Journal Articles

A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice

ABSTRACT: Antigen-encoding, lipoplex-formulated RNA (RNA-LPX) enables systemic delivery to lymphoid compart- ments and selective expression in resident antigen-presenting cells. We report here that the rejection of CT26 tumors, mediated by local radiotherapy (LRT), is further augmented in a CD8+ T cell-dependent manner by an RNA-LPX vaccine that encodes CD4+ T cell-recognized neoantigens (CD4 neoantigen vaccine). Whereas CD8+ T cells induced by LRT alone were primarily directed against the immunodomi- nant gp70 antigen, mice treated with LRT plus the CD4 neoantigen vaccine rejected gp70-negative tumors and were protected from rechallenge with these tumors, indicating a potent poly-antigenic CD8+ T cell response and T cell memory. In the spleens of CD4 neoantigen-vaccinated mice, we found a high number of activated, poly-functional, Th1-like CD4+ T cells against ME1, the immunodominant CD4 neoantigen within the poly-neoantigen vaccine. LRT itself strongly increased CD8+ T cell numbers and clonal expansion. However, tumor infiltrates of mice treated with CD4 neoantigen vaccine/LRT, as compared to LRT alone, displayed a higher fraction of activated gp70-specific CD8+ T cells, lower PD-1/ LAG-3 expression and contained ME1-specific IFNγ+ CD4+ T cells capable of providing cognate help. CD4 neoantigen vaccine/LRT treatment followed by anti-CTLA-4 antibody therapy further enhanced the efficacy with complete remission of gp70-negative CT26 tumors and survival of all mice. Our data highlight the power of combining synergistic modes of action and warrants further exploration of the presented treatment schema.

Author Info: (a) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbH, 55131 Mainz, Germany; (b) BioNTech SE, 55131 Mainz, Germany; (c) Rese

Author Info: (a) TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg-University gGmbH, 55131 Mainz, Germany; (b) BioNTech SE, 55131 Mainz, Germany; (c) Research Center for Immunotherapy (FZI) of the University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer

ABSTRACT: Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1–PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.

Author Info: (1) Genentech, Inc., South San Francisco, CA, USA. (2) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) The Precision Immunology

Author Info: (1) Genentech, Inc., South San Francisco, CA, USA. (2) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Present address: Atreca, Inc., Redwood City, CA, USA. 6Present address: NGM Biopharmaceuticals, South San Francisco, CA, USA. e-mail: mellman.ira@gene.com

Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, P = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, P = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8(+) T cells in patients' tumors. The enhanced antitumor effects with LMB-100 plus anti-PD-1 antibody were also observed in a human peripheral blood mononuclear cell-engrafted mesothelioma mouse model and a human mesothelin-expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Thorac

Author Info: (1) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (3) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (4) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (5) Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (6) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (7) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (8) Department of Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD 20892, USA. (9) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (10) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (11) Biostatistics and Data Management Section, NCI, NIH, Bethesda, MD 20892, USA. (12) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (13) Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. hassanr@mail.nih.gov.

New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis

CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development.

Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain ietxeberria@alumni.unav.es. (2) Program of Immunology and Immunoth

Author Info: (1) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain ietxeberria@alumni.unav.es. (2) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. (3) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. (4) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Navarra, Spain. Department of Immunology, Clinica Universidad de Navarra, Pamplona, Navarra, Spain.

MCL-1 is essential for survival but dispensable for metabolic fitness of FOXP3(+) regulatory T cells

FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3(+) Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis.

Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC,

Author Info: (1) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (2) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (3) Cellular and Molecular Metabolism Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. School of Health Sciences, University of Tasmania, Launceston, TAS, Australia. (4) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (5) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (6) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (7) Cellular and Molecular Metabolism Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia. (8) The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia. (9) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (10) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. (11) The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, Australia. dgray@wehi.edu.au. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia. dgray@wehi.edu.au.

Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77(tg)) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Valpha14-Jalpha18 TCR-alpha chain gene into the Nur77(tg) (Nur77(tg);Valpha14(tg)) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-gamma-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.

Author Info: (1) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, N

Author Info: (1) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (2) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Department of Chemistry and Life Science, US Military Academy, West Point, NY (3) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (4) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (5) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (6) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. Department of Biology, Caltech, Pasadena, CA 91125. (7) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX1 2JD, United Kingdom. (8) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232. (9) Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232; sebastian.joyce@vumc.org. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.

Scirpy: A Scanpy extension for analyzing single-cell T-cell receptor sequencing data

SUMMARY: Advances in single-cell technologies have enabled the investigation of T cell phenotypes and repertoires at unprecedented resolution and scale. Bioinformatic methods for the efficient analysis of these large-scale datasets are instrumental for advancing our understanding of adaptive immune responses. However, while well-established solutions are accessible for the processing of single-cell transcriptomes, no streamlined pipelines are available for the comprehensive characterization of T cell receptors. Here we propose Scirpy, a scalable Python toolkit that provides simplified access to the analysis and visualization of immune repertoires from single cells and seamless integration with transcriptomic data. AVAILABILITY AND IMPLEMENTATION: Scirpy source code and documentation are available at https://github.com/icbi-lab/scirpy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Author Info: (1) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (2) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbr

Author Info: (1) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (2) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. Biocenter, Institute of Developmental Immunology, Medical University of Innsbruck, Innsbruck, Austria. (3) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (4) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (5) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (6) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. (7) Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.

Increased Arginase1 expression in tumor microenvironment promotes mammary carcinogenesis via multiple mechanisms

Arginine metabolism plays a significant role in regulating cell function, affecting tumor growth and metastatization. To study the effect of the arginine-catabolizing enzyme arginase 1 (ARG1) on tumor microenvironment, we generated a mouse model of mammary carcinogenesis by crossbreeding a transgenic mouse line overexpressing ARG1 in macrophages (FVBArg+/+) with the MMTV-Neu mouse line (FVBNeu+/+). This double transgenic line (FVBArg+/-;Neu+/+) showed a significant shortening in mammary tumor latency, and an increase in the number of mammary nodules. Transfer of tumor cells from FVBNeu+/+ into either FVB wild type or FVBArg+/+ mice resulted in increase regulatory T-cells in the tumor infiltrate, suggestive of an impaired anti-tumor immune response. However we also found increased frequency of tumor stem cells in tumors from FVBArg+/-;Neu+/+ transgenic compared to FVBNeu+/+ mice, suggesting that increased arginine metabolism in mammary tumor microenvironment may supports the cancer stem cells niche. We provide in vivo evidence of a novel, yet unexploited, mechanism through which ARG1 may contribute to tumor development.

Author Info: (1) IRCCS Ospedale Policlinico San Martino, L.go Rosanna Benzi, Genova, Italy. (2) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (3) Universi

Author Info: (1) IRCCS Ospedale Policlinico San Martino, L.go Rosanna Benzi, Genova, Italy. (2) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (3) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (4) University of Genova, Department of Surgical Science and Integrated Diagnostics, Genova. (5) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (6) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (7) Verona University Hospital, Department of Medicine, Section of Immunology, Verona. (8) University of Genova, Department of Experimental Medicine, Via L.B. Alberti, Genova. (9) IRCCS Ospedale Policlinico San Martino, L.go Rosanna Benzi, Genova, Italy.

Immune related proteins and tumor infiltrating CD8+ lymphocytes in hypopharyngeal cancer in relation to human papillomavirus (HPV) and clinical outcome

BACKGROUND: Hypopharyngeal cancer (HPSCC) shows a poor clinical outcome, while HPSCC, caused by human papillomavirus (HPV), presents a better outcome. Here, HPCC, immune proteins, and tumor infiltrating CD8+ lymphocytes (CD8+ TILs) were evaluated in relation to HPV and outcome. METHODS: Fresh frozen tissue from four HPV-positive HPSCC, 39 HPV-negative HPSCC, and normal samples were analyzed for protein expression by the Proseek immuno-oncology immunoassay. CD8+ TIL numbers evaluated by immunohistochemistry on 144 formalin-fixed biopsies were analyzed in relation to clinical outcome. RESULTS: Proteins differing between HPV-positive and negative HPSCC included CD8A, PD-L1, Fas ligand, and chemokines. High CD8+ TIL numbers were correlated to improve clinical outcome in HPV-negative HPSCC. CONCLUSIONS: High expression of immune proteins in HPV-positive HPSCC may explain the better clinical outcome. CD8+ TILs are of relevance for outcome of HPV-negative HPSCC, while tumors with high immune activity but poor patient survival suggest a role for immune therapy.

Author Info: (1) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Otorhinolaryngolo

Author Info: (1) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden. (2) Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. (3) Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. (4) Department of Surgical and Perioperative Sciences, Urology and Andrology Unit, Umea University, Umea, Sweden. Departement of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Departement of Clinical Pathology and Cytology, Cancer, Center Karolinska, R8:02, Karolinska University hospital, Stockholm, Sweden. (6) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden. (7) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden. (8) Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. (9) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden. (10) Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Transgenic T-cell receptor immunotherapy for cancer: building on clinical success

With the advent of immunotherapy as a realistic and promising option for cancer treatment, adoptive cellular therapies are gaining significant interest in the clinic. Whilst the recent successes of chimeric antigen receptor T-cell therapies for haematological malignancies are widely known, they have yet to show great success in solid cancers. However, immune cells transduced with T-cell receptors have been shown to traffic to and exert anti-cancer effects on solid tumour cells with some great successes. In this review, we explore the field of transgenic T-cell receptor immunotherapy, highlighting some of the key clinical trials which have paved the way for this type of cellular immunotherapy. Some trials have shown amazing clinical results, including long-term remissions and minimal toxicity, and can be looked at as an exemplar for this adoptive cell therapy. There have also been key trials where unexpected, fatal, off-tumour toxicity has occurred, and these trials have also been instrumental in shaping safer clinical trials, particularly regarding preclinical testing. In addition to previous trials, we analysed the current clinical trial space for T-cell receptor T-cell therapy, showing which trials are dominating in the clinic and which targets are being prioritised by researchers around the world. By looking at both past and current trials, we have been able to identify key drivers in developing transgenic T-cell receptor immunotherapy for the future.

Author Info: (1) University of Manchester, Manchester, UK. (2) Immetacyte Ltd., University of Manchester, Manchester, Greater Manchester, UK. (3) Immetacyte Ltd, Manchester, UK. (4) Immetacyte

Author Info: (1) University of Manchester, Manchester, UK. (2) Immetacyte Ltd., University of Manchester, Manchester, Greater Manchester, UK. (3) Immetacyte Ltd, Manchester, UK. (4) Immetacyte Ltd., University of Manchester, Manchester, Greater Manchester, UK.

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