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P06.03 Bispecific antibody-driven synthetic agonistic receptor engineered T cells lead to specific and conditional therapy in melanoma cancer models
  1. M Benmebarek1,
  2. F Märkl1,
  3. J Keyl1,
  4. B Loureiro Cadilha1,
  5. M Geiger2,
  6. C Karches1,
  7. S Endres1,
  8. C Klein1,
  9. S Kobold1,
  10. A Klüver1 and
  11. M Schwerdtfeger1
  1. 1Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany
  2. 2Roche Innovation Center Zurich, Schlieren, Switzerland


Background Immunotherapeutic approaches, including immune checkpoint blockade and adoptive T cell therapy (ACT) in the form of tumor-infiltrating lymphocytes (TIL), have had marked success in the treatment of melanoma. Despite these successes, many patients are refractory to treatment or relapse with therapy-resistant disease. To overcome said limitations, we propose a controlled ACT approach, where T cells are armed with synthetic agonistic receptors (SAR) that are conditionally activated only in the presence of a target melanoma-associated antigen, and a cross-linking bispecific antibody (BiAb) specific for both SAR T cell and tumour cell.

Materials and Methods A SAR composed of an extracellular EGFRvIII, trans- membrane CD28, and intracellular CD28 and CD3z domains was fused via overlap- extension PCR cloning. T cells were retrovirally transduced to stably express our SAR construct. We validated our approach in two murine as well as two human cancer models expressing our melanoma-associated target antigens TYRP (murine) and MCSP (human). We confirmed conditional and specific stimulation and proliferation of our T cells, as well as their tumour-antigen-directed cytotoxicity, in vitro and in vivo.

Results Crosslinking TYRP-EGFRvIII (murine) and MCSP-EGFRvIII (human) BiAb, monovalently selective for our SAR, induced conditional antigen-dependent activation, proliferation of SAR-T cells and directed tumour cell lysis with specificity towards two TYRP-expressing murine melanoma and two MCSP-expressing human melanoma cancer models. In vivo, anti-tumoural activity was mediated by the co-administration of SAR-T cells and BiAb, in A375 and MV3 melanoma xenograft models. Further, we could show that SAR T cells exhibited resistance to MDSC-induced suppression of activation and proliferation.

Conclusions Here we apply the SAR x BiAb approach in efforts to deliver specific and conditional activation of SAR transduced T cells, and targeted tumour cell lysis. The modularity of our platform is key for a targeting approach in a tumor entity with a high mutational load such as melanoma and is fundamental in our drive towards personalised immunotherapies. Further, the SAR approach has demonstrated resistance to MDSC-induced suppression, an interesting axis that requires further investigation.

Disclosure Information M. Benmebarek: None. F. Märkl: None. J. Keyl: None. B. Loureiro Cadilha: None. M. Geiger: None. C. Karches: None. S. Endres: None. C. Klein: None. S. Kobold: None. A. Klüver: None. M. Schwerdtfeger: None.

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