Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity

Olson, M. L.; Vander Mause, E. R.; Radhakrishnan, S. V.; Brody, J. D.; Rapoport, A. P.; Welm, A. L.; Atanackovic, D.; Luetkens, T.

doi:10.1101/2021.12.05.471117

bioRxiv · 10.1101/2021.12.05.471117

Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity

Olson, M. L.·Vander Mause, E. R.·Radhakrishnan, S. V.·Brody, J. D.·Rapoport, A. P.·Welm, A. L.·Atanackovic, D.·Luetkens, T.

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Abstract

Chimeric antigen receptor (CAR) T cells using the high-affinity CD19 binding domain FMC63 are an effective treatment for patients with relapsed and aggressive B cell lymphoma. However, antigen loss and poor CAR T cell persistence remain common causes for relapse in these patients. Using primary patient samples, we now show that FMC63-based CAR T cells confer rapid antigen loss in all major tumor types currently approved for treatment with CD19 CAR T cells via trogocytosis, the stripping of antigen from tumor cells by CAR T cells. We show that CAR T cell-mediated trogocytosis can be dramatically reduced across a wide range of B cell malignancies by replacing FMC63 with a low affinity CD19 antibody. This reduction in trogocytosis does not alter the direct anti-tumor activity of CD19 CAR T cells but prevents the emergence of antigen-negative tumor cells and significantly increases CAR T cell viability by reducing fratricide of CD19 CAR T cells following trogocytosis. TEASERA reduction in CAR affinity does not affect tumor killing but prolongs T cell persistence and prevents antigen-negative tumor escape.

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Olson, M. L., Vander Mause, E. R., Radhakrishnan, S. V., Brody, J. D., Rapoport, A. P., Welm, A. L., Atanackovic, D., Luetkens, T.. 2021-12-07. Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity. https://doi.org/10.1101/2021.12.05.471117

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