Immunotherapy and Combination Strategies in Pancreatic Cancer: Current Status and Emerging Trends

Abstract

Pancreatic cancer is among the most aggressive malignancies with no effective therapeutic options thus far. Immunotherapy has recently emerged as a promising alternative for the treatment of various solid tumors. In particular, promising results in clinical trials were observed for therapies targeting immune checkpoint molecules. Efforts have been put into investigating the potential of immunotherapy in treating pancreatic cancer. While most of the clinical trial results are still being awaited, several intrinsic features of pancreatic cancer such as low mutational load and the presence of highly immunosuppressive desmoplasia significantly hamper the efficacy of immunotherapy in this disease. These unique features of pancreatic cancer, however, have advanced our understanding of tumor immunology and might help to tailor the future direction of immunotherapy. In this review, we summarize the current immunotherapeutic strategies and clinical trials targeting checkpoint molecules in pancreatic cancer. Emerging trends towards various combinations with therapies targeting immunosuppressive myeloid cells are also discussed.

Immunotherapy in Gastrointestinal Carcinoma - How to Separate Hope from Hype

“…Blocking of the B7 immunoglobulin superfamily molecules, such as PD-1 (nivolumab, pembrolizumab), CTLA-4 (tremelimumab, ipilimumab) or PD-L1 (durvalumab, atezolizumab, avelumab), has already shown promising results in many trials in patients with advanced or metastatic GI malignancies. These trials and further upcoming studies are described in more detail in the articles of this review series [1][2][3][4][5][6][7][8].…”

“…Additionally, it is of scientific significance to increase our understanding of the interactions between tumor microenvironment and the immune system to generate more effective therapies, particularly in non-responsive tumors [3].…”

“…Inflammation-induced tumors, such as Epstein-Barr virus (EBV)-positive tumors may also be good models for immune-responsive cancers. Despite the presented accomplishments [1][2][3][4][5][6][7][8], we still lack well-defined selection biomarkers for immunotherapy of the large patient groups with chromosomally instable and stable cancers. The search to switch these mostly non-immunogenic, socalled cold, tumors into hot immune-responsive tumors has become an exciting clinical and translational research field.…”

Outlook: Immunotherapy in Gastrointestinal Carcinoma - Innovative Strategies

“…An adverse effect was the upregulated expression of checkpoint molecules such as CTLA-4 on T cells and PD-L1 on tumor cells, which suggests that a combination with checkpoint inhibitors may be warranted [13,14]. As described for colorectal and pancreatic cancer [2,4], Csf1R blockade induced synergistic effects when combined with other treatment strategies, such as CD40 agonism. One trial combined the Csf1R inhibitor cabiralizumab with nivolumab, with or without chemotherapy, in metastatic pancreatic cancer (NCT03336216 and NCT002526017).…”

Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody

“…The field of cancer immunotherapy has rapidly expanded over the past five years, with FDA approval of multiple checkpoint inhibitory antibodies that abrogate the functions of PD-1, PD-L1 and CTLA4. [4][5][6][7][8][9][10] Recent studies from our group have demonstrated that other multi-kinase inhibitors e.g. pazopanib, can interact with HDAC inhibitors to kill tumor cells, and that HDAC inhibitors as single agents or when combined with other drugs that promote a rapid robust autophagosome formation, can enhance the efficacy of checkpoint inhibitory immunotherapy antibodies.…”