Kurzfassung

Adoptive cellular therapy (ACT) based on T-cell receptors (TCR) or chimeric antigen receptors (CAR)-engineered T cells have achieved tremendous success in cancer immunotherapy, especially against B-cell malignancies. The impressive therapeutic results recently obtained with checkpoint inhibitors have opened a new era in the field of immunotherapy. Yet, clinical responses are still often observed either transiently or in a minority of patients. It is also clear that in addition to inhibitory...Adoptive cellular therapy (ACT) based on T-cell receptors (TCR) or chimeric antigen receptors (CAR)-engineered T cells have achieved tremendous success in cancer immunotherapy, especially against B-cell malignancies. The impressive therapeutic results recently obtained with checkpoint inhibitors have opened a new era in the field of immunotherapy. Yet, clinical responses are still often observed either transiently or in a minority of patients. It is also clear that in addition to inhibitory receptors, T cells express a wide range of stimulatory receptors which could be exploited to improve the antitumor immune response. Therefore a more effective treatment approach combining ACT and modulation of T-cell immune inhibitory and stimulatory receptors will have the advantage to further enhance the efficacy of an antitumor response.
The aim of this proposal is to develop a multi-modal immunotherapeutic combination strategy to unleash the full anti-tumor response of adoptively transferred myeloma-specific T cells. We propose to target multiple myeloma (MM) tumor cells in our established xenograft in vivo adoptive cell therapy model by (1) T cells redirected with two optimized TCRs specific for HLA-A2.1-restricted MDM2 and p53 epitopes in combination with (2) an anti-SLAMF7 antibody (Elotuzumab), (3) key checkpoint inhibitors  (PD-1, LAG-3) and (4) agonists of T cell function (anti-CD137).
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