Chimeric antigen receptors (CARs) in the canonical "second generation" format provide two signals for inducing T cell effector functions; the primary "signal-1" is provided through the TCR CD3_ chain and the "signal-2" through a linked costimulatory domain to augment activation. While therapy with second generation CAR T cells can induce remissions of leukemia/lymphoma in a spectacular fashion, CAR T cell persistence is frequently limited which is thought to be due to timely limited activation. Following the "three-signal" dogma for inducing a sustained T cell response, cytokines were supplemented to provide "signal-3" to CAR T cells. Recent progress in the understanding of structural biology and receptor signaling has allowed to engineer cytokines for more selective, fine-tuned stimulation of CAR T cells including an artificial autocrine loop of a transgenic cytokine, a cytokine anchored to the CAR T cell membrane or inserted into the extracellular CAR domain, and a cytokine receptor signaling moiety co-expressed with the CAR or inserted into the CAR endodomain. Here we discuss the recent strategies and options for engineering such "cytokine help intensified CAR" (CHIC) T cells for use in adoptive cell therapy.

Author Info: (1) Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, Germany. Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (2) Leibniz Institute for Immunotherapy, Div. Genetic Immunotherapy, Regensburg, Germany. Chair for Genetic Immunotherapy, University Regensburg, Regensburg, Germany.