Chimeric antigen receptor (CAR) T cell therapy is effective in lymphoid malignancies, but there has been limited data in myeloid cancers. Here, we start with a CD27-based CAR to target CD70 ("native") in acute myeloid leukemia (AML), and we find modest efficacy in vivo, consistent with prior reports. We then use orthogonal approaches to increase binding on both the tumor and CAR-T cell sides of the immune synapse: a pharmacologic approach (azacitidine) to increase antigen density of CD70 in myeloid tumors, and an engineering approach to stabilize binding of the CAR to CD70. To accomplish the latter, we design a panel of hinge-modified regions to mitigate cleavage of the extracellular portion of CD27. Our CD8 hinge and transmembrane-modified CD70 CAR-T cells are less prone to cleavage, have enhanced binding avidity, and increased expansion, leading to more potent in vivo activity. This enhanced CD70-targeted CAR is a promising candidate for further clinical development.
Competing Interests: Declaration of interests M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). M.V.M. holds equity in 2SeventyBio, Century Therapeutics, Genocea, Neximmune, Oncternal, and TCR2 and has served as a consultant for multiple companies involved in cell therapies. M.V.M. is on the Board of Directors of 2Seventy Bio. M.V.M. has grant/research support from CRISPR therapeutics, Kite Pharma, Servier, and Novartis. M.J.F. has served as a consultant for several cell therapy companies. No other authors report conflicts of interest. M.B.L. and M.V.M. have filed patents on the constructs described herein.
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