cancers12102859] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of one of the most frequent liver cancers and the fourth leading cause of cancer-related mortality worldwide. Current treatment options such as surgery, neoadjuvant chemoradiotherapy, liver transplantation, and radiofrequency ablation will benefit only a very small percentage of patients. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The aim of our study is to present the currently ongoing clinical trials and to evaluate the efficacy of immunotherapy in HCC. In this paper, we demonstrate that combination of different immunotherapies or immunotherapy with other modalities results in better overall survival (OS) and progression-free survival (PFS) compared to single immunotherapy agent. Another objective of this paper is to demonstrate and highlight the importance of tumor microenvironment as a predictive and prognostic marker and its clinical implications in immunotherapy response.
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Affiliation(s)
- Christo Kole
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital, 185 37 Athens, Greece; (N.C.); (S.T.)
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital, 185 37 Athens, Greece; (N.C.); (S.T.)
| | - Michail Vailas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Dimitrios Moris
- Department of Surgery, Duke University School of Medicine, Durham, NC 27707, USA;
| | - Efthymios Gkotsis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece;
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 115 27 Athens, Greece; (C.K.); (M.V.); (E.G.); (D.S.)
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Sutherland AR, Owens MN, Geyer CR. Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting. Int J Mol Sci 2020; 21:E7222. [PMID: 33007850 PMCID: PMC7582510 DOI: 10.3390/ijms21197222] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/29/2020] [Accepted: 09/29/2020] [Indexed: 12/16/2022] Open
Abstract
The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.
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Affiliation(s)
- Ashley R. Sutherland
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (A.R.S.); (M.N.O.)
| | - Madeline N. Owens
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; (A.R.S.); (M.N.O.)
| | - C. Ronald Geyer
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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