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

• Published in: Immunological reviews Vol. 257; no. 1; pp. 83 - 90
• Main Authors: Chmielewski, Markus, Hombach, Andreas A., Abken, Hinrich
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2014
• Subjects: adoptive cell therapy; Animals; chimeric antigen receptor; Cytokines - metabolism; Cytotoxicity, Immunologic; Humans; IL-12; Immunity, Innate; Immunologic Factors - genetics; Immunologic Factors - metabolism; Immunomodulation; Immunotherapy, Adoptive; inducible cytokine; innate immunity; Interleukin-12 - metabolism; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins; stroma; Stromal Cells - metabolism; T cell; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; inducible cytokine; innate immunity; T cell; stroma; chimeric antigen receptor; IL-12; adoptive cell therapy
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1111/imr.12125

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 TRUCKs, 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.