TRUCKs: the fourth generation of CARs

Abstract

Introduction: Adoptive cell therapy of malignant diseases takes advantage of the cellular immune system to recognize and destroy cancer cells. This is impressively demonstrated by redirecting T cells with a chimeric antigen receptor (CAR) towards CD19, inducing complete and lasting remission of leukemia in more than two-thirds of patients in early phase trials.

Areas covered: We outline how the CAR strategy is highly specific in redirecting T cells towards pre-defined target cells, however, reaches its limits when targeting solid tumors with a tremendous phenotypic heterogeneity. After initial tumor reduction by CAR T cells, antigen-negative cancer cells not recognized by CAR may give rise to tumor relapse. The situation may be overcome by CAR-mediated activation of T cells in the tumor, releasing inducible IL-12 which augments T-cell activation and attracts and activates innate immune cells to eliminate antigen-negative cancer cells in the targeted lesion.

Expert opinion: CAR T cells with a transgenic ‘payload’, so-called TRUCK T cells or the ‘fourth-generation’ CAR T cells, are worthwhile to explore to shape the tumor environment by the inducible release of transgenic immune modifiers. Such TRUCK T cells are moreover envisioned to be applied in fields beyond cancer therapy including the therapy of virus infections, auto-immune diseases or metabolic disorders.

Keywords:

• adoptive cell therapy
• chimeric antigen receptor
• IL-12
• inducible cytokine
• innate immunity
• T cell

Declaration of interest

Work in the author’s laboratory was supported by the Deutsche Forschungsgemeinschaft, Bonn, the Deutsche Krebshilfe, Bonn, the Else Kröner-Fresenius Stiftung, Bad Homburg v.d.H., the Wilhelm Sander-Stiftung, München, the European Union (European Regional Development Fund - Investing in Your Future), German federal state North Rhine-Westphalia (NRW), and the Medical Faculty of the University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Notes

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