Leucine zipper-based sorting system enables generation of multi-functional CAR T cells
James, S. E.; Chen, S.; Ng, B. D.; Fischman, J. S.; Jahn, L.; Boardman, A. P.; Rajagopalan, A.; Elias, H. K.; Massa, A.; Manuele, D.; Nichols, K. B.; Lazrak, A.; Lee, N.; Fei, T.; DeWolf, S.; Peled, J.; Vardhana, S. A.; Klebanoff, C. A.; van den Brink, M. R. M.
Show abstract
Resistance to chimeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms including antigen-loss escape and tumor-induced immune suppression. Expression of multiple CARs may overcome multi-antigen-loss escape. Similarly, expression of switch receptors that convert inhibitory immune checkpoint signals into positive costimulatory signals may enhance CAR T cell activity in the tumor microenvironment. Engineering multiple features into one cell product, however, is limited by transgene packaging constraints of current vector systems. Here, we describe a leucine zipper-based cell sorting methodology that enables selective single-step immunomagnetic purification of cells co-transduced with two vectors, designed to potentially double the number of incorporated transgenes. This "Zip-sorting" system facilitated generation of T cells simultaneously expressing up to four CARs and co-expressing up to three switch receptors. These multi-CAR multi-Switch receptor arrays enabled T cells to eliminate antigenically heterogeneous syngeneic leukemia populations co-expressing multiple inhibitory ligands. Zip-sorted multi-CAR multi-Switch receptor T cells represent a potent therapeutic strategy to overcome multiple mechanisms of CAR T cell resistance.
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