The next wave of cellular immunotherapies in pancreatic cancer

Abstract

Pancreatic cancer is an aggressive disease that is predicted to become the second leading cause of cancer-related death worldwide by 2030. The overall 5-year survival rate is around 10%. Pancreatic cancer typically presents late with locally advanced or metastatic disease, and there are limited effective treatments available. Cellular immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has had significant success in treating hematological malignancies. However, CAR T cell therapy efficacy in pancreatic cancer has been limited. This review provides an overview of current and ongoing CAR T cell clinical studies of pancreatic cancer and the major challenges and strategies to improve CAR T cell efficacy. These strategies include arming CAR T cells; developing off-the-shelf allogeneic CAR T cells; using other immune CAR cells, like natural killer cells and tumor-infiltrating lymphocytes; and combination therapy. Careful incorporation of preclinical models will enhance management of affected individuals, assisting incorporation of cellular immunotherapies. A multifaceted, personalized approach involving cellular immunotherapy treatment is required to improve pancreatic cancer outcomes.

Keywords: CAR T cell therapy; adoptive T cell therapy; cellular immunotherapy; checkpoint blockade; combination therapy; organoids; pancreatic cancer; preclinical models; tumor microenvironment.

Graphical abstract

Figure 1

Schematic of the different CAR generations Chimeric antigen receptors (CARs) are receptors composed of an extracellular single-chain variable fragment (scFv) comprising a variable light (VL) and variable heavy (VH) chain fused to a transmembrane domain. The intracellular signaling domain varies across generations for T cell activation. First-generation CARs contain a CD3ζ chain. Second- and third-generation CARs contain one or two co-stimulatory domains, respectively. Fourth-generation CARs, also known as TRUCKs, have an interleukin (IL) inducer, which leads to release of cytokines to improve CAR T cell function. Fifth-generation CARs are based on the second-generation CAR with an additional IL-2Rβ domain to induce JAK/STAT antigen-dependent signaling pathways for enhanced proliferation and antitumor activity.

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.^,

Figure 3

Proposed workflow for implementing preclinical PDAC models to evaluate cellular immunotherapies Pancreatic cancer tissue is sampled, and preclinical organoids and xenograft models are generated. CAR immune cells are screened for suitable CAR candidates in PDOs or used to identify individual-specific antigens and improve CAR design. Positive candidates can then be translated for personalized treatment (back to the same individual) or tested in clinical trials. PDX models can also be utilized for cytotoxicity validation (immunocompetent mouse models) and to examine potential on-target/off-tumor effects and CRS (humanized transgenic mouse models).