Figure 2.

The four major barriers hindering cellular immunotherapies in PDAC and potential strategies to overcome them

(A) The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) form a dense physical barrier, limiting the ability of CAR cells to infiltrate and target tumor cells. Intratumoral delivery, CAR design, and arming CARs with chemokine receptors can assist with trafficking and tumor infiltration. (B) The heterogeneity of tumor cells results in varying antigen expression, which limits CAR cell efficacy. Dual-targeting CARs or antibody-targeting CARs can target multiple antigens, potentially increasing efficacy by targeting more tumor cells. The TME consists of ECM; various structural and immune cells, such as myeloid-derived suppressor cells (MDSCs); tumor-associated macrophages (TAMs); monocytes; and regulatory T cells. (C) This results in an immunosuppressive environment that can inhibit CAR T cell fitness (exhaustion) and survival. Preconditioning regimens assist with altering the immune TME, and checkpoint inhibitors may help avoid CAR cell exhaustion. (D) Combination therapy, such as addition of oncolytic viruses with CAR cell therapy or targeting CAFs, can overcome the immunosuppressive TME to increase CAR cell therapy efficacy. References to key articles on these strategies are shown.^149,150