Immunotherapy and pancreatic cancer: unique challenges and potential opportunities

Abstract

Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) continues to have the worst 5-year survival of any malignancy. With 338,000 new cases diagnosed and over 300,000 deaths per year globally there is an urgent unmet need to improve the therapeutic options available.Novel immunotherapies have shown promising results across multiple solid tumours, in a number of cases surpassing chemotherapy as a first-line therapeutic option. However, to date, trials of single-agent immunotherapies in PDAC have been disappointing and PDAC has been labelled as a nonimmunogenic cancer. This lack of response may in part be attributed to PDAC’s unique tumour microenvironment (TME), consisting of a dense fibrotic stroma and a scarcity of tumour infiltrating lymphocytes. However, as our understanding of the PDAC TME evolves, it is becoming apparent that the problem is not simply the immune system failing to recognize the cancer. There is a highly complex interplay between stromal signals, the immune system and tumour cells, at times possibly restraining tumour growth and at others supporting growth and metastasis.Understanding this complexity will enable the development of rational combinations with immunotherapy, priming the TME to offer immunotherapy the best chance of success. This review seeks to describe the unique challenges of the PDAC TME, the potential opportunities it may afford and the trials in progress capitalizing on recent insights in this area.

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers

“…CPI- and CTL-based immunotherapies have unfortunately not shown the same beneficial impact in treating PDAC patients 20 , 21 . This lack of success has been attributed to the highly immune-suppressive tumor microenvironment (TME) of PDAC, in addition to the relatively low mutational burden that contributes to a dearth of neo-antigen targets 22 – 25 .…”

“…A number of potentially targetable HLA class I-restricted peptide antigens have been identified in PDAC, most notably those derived from carcinoembryonic antigen-related cell adhesion molecule (CEACAM), mucin 16 (MUC16), mesothelin (MSLN), and mutated KRAS , among others 26 – 30 . Although promising, therapies targeting non-mutated TAAs have faced inherent limitations, including the induction of toxicities in non-tumor tissues, low prevalence of target antigen expression, or inability to break self-tolerance mechanisms that often hinders the generation of high-affinity CTLs 20 , 31 , 32 . With limited exceptions, clinical trials targeting these antigens have yielded disappointing results, underscoring the need to identify safe, immunogenic targets that demonstrate higher prevalence in PDAC patients.…”

A Combination of Radiotherapy, Hyperthermia, and Immunotherapy Inhibits Pancreatic Tumor Growth and Prolongs the Survival of Mice

“…Further, immunosuppressive TME is infiltrated by large numbers of potentially tumor-reactive effector T-cells and regulatory T-cells that show evidence of prior activation [36]. Most of these cells express the co-inhibitory molecule PD-1, however, blockade of its ligand, PD-L1 was unsuccessful in a small number of patients with locally-advanced-stage PC [37,38]. The lack of clinical efficacy of PD-L1 blockade in PC patients suggests that it may be necessary to address the immunosuppressive effects by employing immune co-stimulatory agents such as agonistic OX40 immunotherapy, combined with RT or hyperthermia (HT) [10,39].…”

The Identification of the Anthracycline Aclarubicin as an Effective Cytotoxic Agent for Pancreatic Cancer

“…To date, PDAC remains unresponsive to treatment with chemotherapeutic compounds [27]. Gemcitabine has been the cornerstone of PDAC treatment for many years, with limited effect.…”