TRUCKS, the fourth‐generation CAR T cells: Current developments and clinical translation

The overriding goal of adoptive cell therapy with chimeric antigen receptor (CAR) redirected T cells in oncology is to eliminate cancer cells from infiltrated tissues. Clinical trials document that this form of immunotherapy can induce lasting remissions of hematologic malignancies; however, the successes could not yet be transferred to the treatment of solid tumors. In this situation, modulating the immune regulation within the solid tumor tissue is thought to be a key point. In order to induce a pro‐inflammatory milieu CAR T cells were additionally engineered to release a transgenic cytokine upon CAR signaling in the targeted tumor tissue. Such TRUCKs (“T cells redirected for antigen‐unrestricted cytokine‐initiated killing”), also called “4th generation” CAR T cells, combine the direct antitumor attack of the CAR T cell with the immune modulating capacities of the delivered cytokine. Through CAR‐induced release, the cytokine is ideally deposited in the targeted tissue alleviating systemic side effects. The TRUCK concept is currently explored using a panel of cytokines, including IL‐7, IL‐12, IL‐15, IL‐18, IL‐23, and combinations thereof, and is entering early phase trials. Future developments will expand the application to a broader panel of released proteins converting CAR T cells to “living factories” of therapeutically active, locally deposited products with the potential to eliminate some clinical deficits of the currently used CAR T cells in the field of solid tumors.