Immunotherapy for pancreatic cancer: Barriers and breakthroughs.

Robert J Torphy,Yuwen Zhu,Richard D Schulick

doi:10.1002/ags3.12176

Abstract

Immunotherapy is a rapidly growing field and represents a paradigm shift in the treatment of malignancies as it offers a new therapeutic approach beyond surgery, conventional chemotherapy, and radiation treatment. Targeting immune checkpoints, such as cytotoxic T‐lymphocyte‐associated antigen 4 and programmed death 1/programmed death ligand 1 has had immense clinical success resulting in sustained treatment response for a subset of patients with certain malignancies such as melanoma, non‐small‐cell lung cancer, urothelial carcinoma, squamous cell carcinoma of the head and neck, renal cell cancer, hepatocellular cancer, and metastatic colorectal cancer. Importantly, there has been limited success in the use of immunotherapy in the treatment of pancreatic cancer. Investigation into the complex tumor microenvironment of pancreatic cancer that is composed of immune cells, stromal cells, and extracellular matrix proteins has begun to shed light on important attributes of this microenvironment that act as barriers to the effective use of immunotherapy. In this review, we will discuss the progress that has been made in treating pancreatic cancer with immunotherapy, the barriers that have limited treatment success, and breakthroughs with combination treatments that hold promise for the future.

Highlights

Pancreatic cancer is projected to be the third leading cause of cancer-related death in the USA in 2018.1 Significant improvements in the treatment of pancreatic cancer have been made over the past two decades, with a median survival of 28.0 months reported for patients with resectable disease who receive adjuvant gemcitabine plus capecitabine.[2]
Despite the decreased antigenicity of pancreatic cancer when compared to melanoma and lung cancer, multiple studies have indicated that the human immune system can develop an immune response to pancreatic cancer and generate functional anti-tumor T cells.[9,10]
These findings led to the hypothesis that anti-CD40 agonist monoclonal antibody (mAb) therapy could be used in conjunction with chemotherapy as a novel treatment for pancreatic cancer.[58]

Summary

Introduction

Pancreatic cancer is projected to be the third leading cause of cancer-related death in the USA in 2018.1 Significant improvements in the treatment of pancreatic cancer have been made over the past two decades, with a median survival of 28.0 months reported for patients with resectable disease who receive adjuvant gemcitabine plus capecitabine.[2]. Multiple human studies have indicated that high PD-L1 expression in pancreatic cancer tumors is associated with worse outcomes suggesting that targeting the PD-1/PD-L1 interaction may have therapeutic benefit in these patients.[19,20,21] An early preclinical study in a mouse tumor transplant model showed that PD-1 or PD-L1 blockade had an anti-tumor effect which was enhanced when given together with gemcitabine.[19] these preclinical findings have not translated to clinical success.

Results

Conclusion