Multi-antigen recognition circuits overcome challenges of specificity, heterogeneity, and durability in T cell therapy for glioblastoma
Choe, J. H.; Watchmaker, P. B.; Simic, M. S.; Gilbert, R. D.; Li, A. W.; Krasnow, N. A.; Carrera, D. A.; Yu, W.; Downey, K. M.; Celli, A.; Cho, J.; Briones, J. D.; Dannenfelser, R.; Cardarelli, L.; Sidhu, S. S.; Roybal, K. T.; Okada, H.; Lim, W. A.
Show abstract
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of target antigens that are both tumor-specific and homogeneously expressed. We show that multiantigen prime-and-kill recognition circuits have the flexibility and precision to overcome these challenges in attacking glioblastoma. A synNotch receptor that recognizes a specific priming antigen - the heterogeneous glioblastoma neoantigen EGFRvIII or a brain tissue-specific antigen - is used to locally induce expression of a CAR, enabling thorough but controlled tumor killing by targeting of homogeneous antigens that are not absolutely tumor specific. Moreover, regulated CAR expression maintains a higher fraction of the T cells in the naive-like state which is associated with higher durability in vivo. In summary, using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
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