(1) Märkl F (2) Benmebarek MR (3) Keyl J (4) Cadilha BL (5) Geiger M (6) Karches C (7) Obeck H (8) Schwerdtfeger M (9) Michaelides S (10) Briukhovetska D (11) Stock S (12) Jobst J (13) Müller PJ (14) Majed L (15) Seifert M (16) Klüver AK (17) Lorenzini T (18) Grünmeier R (19) Thomas M (20) Gottschlich A (21) Klaus R (22) Marr C (23) von Bergwelt-Baildon M (24) Rothenfusser S (25) Levesque MP (26) Heppt MV (27) Endres S (28) Klein C (29) Kobold S

Journal for immunotherapy of cancer

Märkl and Benmebarek et al. demonstrated the modularity and controllability of a combination of a CAR T cell with a synthetic agonistic receptor (SAR; the extracellular domain of EGFRvIII linked to conventional CAR intracellular domains [E3]) and a bispecific antibody that can link that CAR to melanoma cell targets (TYRP1 and MCSP). In vitro studies demonstrated activation (dependent on both components), specificity, cytotoxicity, reversibility, and independence of the presence of soluble targets (likely due to the use of bivalent, low-affinity target-binding scFvs). Specific tumor control was demonstrated in syngeneic and xenograft melanoma models.

Contributed by Ed Fritsch

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 UniversitŠt MŸnchen, Munich, Germany. (2) Department of Medicine IV, Division of Clinical Pharmacolog

Author Info: (1) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (2) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (3) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (4) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, 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 UniversitŠt MŸnchen, Munich, Germany. (7) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (8) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (9) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (10) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (11) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. Department of Medicine III, Klinikum der UniversitŠt MŸnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (12) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (13) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (14) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (15) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (16) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (17) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (18) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, 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 UniversitŠt MŸnchen, Munich, Germany. (21) Division of Pediatric Nephrology, Department of Pediatrics, Dr. v. Haunersches Kinderspital, Klinikum der UniversitŠt MŸnchen, 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 UniversitŠt MŸnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (24) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. (25) Department of Dermatology, University Hospital Zurich, Schlieren, Switzerland. (26) Department of Dermatology, UniversitŠtsklinikum Erlangen, Friedrich-Alexander UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg, Erlangen, Germany. (27) Department of Medicine IV, Division of Clinical Pharmacology, Klinikum der UniversitŠt MŸnchen, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Einheit fŸr 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 UniversitŠt MŸnchen, Munich, Germany sebastian.kobold@med.uni-muenchen.de. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Einheit fŸr Klinische Pharmakologie (EKLiP), Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.

Citation: J Immunother Cancer 2023 May 11: Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/37208128

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