Immune checkpoint therapy for pancreatic cancer

Abstract

Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy. However, due to small sample sizes, major results are not yet identifiable. The present article provides a clinical overview of immune checkpoint inhibition in pancreatic cancer. PubMed, ClinicalTrials.gov and American Society of Clinical Oncology's meeting abstracts were systematically searched for relevant clinical studies. Four articles, five abstracts and 25 clinical trials were identified and analyzed in detail.

Keywords: Clinical trials; Immune checkpoint inhibitors; Pancreatic cancer.

Figure 1

Flow diagram of article selection. ASCO: American Society of Clinical Oncology’s.

Figure 2

Check-point inhibition. A: Natural killer cell (NK cell) interacts with a PDA cell and gets activated through the binding of its activating receptor (AR) with PDA’s tumor associated antigen (TTA). Tolerance occurs when the programmed-death-receptor (PD-1) molecule on the NK cell interacts with its ligand, the programmed-death-ligand (PD-L1), on the PDA cell. Treatment with monoclonal antibody to bind these inhibitory proteins such as either α-PD-1 (Nivolumab, Pembrolizumab, Pidilizumab) or α-PD-L1 (Druvalumab, BMS-936559) prevents this interaction; B: CD8⁺ T cell interacts with a PDA cell and gets activated through the binding of its T cell receptor (TCR) with PDA’s major histocompatibility complex (MHC). Tolerance occurs when the PD-1 molecule on the NK cell interacts with PD-L1 on the PDA cell. Treatment with monoclonal antibody to bind these inhibitory proteins such as either α-PD-1 (Nivolumab, Pembrolizumab, Pidilizumab) or α-PD-L1 (Druvalumab, BMS-936559) prevents this interaction, resulting in suppression of T cell tumor attack; C: CD4⁺ helper T cell interacts with an antigen presenting cell (APC) through the binding of its TCR with APC’sMHC that present TAA. The co-stimulatory APC-signal-binding is induced by the CD28-B7-I/II interaction. The inhibitory checkpoint molecules: PD-L1, PD-1 and CTLA-4 are either presented before CD4⁺ activation or upregulated after activation and might result in inhibition and anergy of the helper T cell via PD-L1–PD-1, PD-L1–B7-1 and/or CTLA-4–B7-I/II interactions. Treatment with monoclonal antibody to bind these inhibitory proteins such as either α-PD-1 (Nivolumab, Pembrolizumab, Pidilizumab), α-PD-L1 (Druvalumab, BMS-936559) or α-CTLA-4 (Ipilimumab, Tremelimumab) can prevent this interaction, thus maintain antitumor activity.