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.