BACKGROUND: Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens. METHODS: Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo. RESULTS: MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 _ anti-SAR or anti-MCSP _ anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model. CONCLUSION: The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.
Author Info: (1) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (2) Department of Medicine IV, Division of Clinical Pharmacolog
Author Info: (1) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (2) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (3) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (4) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (5) Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland. (6) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (7) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (8) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (9) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (10) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (11) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. Department of Medicine III, Klinikum der Universitt Mnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (12) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (13) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (14) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (15) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (16) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (17) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (18) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (19) Institute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Freising, Germany. (20) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (21) Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Haunersches Kinderspital, Klinikum der Universitt Mnchen, Munich, Germany. (22) Institute of AI for Health, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. Institute of Computational Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. (23) Department of Medicine III, Klinikum der Universitt Mnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (24) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (25) Department of Dermatology, University Hospital Zurich, Schlieren, Switzerland. (26) Department of Dermatology, Universittsklinikum Erlangen, Friedrich-Alexander Universitt Erlangen-Nrnberg (FAU), Erlangen, Germany. Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (27) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Einheit fr Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. (28) Roche Innovation Center Zurich, Roche Pharma Research & Early Development, Schlieren, Switzerland. (29) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany sebastian.kobold@med.uni-muenchen.de. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Einheit fr Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.