Combination immunotherapy for pancreatic cancer: challenges and future considerations

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA.

Areas covered

We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA.

Expert opinion

Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.

KEYWORDS:

• Combination therapy
• immune checkpoint inhibitors
• immunosuppression
• immunotherapy
• pancreatic cancer
• tumor microenvironment

Article highlights

• Notable mechanisms which confer immunotherapy resistance for pancreatic cancer include low tumor antigenicity, low tumor mutational burden, impaired tumor cell recognition, poor immune cells activation and infiltration, and defective immunotoxicity

• Immune checkpoint inhibition (ICI) has not been effective as monotherapy or combined with chemotherapy in patients with advanced pancreatic cancer, but novel combinations are undergoing clinical trials with some preliminary evidence of efficacy

• While traditional biomarkers such as deficient mismatch repair (dMMR)/microsatellite instability MSI high status and high tumor mutational burden predict response to ICI in many tumors, clinical benefit is lower in pancreatic cancer as compared to other cancers

• Novel immunotherapies being explored in clinical trials include combinations of C-X-C motif chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12), CC motif chemokine ligand 2 (CCL2)/CC motif chemokine receptor 2 (CCR2), C-X-C motif chemokine receptor 2 (CXCR2) inhibitors, personalized neoantigen vaccines, and adoptive T-cell therapies, several in combination with ICI and/or chemo and radiotherapy

• Translational research focuses on biomarkers of sensitivity and resistance, including in early and advanced stages of disease

Declaration of interest

G Gossling Gustavo declares research grants: Pfizer, Bayer, Crinetics. D Zhen declares: research grants: Astra Zeneca, Bristol Myers Squibb, Cornerstone, Daiichi Sankyo, Eli Lilly, Legend, Merck, Roche, SeaGen; scientific advisory board/consultant: Ipsen, QED Therapeutics, Cornerstone. V Pillarisetty declares: research grants: Astra Zeneca, Ipsen, Merck, OncoResponse, NGM; scientific advisory boards/consultant: TriSalus, Merck, GlaxoSmithKline, Imvax, Takeda, Umoja, Sensei.

G Chiorean declares: research grants: AADi, BioMed Valley, Boehringer-Ingelheim, Clovis, Corcept, Cornerstone, Erasca, Fibrogen, Lonza, Merck, Stemline; scientific advisory boards/consultant: Bayer, BioNTech, Cardiff, Foundation, G1 Therapeutics, Ipsen, Novartis, Noxxon, Pfizer, Stemline.

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.