Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma

Summary Adoptive T‐cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo‐ engineered patient T cells, which are redirected by a chimeric antigen receptor ( CAR ) and recognize a predefined target by an antibody‐derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. However, given the tremendous phenotypic diversity in solid tumor lesions, a reasonable number of cancer cells are not recognized by a given CAR , considerably reducing the therapeutic success. This article reviews a recently described strategy for overcoming this shortcoming of the CAR T‐cell therapy by modulating the tumor stroma by a CAR T‐cell‐secreted transgenic cytokine like interleukin‐12 ( IL ‐12). The basic process is that CAR T cells, when activated by their CAR , deposit IL ‐12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCK s, T cells redirected for universal cytokine‐mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials.