Autocrine cytokine signaling in CAR-T cells

Autocrine cytokine signaling in CAR-T cells is a synthetic biology strategy designed to enhance the efficacy and persistence of Chimeric Antigen Receptor (CAR) T-cell therapies, particularly against solid tumors. This approach involves engineering CAR-T cells to constitutively or inducibly secrete specific cytokines—such as Interleukin-12 (IL-12), Interleukin-15 (IL-15), or Interleukin-18 (IL-18)—which then bind to their respective receptors on the same T-cell (autocrine) or nearby immune cells (paracrine) (Yeku et al., 2017). These armored CAR-T cells, also known as TRUCKs, are designed to overcome the immunosuppressive tumor microenvironment by providing continuous stimulatory signals that promote T-cell expansion and prevent exhaustion (Chmielewski & Abken, 2015). While this mechanism significantly boosts anti-tumor activity in preclinical models, it poses clinical challenges regarding the control of cytokine levels to avoid severe systemic toxicities like cytokine release syndrome (CRS) (Kuhn et al., 2019). Current research focuses on using inducible promoters or logic gates to ensure that cytokine secretion occurs primarily within the tumor site to maximize safety and therapeutic index.

Other names

Armored CAR-T cellsCytokine-secreting CAR-T cellsTRUCKs (T-cells redirected for universal cytokine killing)Constitutive cytokine signalingSelf-stimulatory CAR-T cells

Genetic modification of T-cells to co-express cytokines that act in an autocrine or paracrine fashion to enhance anti-tumor activity, persistence, and recruitment of endogenous immune cells (Chmielewski & Abken, 2015).