Project Summary
The implementation of immunotherapies has considerably improved outcomes in multiple myeloma (MM). Specifically, BCMA-directed chimeric antigen receptor (CAR-) T cell therapies lead to unprecedented response rates, yet relapse occurs in almost all patients. As we have previously demonstrated, antigen escape is one crucial mode of resistance, making combinatorial targeting a potential relapse mitigation strategy. Further, T cell fitness in MM patients is reduced, hence documented CAR-T cell persistence is very limited in these patients. We have recently shown that different qualities of neoantigen-specific TCR (NeoTCR)-modified T cells correlate with enduring tumor control after repeated in vivo exposure and clonotype persistence. However, downregulation of the human leukocyte antigen (HLA) is possible, being one of the multi-facetted effects of a deregulated proto-oncogene MYC, a known driver of MM progression.
The overall aim of this project is to overcome these critical resistance mechanisms in order to guide the setup of a next generation of potentially curative cellular therapies by combining the advantages of NeoTCR- and CAR-transgenic cell products. To this end, we will (1) characterize different types of combinatorial receptor (NeoTCR- and CAR-) modified cell products to elicit signaling patterns, T cell fitness and anti-MM efficacy in the setting of defined target antigen levels. Further, we will (2) develop strategies to improve effector cell fitness in MM patients through pharmacological interventions (pentanoate, CELMoDs and others) during manufacture and/or treatment and benchmark them to cell products of healthy donor origin. Additionally, we will (3) investigate the interplay of receptor-modified T cells with additional immune cells (macrophages, monocytes and inhibitory lymphocytes) including evaluations on the role of MYC deregulation and antigen spreading. Technically, we will make use of our established CAR and NeoTCR platforms as well as humanized and murine myeloma models. With the results generated in this project, we envision to lay the cornerstone for highly effective cell products that overcome crucial resistance mechanisms. This may not only take MM treatment one step further towards cure but also pave the way for future applications of the characterized combined therapeutic strategies in different hematologic and solid malignancies.
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