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1
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Chai D, Wang X, Fan C, Wang J, Lim JM, Yu X, Young KH, Li Y. Vaccines targeting p53 mutants elicit anti-tumor immunity. Cancer Lett 2024; 611:217421. [PMID: 39740750 DOI: 10.1016/j.canlet.2024.217421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/09/2024] [Accepted: 12/22/2024] [Indexed: 01/02/2025]
Abstract
The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD-1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8+ T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c+, CD103+CD11c+, and CD8+CD11c+ cells, which in turn promoted tumor-specific antibody production, as well as Th1 and CD8+ T cell-mediated immune responses. Several antigenic epitopes of p53-S237G effectively stimulated multifunctional CD8+ T cells to secrete IFN-γ and TNF-α. The vaccine showed long-term anti-tumor effects that were dependent on memory CD8+ T cells. Furthermore, the anti-p53-S237G vaccine exhibited significant protective efficacy in the A20 liver metastasis models. When combined with PD-1 inhibition, the vaccine showed superior inhibition of tumor growth and liver metastasis. Targeting p53 mutants by vaccination represents a potential precision medicine strategy against cancers harboring p53 mutations.
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Affiliation(s)
- Dafei Chai
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Xu Wang
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chunmei Fan
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Junhao Wang
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jing Ming Lim
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Xinfang Yu
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ken H Young
- Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Yong Li
- Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
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2
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Zhang T, Zhang X, Chen J, Zhang X, Zhang Y. Harnessing microbial antigens as cancer antigens: a promising avenue for cancer immunotherapy. Front Immunol 2024; 15:1411490. [PMID: 39139570 PMCID: PMC11319170 DOI: 10.3389/fimmu.2024.1411490] [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: 04/03/2024] [Accepted: 07/16/2024] [Indexed: 08/15/2024] Open
Abstract
Immunotherapy has revolutionized cancer treatment by leveraging the immune system's innate capabilities to combat malignancies. Despite the promise of tumor antigens in stimulating anti-tumor immune responses, their clinical utility is hampered by limitations in eliciting robust and durable immune reactions, exacerbated by tumor heterogeneity and immune evasion mechanisms. Recent insights into the immunogenic properties of host homologous microbial antigens have sparked interest in their potential for augmenting anti-tumor immunity while minimizing off-target effects. This review explores the therapeutic potential of microbial antigen peptides in tumor immunotherapy, beginning with an overview of tumor antigens and their challenges in clinical translation. We further explore the intricate relationship between microorganisms and tumor development, elucidating the concept of molecular mimicry and its implications for immune recognition of tumor-associated antigens. Finally, we discuss methodologies for identifying and characterizing microbial antigen peptides, highlighting their immunogenicity and prospects for therapeutic application.
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Affiliation(s)
- Tao Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
- Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Xilong Zhang
- Department of Burns and Plastic Surgery, First People’s Hospital of Xuzhou City, Xuzhou, China
| | - Jianquan Chen
- Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Xiuwei Zhang
- Department of Burns and Plastic Surgery, First People’s Hospital of Xuzhou City, Xuzhou, China
| | - Yunlei Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
- Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
- Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
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3
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Parhiz H, Atochina-Vasserman EN, Weissman D. mRNA-based therapeutics: looking beyond COVID-19 vaccines. Lancet 2024; 403:1192-1204. [PMID: 38461842 DOI: 10.1016/s0140-6736(23)02444-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 07/06/2023] [Accepted: 10/30/2023] [Indexed: 03/12/2024]
Abstract
Recent advances in mRNA technology and its delivery have enabled mRNA-based therapeutics to enter a new era in medicine. The rapid, potent, and transient nature of mRNA-encoded proteins, without the need to enter the nucleus or the risk of genomic integration, makes them desirable tools for treatment of a range of diseases, from infectious diseases to cancer and monogenic disorders. The rapid pace and ease of mass-scale manufacturability of mRNA-based therapeutics supported the global response to the COVID-19 pandemic. Nonetheless, challenges remain with regards to mRNA stability, duration of expression, delivery efficiency, and targetability, to broaden the applicability of mRNA therapeutics beyond COVID-19 vaccines. By learning from the rapidly expanding preclinical and clinical studies, we can optimise the mRNA platform to meet the clinical needs of each disease. Here, we will summarise the recent advances in mRNA technology; its use in vaccines, immunotherapeutics, protein replacement therapy, and genomic editing; and its delivery to desired specific cell types and organs for development of a new generation of targeted mRNA-based therapeutics.
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Affiliation(s)
- Hamideh Parhiz
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Drew Weissman
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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4
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Klebanoff CA, Chandran SS, Baker BM, Quezada SA, Ribas A. T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. Nat Rev Drug Discov 2023; 22:996-1017. [PMID: 37891435 PMCID: PMC10947610 DOI: 10.1038/s41573-023-00809-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2023] [Indexed: 10/29/2023]
Abstract
The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. As such, TCRs have provided the basis for an emerging class of oncology therapeutics. Herein, we review the current cancer treatment landscape using TCRs and TCR-like molecules. This includes adoptive cell transfer of T cells expressing endogenous or engineered TCRs, TCR bispecific engagers and antibodies specific for human leukocyte antigen (HLA)-bound peptides (TCR mimics). We discuss the unique complexities associated with the clinical development of these therapeutics, such as HLA restriction, TCR retrieval, potency assessment and the potential for cross-reactivity. In addition, we highlight emerging clinical data that establish the antitumour potential of TCR-based therapies, including tumour-infiltrating lymphocytes, for the treatment of diverse human malignancies. Finally, we explore the future of TCR therapeutics, including emerging genome editing methods to safely enhance potency and strategies to streamline patient identification.
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Affiliation(s)
- Christopher A Klebanoff
- Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program, New York, NY, USA.
| | - Smita S Chandran
- Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program, New York, NY, USA
- Parker Institute for Cancer Immunotherapy, New York, NY, USA
- Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Brian M Baker
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, ID, USA
- The Harper Cancer Research Institute, University of Notre Dame, Notre Dame, ID, USA
| | - Sergio A Quezada
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Achilles Therapeutics, London, UK
| | - Antoni Ribas
- Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA
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5
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Haldar SD, Vilar E, Maitra A, Zaidi N. Worth a Pound of Cure? Emerging Strategies and Challenges in Cancer Immunoprevention. Cancer Prev Res (Phila) 2023; 16:483-495. [PMID: 37001882 PMCID: PMC10548442 DOI: 10.1158/1940-6207.capr-22-0478] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/06/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023]
Abstract
Cancer immunoprevention applies immunologic approaches such as vaccines to prevent, rather than to treat or cure, cancer. Despite limited success in the treatment of advanced disease, the development of cancer vaccines to intercept premalignant states is a promising area of current research. These efforts are supported by the rationale that vaccination in the premalignant setting is less susceptible to mechanisms of immune evasion compared with established cancer. Prophylactic vaccines have already been developed for a minority of cancers mediated by oncogenic viruses (e.g., hepatitis B and human papillomavirus). Extending the use of preventive vaccines to non-virally driven malignancies remains an unmet need to address the rising global burden of cancer. This review provides a broad overview of clinical trials in cancer immunoprevention with an emphasis on emerging vaccine targets and delivery platforms, translational challenges, and future directions.
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Affiliation(s)
- Saurav D. Haldar
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anirban Maitra
- Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Neeha Zaidi
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
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6
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Gouttefangeas C, Klein R, Maia A. The good and the bad of T cell cross-reactivity: challenges and opportunities for novel therapeutics in autoimmunity and cancer. Front Immunol 2023; 14:1212546. [PMID: 37409132 PMCID: PMC10319254 DOI: 10.3389/fimmu.2023.1212546] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/24/2023] [Indexed: 07/07/2023] Open
Abstract
T cells are main actors of the immune system with an essential role in protection against pathogens and cancer. The molecular key event involved in this absolutely central task is the interaction of membrane-bound specific T cell receptors with peptide-MHC complexes which initiates T cell priming, activation and recall, and thus controls a range of downstream functions. While textbooks teach us that the repertoire of mature T cells is highly diverse, it is clear that this diversity cannot possibly cover all potential foreign peptides that might be encountered during life. TCR cross-reactivity, i.e. the ability of a single TCR to recognise different peptides, offers the best solution to this biological challenge. Reports have shown that indeed, TCR cross-reactivity is surprisingly high. Hence, the T cell dilemma is the following: be as specific as possible to target foreign danger and spare self, while being able to react to a large spectrum of body-threatening situations. This has major consequences for both autoimmune diseases and cancer, and significant implications for the development of T cell-based therapies. In this review, we will present essential experimental evidence of T cell cross-reactivity, implications for two opposite immune conditions, i.e. autoimmunity vs cancer, and how this can be differently exploited for immunotherapy approaches. Finally, we will discuss the tools available for predicting cross-reactivity and how improvements in this field might boost translational approaches.
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Affiliation(s)
- Cécile Gouttefangeas
- Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Tübingen, Germany
| | - Reinhild Klein
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Ana Maia
- Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
- Cluster of Excellence iFIT (EXC2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
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7
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Tagliamonte M, Cavalluzzo B, Mauriello A, Ragone C, Buonaguro FM, Tornesello ML, Buonaguro L. Molecular mimicry and cancer vaccine development. Mol Cancer 2023; 22:75. [PMID: 37101139 PMCID: PMC10131527 DOI: 10.1186/s12943-023-01776-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/14/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND The development of cancer immunotherapeutic strategies relies on the identification and validation of optimal target tumor antigens, which should be tumor-specific as well as able to elicit a swift and potent anti-tumor immune response. The vast majority of such strategies are based on tumor associated antigens (TAAs) which are shared wild type cellular self-epitopes highly expressed on tumor cells. Indeed, TAAs can be used to develop off-the-shelf cancer vaccines appropriate to all patients affected by the same malignancy. However, given that they may be also presented by HLAs on the surface of non-malignant cells, they may be possibly affected by immunological tolerance or elicit autoimmune responses. MAIN BODY In order to overcome such limitations, analogue peptides with improved antigenicity and immunogenicity able to elicit a cross-reactive T cell response are needed. To this aim, non-self-antigens derived from microorganisms (MoAs) may be of great benefit.
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Affiliation(s)
- Maria Tagliamonte
- Lab of Innovative Immunological Models, Istituto Nazionale Tumori, IRCCS - "Fond. G. Pascale", Naples, Italy
| | - Beatrice Cavalluzzo
- Lab of Innovative Immunological Models, Istituto Nazionale Tumori, IRCCS - "Fond. G. Pascale", Naples, Italy
| | - Angela Mauriello
- Lab of Innovative Immunological Models, Istituto Nazionale Tumori, IRCCS - "Fond. G. Pascale", Naples, Italy
| | - Concetta Ragone
- Lab of Innovative Immunological Models, Istituto Nazionale Tumori, IRCCS - "Fond. G. Pascale", Naples, Italy
| | - Franco M Buonaguro
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori, IRCCS - "Fond G. Pascale", Naples, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori, IRCCS - "Fond G. Pascale", Naples, Italy
| | - Luigi Buonaguro
- Lab of Innovative Immunological Models, Istituto Nazionale Tumori, IRCCS - "Fond. G. Pascale", Naples, Italy.
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8
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de Rooij MA, Remst DF, van der Steen DM, Wouters AK, Hagedoorn RS, Kester MG, Meeuwsen MH, Wachsmann TL, de Ru AH, van Veelen PA, Verdegaal EM, Falkenburg JF, Heemskerk MH. A library of cancer testis specific T cell receptors for T cell receptor gene therapy. Mol Ther Oncolytics 2023; 28:1-14. [PMID: 36589698 PMCID: PMC9792401 DOI: 10.1016/j.omto.2022.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
To increase the number of cancer patients that can be treated with T cell receptor (TCR) gene therapy, we aimed to identify a set of high-affinity cancer-specific TCRs targeting different melanoma-associated antigens (MAGEs). In this study, peptides derived from MAGE genes with tumor-specific expression pattern were identified by human leukocyte antigen (HLA) peptidomics. Next, peptide-HLA tetramers were generated, and used to sort MAGE-specific CD8+ T cell clones from the allogeneic (allo) HLA repertoire of healthy donors. To evaluate the clinical potential, most potent TCRs were sequenced, transferred into peripheral blood-derived CD8+ T cells, and tested for antitumor efficacy. In total we identified, seven MAGE-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6, and MAGE-A9 in the context of HLA-A∗01:01, -A∗02:01, -A∗03:01, -B∗07:02, -B∗35:01, or -C∗07:02. TCR gene transfer into CD8⁺ T cells resulted in efficient reactivity against a variety of different tumor types, while no cross-reactivity was detected. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells were observed in the orthotopic xenograft model for established multiple myeloma. The identification of seven MAGE-specific TCRs expands the pool of cancer patients eligible for TCR gene therapy and increases possibilities for personalized TCR gene therapy.
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Affiliation(s)
- Marije A.J. de Rooij
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Dennis F.G. Remst
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Dirk M. van der Steen
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Anne K. Wouters
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Renate S. Hagedoorn
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Michel G.D. Kester
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Miranda H. Meeuwsen
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Tassilo L.A. Wachsmann
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Arnoud H. de Ru
- Center for Proteomics and Metabolics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Peter A. van Veelen
- Center for Proteomics and Metabolics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - Els M.E. Verdegaal
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
| | - J.H. Frederik Falkenburg
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Mirjam H.M. Heemskerk
- Department of Hematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
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Oladejo M, Paulishak W, Wood L. Synergistic potential of immune checkpoint inhibitors and therapeutic cancer vaccines. Semin Cancer Biol 2023; 88:81-95. [PMID: 36526110 DOI: 10.1016/j.semcancer.2022.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022]
Abstract
Cancer vaccines and immune checkpoint inhibitors (ICIs) function at different stages of the cancer immune cycle due to their distinct mechanisms of action. Therapeutic cancer vaccines enhance the activation and infiltration of cytotoxic immune cells into the tumor microenvironment (TME), while ICIs, prevent and/or reverse the dysfunction of these immune cells. The efficacy of both classes of immunotherapy has been evaluated in monotherapy, but they have been met with several challenges. Although therapeutic cancer vaccines can activate anti-tumor immune responses, these responses are susceptible to attenuation by immunoregulatory molecules. Similarly, ICIs are ineffective in the absence of tumor-infiltrating lymphocytes (TILs). Further, ICIs are often associated with immune-related adverse effects that may limit quality of life and compliance. However, the combination of the improved immunogenicity afforded by cancer vaccines and restrained immunosuppression provided by immune checkpoint inhibitors may provide a suitable platform for therapeutic synergism. In this review, we revisit the history and various classifications of therapeutic cancer vaccines. We also provide a summary of the currently approved ICIs. Finally, we provide mechanistic insights into the synergism between ICIs and cancer vaccines.
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Affiliation(s)
- Mariam Oladejo
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Wyatt Paulishak
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Laurence Wood
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
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Nagel R, Pataskar A, Champagne J, Agami R. Boosting Antitumor Immunity with an Expanded Neoepitope Landscape. Cancer Res 2022; 82:3637-3649. [PMID: 35904353 PMCID: PMC9574376 DOI: 10.1158/0008-5472.can-22-1525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/07/2022] [Accepted: 07/21/2022] [Indexed: 01/07/2023]
Abstract
Immune-checkpoint blockade therapy has been successfully applied to many cancers, particularly tumors that harbor a high mutational burden and consequently express a high abundance of neoantigens. However, novel approaches are needed to improve the efficacy of immunotherapy for treating tumors that lack a high load of classic genetically derived neoantigens. Recent discoveries of broad classes of nongenetically encoded and inducible neoepitopes open up new avenues for therapeutic development to enhance sensitivity to immunotherapies. In this review, we discuss recent work on neoantigen discovery, with an emphasis on novel classes of noncanonical neoepitopes.
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Affiliation(s)
- Remco Nagel
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Abhijeet Pataskar
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Julien Champagne
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Reuven Agami
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Erasmus MC, Rotterdam University, Rotterdam, the Netherlands
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11
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Li Q, Hu W, Liao B, Song C, Li L. Natural high-avidity T-cell receptor efficiently mediates regression of cancer/testis antigen 83 positive common solid cancers. J Immunother Cancer 2022; 10:jitc-2022-004713. [PMID: 35798537 PMCID: PMC9263944 DOI: 10.1136/jitc-2022-004713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND T-cell receptor-engineered T cells (TCR-Ts) have achieved encouraging success in anticancer clinical trials. The antigenic targets, however, were primarily focused on human leukocyte antigen (HLA) A*02:01 restricted epitopes from a few cancer/testis antigens (CTAs) which are not widely expressed in common solid cancers; the tested T-cell receptors (TCRs) were frequently from tumor-infiltrating lymphocytes of old patients and were not assured to have higher avidity. Here, we propose the isolation of high-avidity TCRs against CTAs that are frequently expressed in common solid cancers. METHODS We selected the CT83 protein, which is frequently expressed in common solid cancers, as a model antigen for screening of its specific TCR. The predicted CT83 epitopes with strong or weak binding to HLA-I molecules, popular in the Chinese population, were integrated into three synthetic long peptides. CT83 reactive CD8+ T cells were stimulated with peptide-loaded dendritic cells (DCs) and sorted using the CD137 biomarker for single-cell sequencing to obtain the paired TCRαβ sequence. The higher frequency TCRs were reconstructed for characterization of the CT83 epitope and for assessment of in vitro and in vivo antitumor activities. RESULTS CT83 reactive T cells from young healthy donors (YHDs) were generated by repeated stimulation with DCs and peptides. The single-cell TCR sequencing results of reactive T cells indicated that a single TCR clonotype dominated the paired TCRs. T cells engineered with this dominant TCR led to HLA-A*11:01-restricted recognition of the CT8314-22 epitope, with higher avidity. Functional assays showed powerful cytotoxicity in vitro against the targets of several CT83-positive solid cancer cell lines. Furthermore, TCR-Ts showed therapeutic efficacy in three xenograft solid tumor models. The meta-analysis of gene expression of 92 CTAs indicated that most CTAs did not or at low levels in the thymus, which suggested that those CTAs may experience incomplete thymic central tolerance. CONCLUSIONS High-avidity TCR against CT83 could be isolated from YHDs and efficiently mediate regression of well-established xenograft common solid tumors. The high-avidity TCR repertoire in the peripheral blood of some donors for CT83 and other CTAs provides the basis for the efficient isolation of high-avidity TCRs to target numerous solid cancers.
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Affiliation(s)
- Qingyang Li
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wei Hu
- T Cell Immune Technology Co., Ltd, Guangzhou, China
| | - Baoyi Liao
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chanchan Song
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liangping Li
- Department of Clinical Oncology, the First Affiliated Hospital of Jinan University, Guangzhou, China
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12
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Grace BE, Backlund CM, Morgan DM, Kang BH, Singh NK, Huisman BD, Rappazzo CG, Moynihan KD, Maiorino L, Dobson CS, Kyung T, Gordon KS, Holec PV, Mbah OCT, Garafola D, Wu S, Love JC, Wittrup KD, Irvine DJ, Birnbaum ME. Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma. Front Immunol 2022; 13:886683. [PMID: 35812387 PMCID: PMC9260506 DOI: 10.3389/fimmu.2022.886683] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/20/2022] [Indexed: 11/16/2022] Open
Abstract
While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.
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Affiliation(s)
- Beth E. Grace
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Coralie M. Backlund
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Duncan M. Morgan
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Byong H. Kang
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Nishant K. Singh
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
| | - Brooke D. Huisman
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - C. Garrett Rappazzo
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Kelly D. Moynihan
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Laura Maiorino
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Connor S. Dobson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Taeyoon Kyung
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Khloe S. Gordon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Patrick V. Holec
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | | | - Daniel Garafola
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Shengwei Wu
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - J. Christopher Love
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
| | - K. Dane Wittrup
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Darrell J. Irvine
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
| | - Michael E. Birnbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- *Correspondence: Michael E. Birnbaum,
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Ladak RJ, He AJ, Huang YH, Ding Y. The Current Landscape of mRNA Vaccines Against Viruses and Cancer-A Mini Review. Front Immunol 2022; 13:885371. [PMID: 35603213 PMCID: PMC9120423 DOI: 10.3389/fimmu.2022.885371] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/14/2022] [Indexed: 12/11/2022] Open
Abstract
Both infectious viral diseases and cancer have historically been some of the most common causes of death worldwide. The COVID-19 pandemic is a decidedly relevant example of the former. Despite progress having been made over past decades, new and improved techniques are still needed to address the limitations faced by current treatment standards, with mRNA-based therapy emerging as a promising solution. Highly flexible, scalable and cost-effective, mRNA therapy is proving to be a compelling vaccine platform against viruses. Likewise, mRNA vaccines show similar promise against cancer as a platform capable of encoding multiple antigens for a diverse array of cancers, including those that are patient specific as a novel form of personalized medicine. In this review, the molecular mechanisms, biotechnological aspects, and clinical developments of mRNA vaccines against viral infections and cancer are discussed to provide an informative update on the current state of mRNA therapy research.
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Affiliation(s)
- Reese Jalal Ladak
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Alexander J. He
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, United Kingdom
| | - Yu-Hsun Huang
- Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
| | - Yu Ding
- Department of Biochemistry, McGill University, Montreal, QC, Canada
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14
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Zhou S, Fan C, Zeng Z, Young KH, Li Y. Clinical and Immunological Effects of p53-Targeting Vaccines. Front Cell Dev Biol 2021; 9:762796. [PMID: 34805170 PMCID: PMC8595300 DOI: 10.3389/fcell.2021.762796] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor T cells, is one of the most promising approaches to treat cancer. Vaccines have been effective in preventing cancers like liver cancer and cervical cancer with a viral etiology. Instead of preventing disease, therapeutic cancer vaccines mobilize the immune system to attack existing cancer. p53 is dysregulated in the majority of human cancers and is a highly promising target for cancer vaccines. Over twenty clinical trials have targeted p53 in malignant diseases using vaccines. In this work, we review the progress of vaccinations with p53 or its peptides as the antigens and summarize the clinical and immunological effects of p53-targeting vaccines from clinical trials. The delivery platforms include p53 peptides, viral vectors, and dendritic cells pulsed with short peptides or transduced by p53-encoding viruses. These studies shed light on the feasibility, safety, and clinical benefit of p53 vaccination in select groups of patients, implicating that p53-targeting vaccines warrant further investigations in experimental animals and human studies.
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Affiliation(s)
- Shan Zhou
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Chunmei Fan
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, China
| | - Zhaoyang Zeng
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, China
| | - Ken H. Young
- Hematopathology Division, Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Yong Li
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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15
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Zhang Y, Yu X, Liu Q, Gong H, Chen AA, Zheng H, Zhong S, Li Y. SAGE1: a Potential Target Antigen for Lung Cancer T-Cell Immunotherapy. Mol Cancer Ther 2021; 20:2302-2313. [PMID: 34465596 DOI: 10.1158/1535-7163.mct-21-0203] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/17/2021] [Accepted: 08/25/2021] [Indexed: 12/24/2022]
Abstract
A fundamental understanding of cancer-specific antigens is crucial for successful T-cell immunotherapy. Sarcoma antigen 1 (SAGE1) is a cancer/testis antigen that has not yet been verified for T-cell immunotherapy applications. Here, we examined SAGE1 RNA expression and carried out IHC analyses, revealing that SAGE1 is expressed in 50% of non-small cell lung-cancer samples (n = 40). To verify the immunogenicity of SAGE1, we discovered a novel HLA-A*24:02 (HLA-A24)-restricted SAGE1 epitope (SAGE1597-606, VFSTAPPAFI) using mass spectrometry and identified SAGE1597-606-specific T-cell clones and T-cell receptors (TCR) from peripheral bloods of HLA-A24+ donors. The highest affinity TCR VF3 (KD = 4.3 μM) demonstrated the highest antitumor potency. Moreover, VF3-transduced T cells mediated the efficient killing of HLA-A24+/SAGE1+ tumor cells in vitro and effectively inhibited the growth of lung cancer xenografts in mice. Together, our data suggest that SAGE1 could be a target for T-cell immunotherapies against lung cancer, while its specific TCRs could be candidates for developing reagents to treat SAGE1+ tumors.
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Affiliation(s)
- Yajing Zhang
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaohong Yu
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China
| | - Qiuping Liu
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China
| | - Haiping Gong
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China
| | - An-An Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
| | - Hongjun Zheng
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China
| | - Shi Zhong
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China.
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China.
- University of Chinese Academy of Sciences, Beijing, China
- Xiangxue Pharmaceutical Co., Ltd., Guangzhou, Guangdong, China
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16
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Xu Y, Su GH, Ma D, Xiao Y, Shao ZM, Jiang YZ. Technological advances in cancer immunity: from immunogenomics to single-cell analysis and artificial intelligence. Signal Transduct Target Ther 2021; 6:312. [PMID: 34417437 PMCID: PMC8377461 DOI: 10.1038/s41392-021-00729-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/06/2021] [Accepted: 07/18/2021] [Indexed: 02/07/2023] Open
Abstract
Immunotherapies play critical roles in cancer treatment. However, given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies, more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment (TIME). Tumor immunomics refers to the integrated study of the TIME using immunogenomics, immunoproteomics, immune-bioinformatics, and other multi-omics data reflecting the immune states of tumors, which has relied on the rapid development of next-generation sequencing. High-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune cells and predicting tumor antigens, referring to immunogenomics. However, as bulk sequencing represents the average characteristics of a heterogeneous cell population, it fails to distinguish distinct cell subtypes. Single-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture investigations. In addition, radiomics and digital pathology-based deep learning models largely contribute to research on cancer immunity. These artificial intelligence technologies have performed well in predicting response to immunotherapy, with profound significance in cancer therapy. In this review, we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics, single-cell and artificial intelligence, and present prospects for future research.
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Affiliation(s)
- Ying Xu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guan-Hua Su
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ding Ma
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yi Xiao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Yi-Zhou Jiang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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17
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Bogen JP, Grzeschik J, Jakobsen J, Bähre A, Hock B, Kolmar H. Treating Bladder Cancer: Engineering of Current and Next Generation Antibody-, Fusion Protein-, mRNA-, Cell- and Viral-Based Therapeutics. Front Oncol 2021; 11:672262. [PMID: 34123841 PMCID: PMC8191463 DOI: 10.3389/fonc.2021.672262] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/11/2021] [Indexed: 01/02/2023] Open
Abstract
Bladder cancer is a frequent malignancy and has a clinical need for new therapeutic approaches. Antibody and protein technologies came a long way in recent years and new engineering approaches were applied to generate innovative therapeutic entities with novel mechanisms of action. Furthermore, mRNA-based pharmaceuticals recently reached the market and CAR-T cells and viral-based gene therapy remain a major focus of biomedical research. This review focuses on the engineering of biologics, particularly therapeutic antibodies and their application in preclinical development and clinical trials, as well as approved monoclonal antibodies for the treatment of bladder cancer. Besides, newly emerging entities in the realm of bladder cancer like mRNA, gene therapy or cell-based therapeutics are discussed and evaluated. As many discussed molecules exhibit unique mechanisms of action based on innovative protein engineering, they reflect the next generation of cancer drugs. This review will shed light on the engineering strategies applied to develop these next generation treatments and provides deeper insights into their preclinical profiles, clinical stages, and ongoing trials. Furthermore, the distribution and expression of the targeted antigens and the intended mechanisms of action are elucidated.
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Affiliation(s)
- Jan P Bogen
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Darmstadt, Germany.,Ferring Darmstadt Laboratory, Biologics Technology and Development, Darmstadt, Germany
| | - Julius Grzeschik
- Ferring Darmstadt Laboratory, Biologics Technology and Development, Darmstadt, Germany
| | - Joern Jakobsen
- Ferring Pharmaceuticals, International PharmaScience Center, Copenhagen, Denmark
| | - Alexandra Bähre
- Ferring Pharmaceuticals, International PharmaScience Center, Copenhagen, Denmark
| | - Björn Hock
- Global Pharmaceutical Research and Development, Ferring International Center S.A., Saint-Prex, Switzerland
| | - Harald Kolmar
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Darmstadt, Germany
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18
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Ragone C, Manolio C, Cavalluzzo B, Mauriello A, Tornesello ML, Buonaguro FM, Castiglione F, Vitagliano L, Iaccarino E, Ruvo M, Tagliamonte M, Buonaguro L. Identification and validation of viral antigens sharing sequence and structural homology with tumor-associated antigens (TAAs). J Immunother Cancer 2021; 9:e002694. [PMID: 34049932 PMCID: PMC8166618 DOI: 10.1136/jitc-2021-002694] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND The host's immune system develops in equilibrium with both cellular self-antigens and non-self-antigens derived from microorganisms which enter the body during lifetime. In addition, during the years, a tumor may arise presenting to the immune system an additional pool of non-self-antigens, namely tumor antigens (tumor-associated antigens, TAAs; tumor-specific antigens, TSAs). METHODS In the present study, we looked for homology between published TAAs and non-self-viral-derived epitopes. Bioinformatics analyses and ex vivo immunological validations have been performed. RESULTS Surprisingly, several of such homologies have been found. Moreover, structural similarities between paired TAAs and viral peptides as well as comparable patterns of contact with HLA and T cell receptor (TCR) α and β chains have been observed. Therefore, the two classes of non-self-antigens (viral antigens and tumor antigens) may converge, eliciting cross-reacting CD8+ T cell responses which possibly drive the fate of cancer development and progression. CONCLUSIONS An established antiviral T cell memory may turn out to be an anticancer T cell memory, able to control the growth of a cancer developed during the lifetime if the expressed TAA is similar to the viral epitope. This may ultimately represent a relevant selective advantage for patients with cancer and may lead to a novel preventive anticancer vaccine strategy.
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Affiliation(s)
- Concetta Ragone
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Carmen Manolio
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Beatrice Cavalluzzo
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Angela Mauriello
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Maria Lina Tornesello
- Esperimental Oncology - Molecular Biology and Viral Oncogenesis, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Franco M Buonaguro
- Esperimental Oncology - Molecular Biology and Viral Oncogenesis, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | | | | | | | - Menotti Ruvo
- Institute for Biostructures and Bioimages, CNR, Roma, Italy
| | - Maria Tagliamonte
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
| | - Luigi Buonaguro
- Experimental Oncology - Innovative Immunological Models, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale"- IRCCS, Naples, Italy
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19
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Comprehensive mutagenesis identifies the peptide repertoire of a p53 T-cell receptor mimic antibody that displays no toxicity in mice transgenic for human HLA-A*0201. PLoS One 2021; 16:e0249967. [PMID: 33836029 PMCID: PMC8034716 DOI: 10.1371/journal.pone.0249967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/11/2021] [Indexed: 11/24/2022] Open
Abstract
T-cell receptor mimic (TCRm) antibodies have expanded the repertoire of antigens targetable by monoclonal antibodies, to include peptides derived from intracellular proteins that are presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface. We have previously used this approach to target p53, which represents a valuable target for cancer immunotherapy because of the high frequency of its deregulation by mutation or other mechanisms. The T1-116C TCRm antibody targets the wild type p5365-73 peptide (RMPEAAPPV) presented by HLA-A*0201 (HLA-A2) and exhibited in vivo efficacy against triple receptor negative breast cancer xenografts. Here we report a comprehensive mutational analysis of the p53 RMPEAAPPV peptide to assess the T1-116C epitope and its peptide specificity. Antibody binding absolutely required the N-terminal arginine residue, while amino acids in the center of the peptide contributed little to specificity. Data mining the immune epitope database with the T1-116C binding consensus and validation of peptide recognition using the T2 stabilization assay identified additional tumor antigens targeted by T1-116C, including WT1, gp100, Tyrosinase and NY-ESO-1. Most peptides recognized by T1-116C were conserved in mice and human HLA-A2 transgenic mice showed no toxicity when treated with T1-116C in vivo. We conclude that comprehensive validation of TCRm antibody target specificity is critical for assessing their safety profile.
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20
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Davari K, Holland T, Prassmayer L, Longinotti G, Ganley KP, Pechilis LJ, Diaconu I, Nambiar PR, Magee MS, Schendel DJ, Sommermeyer D, Ellinger C. Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy. J Immunother Cancer 2021; 9:e002035. [PMID: 33771892 PMCID: PMC7996660 DOI: 10.1136/jitc-2020-002035] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The cancer-testis antigen MAGE-A4 is an attractive target for T-cell-based immunotherapy, especially for indications with unmet clinical need like non-small cell lung or triple-negative breast cancer. METHODS An unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (HLA)-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high-avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies. RESULTS A MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation. CONCLUSION The extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8+ and CD4+ T cells could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T-cell subsets that goes beyond what is currently tested in the clinic.
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MESH Headings
- A549 Cells
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- CD8 Antigens/genetics
- CD8 Antigens/immunology
- CD8 Antigens/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/transplantation
- Coculture Techniques
- Cytotoxicity, Immunologic
- Female
- HEK293 Cells
- HLA-A2 Antigen/immunology
- HLA-A2 Antigen/metabolism
- Humans
- Immunodominant Epitopes
- Immunotherapy, Adoptive
- K562 Cells
- Mice, Inbred NOD
- Mice, SCID
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Neoplasm Proteins/metabolism
- Neoplasms/genetics
- Neoplasms/immunology
- Neoplasms/metabolism
- Neoplasms/therapy
- Phenotype
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- Tumor Burden
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- Kathrin Davari
- Medigene Immunotherapies GmbH, Planegg-Martinsried, Germany
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21
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Tsuji T, Gnjatic S. Split T-cell tolerance as a guide for the development of tumor antigen-specific immunotherapy. Oncoimmunology 2021; 1:405-407. [PMID: 22737632 PMCID: PMC3382850 DOI: 10.4161/onci.19310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Tumor antigens NY-ESO-1 and p53 both frequently induce spontaneous serum antibody in cancer patients. While NY-ESO-1-specific CD8+ and CD4+ circulating T-cells occur mainly in NY-ESO-1-seropositive patients, p53-specific circulating CD8+ and CD4+ T-cells are respectively undetectable and common in most individuals. Understanding T-cell split tolerance can help define suitable targets for immunotherapy.
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Affiliation(s)
- Takemasa Tsuji
- Ludwig Institute for Cancer Research Ltd.; New York Branch at Memorial Sloan-Kettering Cancer Center; New York, NY USA
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22
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Fridman A, Finnefrock AC, Peruzzi D, Pak I, La Monica N, Bagchi A, Casimiro DR, Ciliberto G, Aurisicchio L. An efficient T-cell epitope discovery strategy using in silico prediction and the iTopia assay platform. Oncoimmunology 2021; 1:1258-1270. [PMID: 23243589 PMCID: PMC3518498 DOI: 10.4161/onci.21355] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Functional T-cell epitope discovery is a key process for the development of novel immunotherapies, particularly for cancer immunology. In silico epitope prediction is a common strategy to try to achieve this objective. However, this approach suffers from a significant rate of false-negative results and epitope ranking lists that often are not validated by practical experience. A high-throughput platform for the identification and prioritization of potential T-cell epitopes is the iTopia(TM) Epitope Discovery System(TM), which allows measuring binding and stability of selected peptides to MHC Class I molecules. So far, the value of iTopia combined with in silico epitope prediction has not been investigated systematically. In this study, we have developed a novel in silico selection strategy based on three criteria: (1) predicted binding to one out of five common MHC Class I alleles; (2) uniqueness to the antigen of interest; and (3) increased likelihood of natural processing. We predicted in silico and characterized by iTopia 225 candidate T-cell epitopes and fixed-anchor analogs from three human tumor-associated antigens: CEA, HER2 and TERT. HLA-A2-restricted fragments were further screened for their ability to induce cell-mediated responses in HLA-A2 transgenic mice. The iTopia binding assay was only marginally informative while the stability assay proved to be a valuable experimental screening method complementary to in silico prediction. Thirteen novel T-cell epitopes and analogs were characterized and additional potential epitopes identified, providing the basis for novel anticancer immunotherapies. In conclusion, we show that combination of in silico prediction and an iTopia-based assay may be an accurate and efficient method for MHC Class I epitope discovery among tumor-associated antigens.
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23
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Ecsedi M, McAfee MS, Chapuis AG. The Anticancer Potential of T Cell Receptor-Engineered T Cells. Trends Cancer 2021; 7:48-56. [PMID: 32988787 PMCID: PMC7770096 DOI: 10.1016/j.trecan.2020.09.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/07/2020] [Accepted: 09/04/2020] [Indexed: 12/19/2022]
Abstract
Adoptively transferred T cell receptor (TCR)-transgenic T cells (TCR-T cells) are not restricted by cell surface expression of their targets and are therefore poised to become a main pillar of cellular cancer immunotherapies. Addressing clinical and laboratory data, we discuss emerging features for the efficient deployment of novel TCR-T therapies, such as selection of ideal TCRs targeting validated epitopes with well-characterized cancer cell expression and processing, enhancing TCR-T effector function, trafficking, expansion, persistence, and memory formation by strategic selection of substrate cells, and gene-engineering with synthetic co-stimulatory circuits. Overall, a better understanding of the relevant mechanisms of action and resistance will help prioritize the vast array of potential TCR-T optimizations for future clinical products.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Autoantigens/genetics
- Autoantigens/immunology
- Autoantigens/metabolism
- Clinical Trials as Topic
- Disease Models, Animal
- Humans
- Immunotherapy, Adoptive/methods
- Mice
- Mutation
- Neoplasms/genetics
- Neoplasms/immunology
- Neoplasms/therapy
- Protein Engineering
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- T-Lymphocytes, Cytotoxic/transplantation
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- T-Lymphocytes, Helper-Inducer/transplantation
- Treatment Outcome
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Affiliation(s)
- Matyas Ecsedi
- Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA
| | - Megan S McAfee
- Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA
| | - Aude G Chapuis
- Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
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24
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Buonaguro L, Tagliamonte M. Selecting Target Antigens for Cancer Vaccine Development. Vaccines (Basel) 2020; 8:vaccines8040615. [PMID: 33080888 PMCID: PMC7711972 DOI: 10.3390/vaccines8040615] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
One of the principal goals of cancer immunotherapy is the development of efficient therapeutic cancer vaccines that are able to elicit an effector as well as memory T cell response specific to tumor antigens. In recent years, the attention has been focused on the personalization of cancer vaccines. However, the efficacy of therapeutic cancer vaccines is still disappointing despite the large number of vaccine strategies targeting different tumors that have been evaluated in recent years. While the preclinical data have frequently shown encouraging results, clinical trials have not provided satisfactory data to date. The main reason for such failures is the complexity of identifying specific target tumor antigens that should be unique or overexpressed only by the tumor cells compared to normal cells. Most of the tumor antigens included in cancer vaccines are non-mutated overexpressed self-antigens, eliciting mainly T cells with low-affinity T cell receptors (TCR) unable to mediate an effective anti-tumor response. In this review, the target tumor antigens employed in recent years in the development of therapeutic cancer vaccine strategies are described, along with potential new classes of tumor antigens such as the human endogenous retroviral elements (HERVs), unconventional antigens, and/or heteroclitic peptides.
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25
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Abstract
Adoptive T cell therapy has proven effective against hematologic malignancies and demonstrated efficacy against a variety of solid tumors in preclinical studies and clinical trials. Nonetheless, antitumor responses against solid tumors remain modest, highlighting the need to enhance the effectiveness of this therapy. Genetic modification of T cells with RNA has been explored to enhance T-cell antigen specificity, effector function, and migration to tumor sites, thereby potentiating antitumor immunity. This review describes the rationale for RNA-electroporated T cell modifications and provides an overview of their applications in preclinical and clinical investigations for the treatment of hematologic malignancies and solid tumors.
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Affiliation(s)
- Fernanda Pohl-Guimarães
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Lan B Hoang-Minh
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Duane A Mitchell
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
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26
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Meunier S, de Bourayne M, Hamze M, Azam A, Correia E, Menier C, Maillère B. Specificity of the T Cell Response to Protein Biopharmaceuticals. Front Immunol 2020; 11:1550. [PMID: 32793213 PMCID: PMC7387651 DOI: 10.3389/fimmu.2020.01550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/12/2020] [Indexed: 12/17/2022] Open
Abstract
The anti-drug antibody (ADA) response is an undesired humoral response raised against protein biopharmaceuticals (BPs) which can dramatically disturb their therapeutic properties. One particularity of the ADA response resides in the nature of the immunogens, which are usually human(ized) proteins and are therefore expected to be tolerated. CD4 T cells initiate, maintain and regulate the ADA response and are therefore key players of this immune response. Over the last decade, advances have been made in characterizing the T cell responses developed by patients treated with BPs. Epitope specificity and phenotypes of BP-specific T cells have been reported and highlight the effector and regulatory roles of T cells in the ADA response. BP-specific T cell responses are assessed in healthy subjects to anticipate the immunogenicity of BP prior to their testing in clinical trials. Immunogenicity prediction, also called preclinical immunogenicity assessment, aims at identifying immunogenic BPs and immunogenic BP sequences before any BP injection in humans. All of the approaches that have been developed to date rely on the detection of BP-specific T cells in donors who have never been exposed to BPs. The number of BP-specific T cells circulating in the blood of these donors is therefore limited. T cell assays using cells collected from healthy donors might reveal the weak tolerance induced by BPs, whose endogenous form is expressed at a low level. These BPs have a complete human sequence, but the level of their endogenous form appears insufficient to promote the negative selection of autoreactive T cell clones. Multiple T cell epitopes have also been identified in therapeutic antibodies and some other BPs. The pattern of identified T cell epitopes differs across the antibodies, notwithstanding their humanized, human or chimeric nature. However, in all antibodies, the non-germline amino acid sequences mainly found in the CDRs appear to be the main driver of immunogenicity, provided they can be presented by HLA class II molecules. Considering the fact that the BP field is expanding to include new formats and gene and cell therapies, we face new challenges in understanding and mastering the immunogenicity of new biological products.
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Affiliation(s)
- Sylvain Meunier
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Marie de Bourayne
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Moustafa Hamze
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Aurélien Azam
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Evelyne Correia
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Catherine Menier
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
| | - Bernard Maillère
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France
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27
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Echchannaoui H, Petschenka J, Ferreira EA, Hauptrock B, Lotz-Jenne C, Voss RH, Theobald M. A Potent Tumor-Reactive p53-Specific Single-Chain TCR without On- or Off-Target Autoimmunity In Vivo. Mol Ther 2018; 27:261-271. [PMID: 30528087 DOI: 10.1016/j.ymthe.2018.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/25/2018] [Accepted: 11/07/2018] [Indexed: 12/27/2022] Open
Abstract
Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264-272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2.1 that closely mimic the human setting. Specifically, we showed that adoptive transfer of optimized scTCR-redirected T cells does not induce on-target and off-target autoimmunity. Furthermore, ACT resulted in full tumor protection and led to a long-lived effective, antigen-specific memory T cell response in syngeneic and xenograft models. Taken together, the study demonstrated that our scTCR specific for the broadly expressed tumor-associated antigen p53(264-272) can eradicate p53+A2.1+ tumor cells without inducing off-target or self-directed toxicities in mouse models of ACT. These data strongly support the improved safety and therapeutic efficacy of high-affinity p53scTCR for TCR-based immunotherapy of p53-associated malignancies.
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Affiliation(s)
- Hakim Echchannaoui
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center (UMC), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; German Consortium for Translational Cancer Research (DKTK), Frankfurt/Mainz, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Jutta Petschenka
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Edite Antunes Ferreira
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Beate Hauptrock
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Carina Lotz-Jenne
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Ralf-Holger Voss
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Matthias Theobald
- Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center (UMC), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; German Consortium for Translational Cancer Research (DKTK), Frankfurt/Mainz, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
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28
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Next Generation Cancer Vaccines-Make It Personal! Vaccines (Basel) 2018; 6:vaccines6030052. [PMID: 30096953 PMCID: PMC6161279 DOI: 10.3390/vaccines6030052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/23/2018] [Accepted: 08/07/2018] [Indexed: 12/30/2022] Open
Abstract
Dramatic success in cancer immunotherapy has been achieved over the last decade with the introduction of checkpoint inhibitors, leading to response rates higher than with chemotherapy in certain cancer types. These responses are often restricted to cancers that have a high mutational burden and show pre-existing T-cell infiltrates. Despite extensive efforts, therapeutic vaccines have been mostly unsuccessful in the clinic. With the introduction of next generation sequencing, the identification of individual mutations is possible, enabling the production of personalized cancer vaccines. Combining immune check point inhibitors to overcome the immunosuppressive microenvironment and personalized cancer vaccines for directing the host immune system against the chosen antigens might be a promising treatment strategy.
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29
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Chen L, Tian Y, Zhan K, Chen A, Weng Z, Huang J, Li Y, Sun Y, Zheng H, Li Y. A humanized TCR retaining authentic specificity and affinity conferred potent anti-tumour cytotoxicity. Immunology 2018; 155:123-136. [PMID: 29645087 DOI: 10.1111/imm.12935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 03/05/2018] [Accepted: 03/28/2018] [Indexed: 12/14/2022] Open
Abstract
The affinity of T-cell receptor (TCR) determines the efficacy of TCR-based immunotherapy. By using human leucocyte antigen (HLA)-A*02 transgenic mice, a TCR was generated previously specific for human tumour testis antigen peptide MAGE-A3112-120 (KVAELVHFL) HLA-A*02 complex. We developed an approach to humanize the murine TCR by replacing the mouse framework with sequences of folding optimized human TCR variable domains for retaining binding affinity. The resultant humanized TCR exhibited higher affinity and conferred better anti-tumour activity than its parent murine MAGE-A3 TCR (SRm1). In addition, the affinity of humanized TCR was enhanced further to achieve improved T-cell activation. Our studies demonstrated that the human TCR variable domain frameworks could provide support for complementarity-determining regions from a murine TCR, and retain the original binding activity. It could be used as a generic approach of TCR humanization.
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Affiliation(s)
- Lin Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ye Tian
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Kai Zhan
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, China
| | - Anan Chen
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Zhiming Weng
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, China
| | - Jiao Huang
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, China
| | - Yanyan Li
- School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Yongjie Sun
- Institute of Health Sciences, Anhui University, Hefei, China
| | - Hongjun Zheng
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, China
| | - Yi Li
- State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China.,XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, China
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30
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An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells. Oncotarget 2018; 7:21199-221. [PMID: 27028870 PMCID: PMC5008279 DOI: 10.18632/oncotarget.8385] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 03/10/2016] [Indexed: 12/29/2022] Open
Abstract
Immunotherapy of cancer envisions the adoptive transfer of T-cells genetically engineered with tumor-specific heterodimeric α/β T-cell receptors (TCRα/β). However, potential mispairing of introduced TCRα/β-chains with endogenous β/α-ones may evoke unpredictable autoimmune reactivities. A novel single chain (sc)TCR format relies on the fusion of the Vα-Linker-Vβ-fragment to the TCR Cβ-domain and coexpression of the TCR Cα-domain capable of recruiting the natural CD3-complex for full and hence, native T-cell signaling. Here, we tested whether such a gp100(280-288)- or p53(264-272) tumor antigen-specific scTCR is still prone to mispairing with TCRα. In a human Jurkat-76 T-cell line lacking endogenous TCRs, surface expression and function of a scTCR could be reconstituted by any cointroduced TCRα-chain indicating mispairing to take place on a molecular basis. In contrast, transduction into human TCRα/β-positive T-cells revealed that mispairing is largely reduced. Competition experiments in Jurkat-76 confirmed the preference of dcTCR to selfpair and to spare scTCR. This also allowed for the generation of dc/scTCR-modified cytomegalovirus/tumor antigen-bispecific T-cells to augment T-cell activation in CMV-infected tumor patients. Residual mispairing was prevented by strenghtening the Vα-Li-Vβ-fragment through the design of a novel disulfide bond between a Vα- and a linker-resident residue close to Vβ. Multimer-stainings, and cytotoxicity-, IFNγ-secretion-, and CFSE-proliferation-assays, the latter towards dendritic cells endogenously processing RNA-electroporated gp100 antigen proved the absence of hybrid scTCR/TCRα-formation without impairing avidity of scTCR/Cα in T-cells. Moreover, a fragile cytomegalovirus pp65(495-503)-specific scTCR modified this way acquired enhanced cytotoxicity. Thus, optimized scTCR/Cα inhibits residual TCR mispairing to accomplish safe adoptive immunotherapy for bulk endogenous TCRα/β-positive T-cells.
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31
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Hu Z, Ott PA, Wu CJ. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat Rev Immunol 2017; 18:168-182. [PMID: 29226910 DOI: 10.1038/nri.2017.131] [Citation(s) in RCA: 718] [Impact Index Per Article: 89.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy.
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Affiliation(s)
- Zhuting Hu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
| | - Patrick A Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Harvard Medical School, Boston, Massachusetts 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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32
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Cytotoxic T lymphocytes promote cytarabine-induced acute myeloid leukemia cell apoptosis via inhibiting Bcl-2 expression. Exp Ther Med 2017; 14:1081-1085. [PMID: 28810561 PMCID: PMC5526043 DOI: 10.3892/etm.2017.4620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 03/17/2017] [Indexed: 12/22/2022] Open
Abstract
Acute myeloid leukemia (AML) remains difficult to cure due to its drug tolerance and refractoriness. Immunotherapy is a growing area of cancer research, which has been applied for the treatment of numerous types of cancer, including leukemia. The present study generated AML cell-specific cytotoxic T lymphocytes (CTLs) in vitro and investigated the effect of combining CTL treatment with one of the most commonly used drugs for the treatment of hematological malignancies, cytarabine, on AML cell apoptosis. Firstly, it was observed that monocyte-depleted peripheral blood lymphocytes from healthy donors could be used to generate large numbers of CD3+CD8+ CTLs through immune stimulation. These CD3+CD8+ CTLs could effectively recognize and induce the apoptosis of human Kasumi-3 AML cells. In addition, cytarabine-induced AML cell apoptosis was enhanced by CTL treatment. Western blotting revealed that Bcl-2 expression was downregulated in AML cells following cytarabine and CTL treatment, indicating that the synergistic effect of this treatment on AML cell apoptosis is due to the downregulation of Bcl-2. These results highlight the potential application of CTL immunotherapy for the treatment of AML. Further studies optimizing the specificity and potency of CTLs, and identifying favorable combinations with other chemotherapeutic drug are required.
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33
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Menez-Jamet J, Gallou C, Rougeot A, Kosmatopoulos K. Optimized tumor cryptic peptides: the basis for universal neo-antigen-like tumor vaccines. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:266. [PMID: 27563653 DOI: 10.21037/atm.2016.05.15] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The very impressive clinical results recently obtained in cancer patients treated with immune response checkpoint inhibitors boosted the interest in immunotherapy as a therapeutic choice in cancer treatment. However, these inhibitors require a pre-existing tumor specific immune response and the presence of tumor infiltrating T cells to be efficient. This immune response can be triggered by cancer vaccines. One of the main issues in tumor vaccination is the choice of the right antigen to target. All vaccines tested to date targeted tumor associated antigens (TAA) that are self-antigens and failed to show a clinical efficacy because of the immune self-tolerance to TAA. A new class of tumor antigens has recently been described, the neo-antigens that are created by point mutations of tumor expressing proteins and are recognized by the immune system as non-self. Neo-antigens exhibit two main properties: they are not involved in the immune self-tolerance process and are immunogenic. However, the majority of the neo-antigens are patient specific and their use as cancer vaccines requires their previous identification in each patient individualy that can be done only in highly specialized research centers. It is therefore evident that neo-antigens cannot be used for patient vaccination worldwide. This raises the question of whether we can find neo-antigen like vaccines, which would not be patient specific. In this review we show that optimized cryptic peptides from TAA are neo-antigen like peptides. Optimized cryptic peptides are recognized by the immune system as non-self because they target self-cryptic peptides that escape self-tolerance; in addition they are strongly immunogenic because their sequence is modified in order to enhance their affinity for the HLA molecule. The first vaccine based on the optimized cryptic peptide approach, Vx-001, which targets the widely expressed tumor antigen telomerase reverse transcriptase (TERT), has completed a large phase I clinical study and is currently being tested in a randomized phase II trial in non-small cell lung cancer (NSCLC) patients.
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Affiliation(s)
| | | | - Aude Rougeot
- Vaxon Biotech, 3 rue de l'Arrivée 75015, Paris, France
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34
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Sandri S, Bobisse S, Moxley K, Lamolinara A, De Sanctis F, Boschi F, Sbarbati A, Fracasso G, Ferrarini G, Hendriks RW, Cavallini C, Scupoli MT, Sartoris S, Iezzi M, Nishimura MI, Bronte V, Ugel S. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies. Cancer Res 2016; 76:2540-51. [DOI: 10.1158/0008-5472.can-15-2318] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 01/24/2016] [Indexed: 11/16/2022]
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35
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36
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Obenaus M, Leitão C, Leisegang M, Chen X, Gavvovidis I, van der Bruggen P, Uckert W, Schendel DJ, Blankenstein T. Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat Biotechnol 2015; 33:402-7. [PMID: 25774714 DOI: 10.1038/nbt.3147] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 01/12/2015] [Indexed: 12/21/2022]
Abstract
Identifying T-cell receptors (TCRs) that bind tumor-associated antigens (TAAs) with optimal affinity is a key bottleneck in the development of adoptive T-cell therapy of cancer. TAAs are unmutated self proteins, and T cells bearing high-affinity TCRs specific for such antigens are commonly deleted in the thymus. To identify optimal-affinity TCRs, we generated antigen-negative humanized mice with a diverse human TCR repertoire restricted to the human leukocyte antigen (HLA) A*02:01 (ref. 3). These mice were immunized with human TAAs, for which they are not tolerant, allowing induction of CD8⁺ T cells with optimal-affinity TCRs. We isolate TCRs specific for the cancer/testis (CT) antigen MAGE-A1 (ref. 4) and show that two of them have an anti-tumor effect in vivo. By comparison, human-derived TCRs have lower affinity and do not mediate substantial therapeutic effects. We also identify optimal-affinity TCRs specific for the CT antigen NY-ESO. Our humanized mouse model provides a useful tool for the generation of optimal-affinity TCRs for T-cell therapy.
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Affiliation(s)
| | | | | | - Xiaojing Chen
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | | | - Pierre van der Bruggen
- 1] Ludwig Institute for Cancer Research and WELBIO, Brussels, Belgium. [2] De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Wolfgang Uckert
- 1] Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. [2] Institute of Biology, Humboldt University, Berlin, Germany
| | | | - Thomas Blankenstein
- 1] Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. [2] Institute of Immunology, Charité Campus Buch, Berlin, Germany
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37
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Bhatia A, Kumar Y. Cellular and molecular mechanisms in cancer immune escape: a comprehensive review. Expert Rev Clin Immunol 2013; 10:41-62. [PMID: 24325346 DOI: 10.1586/1744666x.2014.865519] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune escape is the final phase of cancer immunoediting process wherein cancer modulates our immune system to escape from being destroyed by it. Many cellular and molecular events govern the cancer's evasion of host immune response. The tumor undergoes continuous remodeling at the genetic, epigenetic and metabolic level to acquire resistance to apoptosis. At the same time, it effectively modifies all the components of the host's immunome so as to escape from its antitumor effects. Moreover, it induces accumulation of suppressive cells like Treg and myeloid derived suppressor cells and factors which also enable it to elude the immune system. Recent research in this area helps in defining the role of newer players like miRNAs and exosomes in immune escape. The immunotherapeutic approaches developed to target the escape phase appear quite promising; however, the quest for a perfect therapeutic agent that can achieve maximum cure with minimal toxicity continues.
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Affiliation(s)
- Alka Bhatia
- Department of Experimental Medicine & Biotechnology, PGIMER, Chandigarh-160012, India
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38
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Uttenthal B, Martinez-Davila I, Ivey A, Craddock C, Chen F, Virchis A, Kottaridis P, Grimwade D, Khwaja A, Stauss H, Morris EC. Wilms' Tumour 1 (WT1) peptide vaccination in patients with acute myeloid leukaemia induces short-lived WT1-specific immune responses. Br J Haematol 2013; 164:366-75. [PMID: 24422723 PMCID: PMC4253125 DOI: 10.1111/bjh.12637] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 09/06/2013] [Indexed: 12/04/2022]
Abstract
Wilms’ Tumour 1 (WT1) is a zinc finger transcription factor that is over-expressed in acute myeloid leukaemia (AML). Its restricted expression in normal tissues makes it a promising target for novel immunotherapies aiming to accentuate the cytotoxic T lymphocyte (CTL) response against AML. Here we report a phase I/II clinical trial of subcutaneous peptide vaccination with two separate HLA-A2-binding peptide epitopes derived from WT1, together with a pan-DR binding peptide epitope (PADRE), in Montanide adjuvant. Eight HLA-A2-positive patients with poor risk AML received five vaccination cycles at 3-weekly intervals. The three cohorts received 0·3, 0·6 and 1 mg of each peptide, respectively. In six patients, WT1-specific CTL responses were detected using enzyme-linked immunosorbent spot assays and pWT126/HLA-A*0201 tetramer staining, after ex vivo stimulation with the relevant WT1 peptides. However, re-stimulation of these WT1-specific T cells failed to elicit secondary expansion in all four patients tested, suggesting that the WT1-specific CD8+ T cells generated following vaccination may be functionally impaired. No correlation was observed between peptide dose, cellular immune response, reduction in WT1mRNA expression and clinical response. Larger studies are indicated to confirm these findings.
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Affiliation(s)
- Benjamin Uttenthal
- UCL Division of Infection and Immunity, Department of Immunology, University College London, London, UK
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39
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Baia GS, Caballero OL, Ho JSY, Zhao Q, Cohen T, Binder ZA, Salmasi V, Gallia GL, Quinones-Hinojosa A, Olivi A, Brem H, Burger P, Strausberg RL, Simpson AJG, Eberhart CG, Riggins GJ. NY-ESO-1 expression in meningioma suggests a rationale for new immunotherapeutic approaches. Cancer Immunol Res 2013; 1:296-302. [PMID: 24777967 DOI: 10.1158/2326-6066.cir-13-0029] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Meningiomas are the most common primary intracranial tumors. Surgical resection remains the treatment of choice for these tumors. However, a significant number of tumors are not surgically accessible, recur, or become malignant, necessitating the repetition of surgery and sometimes radiation. Chemotherapy is rarely used and is generally not recognized as an effective treatment. Cancer/testis (CT) genes represent a unique class of genes, which are expressed by germ cells, normally silenced in somatic cells, but activated in various cancers. CT proteins can elicit spontaneous immune responses in patients with cancer and this feature makes them attractive targets for immunotherapy-based approaches. We analyzed mRNA expression of 37 testis-restricted CT genes in a discovery set of 18 meningiomas by reverse transcription PCR. The overall frequency of expression of CT genes ranged from 5.6% to 27.8%. The most frequently expressed was NY-ESO-1, in 5 patients (27.8%). We subsequently analyzed NY-ESO-1 protein expression in a larger set of meningiomas by immunohistochemistry and found expression in 108 of 110 cases. In some cases, NY-ESO-1 expression was diffused and homogenous, but in most instances it was heterogeneous. Importantly, NY-ESO-1 expression was positively correlated with higher grade and patients presenting with higher levels of NY-ESO-1 staining had significantly worse disease-free and overall survival. We have also shown that NY-ESO-1 expression may lead to humoral immune response in patients with meningioma. Considering the limited treatment options for patients with meningioma, the potential of NY-ESO-1-based immunotherapy should be explored.
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Affiliation(s)
- Gilson S Baia
- Authors' Affiliations: New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York
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40
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Geironson L, Thuring C, Harndahl M, Rasmussen M, Buus S, Røder G, Paulsson KM. Tapasin facilitation of natural HLA-A and -B allomorphs is strongly influenced by peptide length, depends on stability, and separates closely related allomorphs. THE JOURNAL OF IMMUNOLOGY 2013; 191:3939-47. [PMID: 23980206 DOI: 10.4049/jimmunol.1201741] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Despite an abundance of peptides inside a cell, only a small fraction is ultimately presented by HLA-I on the cell surface. The presented peptides have HLA-I allomorph-specific motifs and are restricted in length. So far, detailed length studies have been limited to few allomorphs. Peptide-HLA-I (pHLA-I) complexes of different allomorphs are qualitatively and quantitatively influenced by tapasin to different degrees, but again, its effect has only been investigated for a small number of HLA-I allomorphs. Although both peptide length and tapasin dependence are known to be important for HLA-I peptide presentation, the relationship between them has never been studied. In this study, we used random peptide libraries from 7- to 13-mers and studied binding in the presence and absence of a recombinant truncated form of tapasin. The data show that HLA-I allomorphs are differentially affected by tapasin, different lengths of peptides generated different amounts of pHLA-I complexes, and HLA-A allomorphs are generally less restricted than HLA-B allomorphs to peptides of the classical length of 8-10 aa. We also demonstrate that tapasin facilitation varies for different peptide lengths, and that the correlation between high degree of tapasin facilitation and low stability is valid for different random peptide mixes of specific lengths. In conclusion, these data show that tapasin has specificity for the combination of peptide length and HLA-I allomorph, and suggest that tapasin promotes formation of pHLA-I complexes with high on and off rates, an important intermediary step in the HLA-I maturation process.
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Affiliation(s)
- Linda Geironson
- Department of Experimental Medical Science, Immunology Section, Lund University, 221 84 Lund, Sweden
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41
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Wooldridge L. Individual MHCI-Restricted T-Cell Receptors are Characterized by a Unique Peptide Recognition Signature. Front Immunol 2013; 4:199. [PMID: 23888160 PMCID: PMC3719040 DOI: 10.3389/fimmu.2013.00199] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 07/03/2013] [Indexed: 11/13/2022] Open
Abstract
Effective immunity requires that a limited TCR repertoire is able to recognize a vast number of foreign peptide-MHCI (peptide-major histocompatibility complex class I) molecules. This challenge is overcome by the ability of individual TCRs to recognize large numbers of peptides. Recently, it was demonstrated that MHCI-restricted TCRs can recognize up to 106 peptides of a defined length. Astonishingly, this remarkable level of promiscuity does not extend to peptides of different lengths, a fundamental observation that has broad implications for CD8+ T-cell immunity. In particular, the findings suggest that effective immunity can only be achieved by mobilization of “length-matched” CD8+ T-cell clonotypes. Overall, recent findings suggest that every TCR is specific for a unique set of peptides, which can be described as a unique “peptide recognition signature” (PRS) and consists of three components: (1) peptide length preference, (2) number of peptides recognized; and, (3) sequence identity (e.g., self versus pathogen derived). In future, the ability to de-convolute peptide recognition signatures across the normal and pathogenic repertoire will be essential for understanding the system requirements for effective CD8+ T-cell immunity and elucidating mechanisms which underlie CD8+ T-cell mediated disease.
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Affiliation(s)
- Linda Wooldridge
- Institute of Infection and Immunity, Cardiff University School of Medicine , Heath Park, Cardiff , UK
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42
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Zeestraten ECM, Speetjens FM, Welters MJP, Saadatmand S, Stynenbosch LFM, Jongen R, Kapiteijn E, Gelderblom H, Nijman HW, Valentijn ARPM, Oostendorp J, Fathers LM, Drijfhout JW, van de Velde CJH, Kuppen PJK, van der Burg SH, Melief CJM. Addition of interferon-α to the p53-SLP® vaccine results in increased production of interferon-γ in vaccinated colorectal cancer patients: a phase I/II clinical trial. Int J Cancer 2012; 132:1581-91. [PMID: 22948952 DOI: 10.1002/ijc.27819] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 08/09/2012] [Indexed: 12/25/2022]
Abstract
We previously established safety and immunogenicity of a p53 synthetic long peptides (p53-SLP®) vaccine. In the current trial, we investigated whether combination of interferon-alpha (IFN-α) with p53-SLP® is both safe and able to improve the induced p53-specific IFN-γ response. Eleven colorectal cancer patients successfully treated for metastatic disease were enrolled in this study. Of these, nine patients completed follow-up after two injections with p53-SLP® together with IFN-α. Safety and p53-specific immune responses were determined before and after vaccination. Furthermore, cryopreserved PBMCs were compared head-to-head to cryopreserved PBMCs obtained in our previous trial with p53-SLP® only. Toxicity of p53-SLP® vaccination in combination with IFN-α was limited to Grade 1 or 2, with predominantly small ongoing swellings at the vaccination site. All patients harbored p53-specific T cells after vaccination and most patients showed p53-specific antibodies. Compared to the previous trial, addition of IFN-α significantly improved the frequency of p53-specific T cells in IFN-γ ELISPOT. Moreover, in this trial, p53-specific T cells were detectable in blood samples of all patients in a direct ex vivo multiparameter flowcytometric assay, opposed to only 2 of 10 patients vaccinated with p53-SLP® only. Finally, patients in this trial displayed a broader p53-specific immunoglobulin-G response, indicating an overall better p53-specific T-helper response. Our study shows that p53-SLP® vaccination combined with IFN-α injection is safe and capable of inducing p53-specific immunity. When compared to a similar trial with p53-SLP® vaccination alone the combination was found to induce significantly more IFN-γ producing p53-specific T cells.
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43
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Buhrman JD, Jordan KR, U'ren L, Sprague J, Kemmler CB, Slansky JE. Augmenting antitumor T-cell responses to mimotope vaccination by boosting with native tumor antigens. Cancer Res 2012; 73:74-85. [PMID: 23161490 DOI: 10.1158/0008-5472.can-12-1005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Vaccination with antigens expressed by tumors is one strategy for stimulating enhanced T-cell responses against tumors. However, these peptide vaccines rarely result in efficient expansion of tumor-specific T cells or responses that protect against tumor growth. Mimotopes, or peptide mimics of tumor antigens, elicit increased numbers of T cells that crossreact with the native tumor antigen, resulting in potent antitumor responses. Unfortunately, mimotopes may also elicit cells that do not crossreact or have low affinity for tumor antigen. We previously showed that one such mimotope of the dominant MHC class I tumor antigen of a mouse colon carcinoma cell line stimulates a tumor-specific T-cell clone and elicits antigen-specific cells in vivo, yet protects poorly against tumor growth. We hypothesized that boosting the mimotope vaccine with the native tumor antigen would focus the T-cell response elicited by the mimotope toward high affinity, tumor-specific T cells. We show that priming T cells with the mimotope, followed by a native tumor-antigen boost, improves tumor immunity compared with T cells elicited by the same prime with a mimotope boost. Our data suggest that the improved tumor immunity results from the expansion of mimotope-elicited tumor-specific T cells that have increased avidity for the tumor antigen. The enhanced T cells are phenotypically distinct and enriched for T-cell receptors previously correlated with improved antitumor immunity. These results suggest that incorporation of native antigen into clinical mimotope vaccine regimens may improve the efficacy of antitumor T-cell responses.
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Affiliation(s)
- Jonathan D Buhrman
- Integrated Department of Immunology, University of Colorado School of Medicine, Denver, CO 80206, USA
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44
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A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J Transl Med 2012; 10:157. [PMID: 22863016 PMCID: PMC3439340 DOI: 10.1186/1479-5876-10-157] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 07/18/2012] [Indexed: 11/10/2022] Open
Abstract
PURPOSE In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. RATIONALE Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR)-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα) is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity. DESIGN Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB) costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features. INNOVATION This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL) is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.
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45
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Wilde S, Sommermeyer D, Leisegang M, Frankenberger B, Mosetter B, Uckert W, Schendel DJ. Human antitumor CD8+ T cells producing Th1 polycytokines show superior antigen sensitivity and tumor recognition. THE JOURNAL OF IMMUNOLOGY 2012; 189:598-605. [PMID: 22689880 DOI: 10.4049/jimmunol.1102165] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Adoptive transfer of T cells expressing transgenic TCR with antitumor specificity provides a hopeful new therapy for patients with advanced cancer. To fulfill a large need for TCR with high affinity and specificity for various tumor entities, we sought to identify parameters for rapid selection of CTL clones with suitable characteristics. Twelve CTL clones displaying different Ag sensitivities for the same peptide-MHC epitope of the melanoma-associated Ag tyrosinase were analyzed in detail. Better MHC-multimer binding and slower multimer release are thought to reflect stronger TCR-peptide-MHC interactions; thus, these parameters would seem well suited to identify higher avidity CTL. However, large disparities were found comparing CTL multimer binding with peptide sensitivity. In contrast, CD8(+) CTL with superior Ag sensitivity mediated good tumor cytotoxicity and also secreted the triple combination of IFN-γ, IL-2, and TNF-α, representing a Th1 pattern often missing in lower avidity CTL. Furthermore, recipient lymphocytes were imbued with high Ag sensitivity, superior tumor recognition, as well as capacity for Th1 polycytokine secretion after transduction with the TCR of a high-avidity CTL. Thus, Th1 polycytokine secretion served as a suitable parameter to rapidly demark cytotoxic CD8(+) T cell clones for further TCR evaluation.
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Affiliation(s)
- Susanne Wilde
- Institute of Molecular Immunology, Helmholtz Center Munich, German
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46
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Quakkelaar ED, Melief CJM. Experience with synthetic vaccines for cancer and persistent virus infections in nonhuman primates and patients. Adv Immunol 2012; 114:77-106. [PMID: 22449779 DOI: 10.1016/b978-0-12-396548-6.00004-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Synthetic vaccines, in particular long synthetic peptides of approximately 25-50 amino acids in length, are attractive for HIV vaccine development and for induction of therapeutic immune responses in patients with (pre-)malignant disorders. In the case of preventive vaccine development against HIV, no major success has been achieved, but the possibilities are by no means exhausted. A long peptide vaccine consisting of 13 overlapping peptides, which together cover the entire length of the two oncogenic proteins E6 and E7 of high-risk human papilloma virus type 16 (HPV16), caused complete regression of all lesions and eradication of virus in 9 out of 20 women with high-grade vulvar intraepithelial neoplasia, a therapy-resistant preneoplastic disorder. The nature and strength of the vaccine-prompted T cell responses were significantly correlated with the clinical response. Synthetic peptide vaccines are attractive, because they allow rational improvement of vaccine design and detailed pharmacokinetic and pharmacodynamic studies not possible with conventional vaccines. Improvements are possible by addition or conjugation of adjuvants, notably TLR ligands, to the synthetic peptides.
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Affiliation(s)
- Esther D Quakkelaar
- Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands
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47
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Simpson AA, Mohammed F, Salim M, Tranter A, Rickinson AB, Stauss HJ, Moss PAH, Steven NM, Willcox BE. Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction. Proc Natl Acad Sci U S A 2011; 108:21176-81. [PMID: 22160697 PMCID: PMC3248497 DOI: 10.1073/pnas.1108422109] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Immunotherapies targeting peptides presented by allogeneic MHC molecules offer the prospect of circumventing tolerance to key tumor-associated self-antigens. However, the degree of antigen specificity mediated by alloreactive T cells, and their ability to discriminate normal tissues from transformed cells presenting elevated antigen levels, is poorly understood. We examined allorecognition of an HLA-A2-restricted Hodgkin's lymphoma-associated antigen and were able to isolate functionally antigen-specific allo-HLA-A2-restricted T cells from multiple donors. Binding and structural studies, focused on a prototypic allo-HLA-A2-restricted T-cell receptor (TCR) termed NB20 derived from an HLA-A3 homozygote, suggested highly peptide-specific allorecognition that was energetically focused on antigen, involving direct recognition of a distinct allopeptide presented within a conserved MHC recognition surface. Although NB20/HLA-A2 affinity was unremarkable, TCR/MHC complexes were very short-lived, consistent with suboptimal TCR triggering and tolerance to low antigen levels. These data provide strong molecular evidence that within the functionally heterogeneous alloreactive repertoire, there is the potential for highly antigen-specific "allo-MHC-restricted" recognition and suggest a kinetic mechanism whereby allo-MHC-restricted T cells may discriminate normal from transformed tissue, thereby outlining a suitable basis for broad-based therapeutic targeting of tolerizing tumor antigens.
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Affiliation(s)
- Amy A. Simpson
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Fiyaz Mohammed
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Mahboob Salim
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Amy Tranter
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Alan B. Rickinson
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Hans J. Stauss
- Division of Infection and Immunity, Department of Immunology, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom
| | - Paul A. H. Moss
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Neil M. Steven
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
| | - Benjamin E. Willcox
- Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
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48
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Recent advance in antigen-specific immunotherapy for acute myeloid leukemia. Clin Dev Immunol 2011; 2011:104926. [PMID: 22028726 PMCID: PMC3199067 DOI: 10.1155/2011/104926] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 08/18/2011] [Indexed: 11/18/2022]
Abstract
Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML.
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49
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Kotsakis A, Vetsika EK, Christou S, Hatzidaki D, Vardakis N, Aggouraki D, Konsolakis G, Georgoulias V, Christophyllakis C, Cordopatis P, Kosmatopoulos K, Mavroudis D. Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: results of an expanded phase II study. Ann Oncol 2011; 23:442-9. [PMID: 21873272 DOI: 10.1093/annonc/mdr396] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND TERT (telomerase reverse transcriptase) plays a critical role in tumor cell growth and survival. In an expanded phase II study, we evaluated the immunological and clinical responses to the TERT-targeting Vx-001 vaccine in patients with advanced solid tumors. METHODS HLA-A*0201-positive patients received two subcutaneous injections of the optimized TERT(572Y) peptide followed by four injections of the native TERT(572) peptide, every 3 weeks. Peptide-specific immune responses were evaluated by enzyme-linked immunosorbent spot at baseline, and after the second and the sixth vaccinations. RESULTS Fifty-five patients were enrolled and 34 (62%) completed the six vaccinations. A TERT-specific T-cell immune response was observed in 55% and 70% of patients after the second and the sixth vaccinations, respectively. The disease control rate (DCR) was 36% [95% confidence interval (CI) 24% to 49%], including one complete and one partial response. Immunologically responding patients had a better clinical outcome than nonresponders [DCR: 44% versus 14% (P = 0.047); progression-free survival (PFS): 5.2 versus 2.2 months (P = 0.0001) and overall survival: 20 versus 10 months (P = 0.041)]. Multivariate analysis revealed that the immunological response was an independent variable associated with increased PFS (hazard ratio = 3.35; 95% CI 1.7-6.7). CONCLUSION Vx-001 vaccine was well tolerated and induced a TERT-specific immunological response, which was significantly correlated with improved clinical outcome.
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Affiliation(s)
- A Kotsakis
- Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece
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50
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Tsuji T, Matsuzaki J, Ritter E, Miliotto A, Ritter G, Odunsi K, Old LJ, Gnjatic S. Split T cell tolerance against a self/tumor antigen: spontaneous CD4+ but not CD8+ T cell responses against p53 in cancer patients and healthy donors. PLoS One 2011; 6:e23651. [PMID: 21858191 PMCID: PMC3155555 DOI: 10.1371/journal.pone.0023651] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 07/22/2011] [Indexed: 12/20/2022] Open
Abstract
Analyses of NY-ESO-1-specific spontaneous immune responses in cancer patients revealed that antibody and both CD4+ and CD8+ T cell responses were induced together in cancer patients. To explore whether such integrated immune responses are also spontaneously induced for other tumor antigens, we have evaluated antibody and T cell responses against self/tumor antigen p53 in ovarian cancer patients and healthy individuals. We found that 21% (64/298) of ovarian cancer patients but no healthy donors showed specific IgG responses against wild-type p53 protein. While none of 12 patients with high titer p53 antibody showed spontaneous p53-specific CD8+ T cell responses following a single in vitro sensitization, significant p53-specific IFN-γ producing CD4+ T cells were detected in 6 patients. Surprisingly, similar levels of p53-specific CD4+ T cells but not CD8+ T cells were also detected in 5/10 seronegative cancer patients and 9/12 healthy donors. Importantly, p53-specific CD4+ T cells in healthy donors originated from a CD45RA− antigen-experienced T cell population and recognized naturally processed wild-type p53 protein. These results raise the possibility that p53-specific CD4+ T cells reflect abnormalities in p53 occurring in normal individuals and that they may play a role in processes of immunosurveillance or immunoregulation of p53-related neoplastic events.
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Affiliation(s)
- Takemasa Tsuji
- Ludwig Institute for Cancer Research Ltd., New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Junko Matsuzaki
- Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America
| | - Erika Ritter
- Ludwig Institute for Cancer Research Ltd., New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Anthony Miliotto
- Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America
| | - Gerd Ritter
- Ludwig Institute for Cancer Research Ltd., New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Kunle Odunsi
- Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, United States of America
| | - Lloyd J. Old
- Ludwig Institute for Cancer Research Ltd., New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Sacha Gnjatic
- Ludwig Institute for Cancer Research Ltd., New York Branch at Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
- * E-mail: .
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