Current T cell engineering approaches redirect patient T cells to tumors by transducing antigen–specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen.1–3 However, few tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell–mediated damage.4–7 Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This “tumor-sensing” strategy may help broaden the applicability and avoid some of the side effects of targeted T cell therapies.

Summary T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Utilizing an in vivo “stress test” to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by 7 different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which utilizes two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.

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