An overview of up-and-coming immune checkpoint inhibitors for pancreatic cancer

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1/PD-L1) pathway as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated substantial potential in several malignancies. Pancreatic adenocarcinoma (PC) still carries a high mortality despite tremendous advances in the anti-cancer arsenal.

Areas covered

In this review, we discuss completed and ongoing studies on various ICIs in PC. ICIs have not yielded significant benefits as monotherapy. However, the combination with currently utilized therapies as well as with several other newer forms of therapy has delineated encouraging results. Larger trials are currently underway to definitively characterize the utility of ICIs in the treatment algorithm of PC. ICIs are approved for cancers with mismatch repair deficiency (dMMR) or microsatellite instability-high tumors (MSI-H) as a tumor-agnostic treatment strategy usually referred to as hot tumors.

Expert opinion

Studies evaluating different drugs to transform the tumor microenvironment (TME) from ‘cold’ to ‘hot’ have not shown promise in PC. There still needs to be more prospective trials evaluating the efficacy of the combination of ICIs with different therapeutic modalities in PC that can augment the immunogenic potential of those ‘cold’ tumors. Exploratory biomarker analysis may help us identify those subsets of PC patients who may particularly benefit from ICIs.

KEYWORDS:

• Pancreatic cancer
• immune checkpoint inhibitor
• immunotherapy
• PD-1
• PD-L1
• CTLA-4

Article highlights

• Immune checkpoint inhibitors (ICIs) need further evaluation in pancreatic cancer (PC).

• ICI monotherapy in combination with standard-of-care chemotherapy has yielded modest benefits in MSI stable disease.

• ICIs have shown good efficacy in PC with MSI-H, dMMR, or TMB ≥ 10.

• Combination of ICIs with certain newer modalities like oncolytic viruses, targeted therapies, and PARP (BRCA) inhibitors may have potential and need substantiation in larger prospective trials.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

H Babiker is a Paul Calabresi Scholar at the Mayo Clinic Cancer Center and acknowledges the K-12 grant Program, K12CA090628.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.