Tumor-specific T cells can be engineered in the absence of a single tumor-specific antigen.

  • Major finding: Tumor-specific T cells can be engineered in the absence of a single tumor-specific antigen.

  • Concept: T cells that recognize 2 antigens coexpressed in tumors spare cells expressing only one of the antigens.

  • Impact: A dual-targeting approach can increase the applicability and safety of adoptive T-cell therapy.

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Adoptive T-cell therapy has shown efficacy in certain cancer types characterized by expression of relatively specific antigens that a patient's own T cells can be genetically modified to recognize. However, the rarity of truly tumor-specific antigens has limited broad use of adoptive T-cell therapy, as intolerable or life-threatening side effects can arise if T cells recognize antigens expressed by normal cells. Kloss and colleagues developed a strategy whereby T cells can be engineered to recognize 2 antigens through transduction of an antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) for 1 antigen and a chimeric costimulatory receptor (CCR) for a second antigen. The authors used this method to modify T cells to express a CAR for the B-cell marker CD19 and a CCR for prostate-specific membrane antigen (PSMA). These T cells eradicated tumors expressing both antigens in immunocompromised mice and led to complete, lasting remission but did not distinguish between single- and double-positive tumors. The authors hypothesized that use of a suboptimal TCR or CAR that required simultaneous CCR engagement for full activity would prevent T-cell activation unless both antigens were expressed in the target cell. A suboptimal CAR recognizing a different antigen, prostate stem cell antigen (PSCA), was cotransduced into T cells with a PSMA-specific CCR, and the engineered T cells were injected into immunodeficient mice harboring tumors that expressed PSMA, PSCA, or both antigens. T cells expressing the suboptimal CAR specifically targeted double-positive tumors and led to long-term, robust tumor eradication. Combinatorial antigen targeting can therefore potentially increase the specificity of adoptive T cells for tumors in cases in which neither targeted antigen is absolutely tumor specific, leading to increased safety and applicability of this promising therapeutic strategy.

Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotech 2012 Dec 16 [Epub ahead of print].

©2012 American Association for Cancer Research.
2012