Immunotherapy for pancreatic cancer

Abstract

Pancreatic cancer, a highly lethal cancer, has the lowest 5-year survival rate for several reasons, including its tendency for the late diagnosis, a lack of serologic markers for screening, aggressive local invasion, its early metastatic dissemination, and its resistance to chemotherapy/radiotherapy. Pancreatic cancer evades immunologic elimination by a variety of mechanisms, including induction of an immunosuppressive microenvironment. Cancer-associated fibroblasts interact with inhibitory immune cells, such as tumor-associated macrophages and regulatory T cells, to form an inflammatory shell-like desmoplastic stroma around tumor cells. Immunotherapy has the potential to mobilize the immune system to eliminate cancer cells. Nevertheless, although immunotherapy has shown brilliant results across a wide range of malignancies, only anti-programmed cell death 1 antibodies have been approved for use in patients with pancreatic cancer who test positive for microsatellite instability or mismatch repair deficiency. Some patients treated with immunotherapy who show progression based on conventional response criteria may prove to have a durable response later. Continuation of immune-based treatment beyond disease progression can be chosen if the patient is clinically stable. Immunotherapeutic approaches for pancreatic cancer treatment deserve further exploration, given the plethora of combination trials with other immunotherapeutic agents, targeted therapy, stroma-modulating agents, chemotherapy, and multi-way combination therapies.

Keywords: Immune checkpoint inhibitor; Immunotherapy; Pancreatic adenocarcinoma; Pancreatic cancer.

Figure 1

T cell checkpoints and their inhibitors to induce anti-cancer immunity. A: cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in priming and activation of T cell in a lymph node. A T cell normally recognizes a specific tumor antigen, which is presented by an antigen presenting cell in the context of a major histocompatibility complex molecule in addition to the costimulatory signal B7. CTLA-4 is a negative regulator of costimulation that mediates inhibitory signaling into the T cell via competitive inhibition of CD28. CTLA-4 pathway to suppress initiation of an immune response can be blocked with anti-CTLA-4 antibodies (e.g. ipilimumab); B: Programmed cell death 1 (PD-1) in recognition and killing of cancer cell by cytotoxic T cell within a tumor. PD-1 is expressed on activated T cell after the triggering of the T cell receptor. Engagement of PD-1 with programmed cell death ligand 1 (PD-L1) mediates inhibitory signaling into the cytotoxic T cell. PD-1 pathway to suppress antitumor T cell responses can be blocked by anti-PD-1 (e.g. pembrolizumab) or anti-PD-L1 antibodies (e.g. atezolizumab). CTLA-4: Cytotoxic T lymphocyte-associated protein 4; APC: Antigen presenting cell; I: Inhibitory signaling; PD-1: Programmed cell death 1; PD-L1: Programmed cell death ligand 1; TCR: T cell receptor; MHC: Major histocompatibility complex; MDSC: Myeloid-derived suppressor cell; M2: M2-polarized macrophage.

Figure 2

Illustrations of chimeric antigen receptor T cells immunotherapy. CEA: Carcinoembryonic antigen; ROR1: Receptor tyrosine kinase-like orphan receptor 1; EpCAM: Epithelial cell adhesion molecule; HER2: Human epidermal growth factor receptor 2; MUC1: Mucin 1; CAR: Chimeric antigen receptor.