Journal for ImmunoTherapy of Cancer (May 2023)

Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma

  • Christian Klein,
  • Daria Briukhovetska,
  • Michael von Bergwelt-Baildon,
  • Sebastian Kobold,
  • Mitchell P Levesque,
  • Bruno L Cadilha,
  • Stefan Endres,
  • Mohamed-Reda Benmebarek,
  • Hannah Obeck,
  • Sophia Stock,
  • Florian Märkl,
  • Julius Keyl,
  • Martina Geiger,
  • Clara Karches,
  • Melanie Schwerdtfeger,
  • Stefanos Michaelides,
  • Jakob Jobst,
  • Philipp Jie Müller,
  • Lina Majed,
  • Matthias Seifert,
  • Anna-Kristina Klüver,
  • Theo Lorenzini,
  • Ruth Grünmeier,
  • Moritz Thomas,
  • Adrian Gottschlich,
  • Richard Klaus,
  • Carsten Marr,
  • Simon Rothenfusser,
  • Markus Vincent Heppt

DOI
https://doi.org/10.1136/jitc-2022-006436
Journal volume & issue
Vol. 11, no. 5

Abstract

Read online

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.