Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single-agent checkpoint blockade

Jun Gong,Richard Tuli,Vincent Chung,Jeremy Chuang,Daneng Li,Ravi Salgia,May Cho,Andrew Hendifar

doi:10.1186/s40169-018-0210-9

Abstract

Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer. Furthermore, early clinical evidence has begun to support the feasibility and efficacy of checkpoint inhibitor-based combination therapy in advanced pancreatic cancer. Despite accumulating preclinical and clinical data, there remains several questions as to the optimal dosing and timing of administration of respective agents, toxicity of combination strategies, and mechanisms by which immune resistance to single-agent checkpoint blockade are overcome. Further development of biomarkers is also important in the advancement of combination systemic therapies incorporating checkpoint blockade in pancreatic cancer. Results from an impressive number of ongoing prospective clinical trials are eagerly anticipated and will seek to validate the viability of combination immuno-oncology strategies in pancreatic cancer.

Highlights

Monoclonal antibodies targeting the programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) are approved as cancer immunotherapy for a number of solid tumors and hematologic malignancies [1]
Immune active tumors that are sensitive to checkpoint inhibitors such as melanoma, lung squamous cell carcinoma, or lung adenocarcinoma are characterized by an abundance of CD8+ tumor-infiltrating lymphocytes (TILs), while pancreatic cancer represents an immune quiescent tumor characterized by lack of infiltration by effector T-cells that is otherwise critical in driving the antitumor response to checkpoint blockade [11]
IV intravenous, GM-CSF cell-based vaccine (GVAX) allogeneic pancreatic tumor cells transfected with granulocyte–macrophage colony-stimulating factor (GM-CSF) gene, SD stable disease, OS overall survival, CI confidence interval, HR hazard ratio, PR partial response, D day, MTD maximum-tolerated dose, PFS progression-free survival, NR not reported, PD-1 programmed cell death protein 1 receptor, PARP poly (ADP-ribose) polymerase, G gemcitabine, N nab-paclitaxel, X capecitabine, RT radiation therapy, Gy gray, adverse events (AEs) adverse event, TGFβ transforming growth factor beta, DCR disease control rate due to futility [50]

Summary

Introduction

Monoclonal antibodies targeting the programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) are approved as cancer immunotherapy for a number of solid tumors and hematologic malignancies [1]. Chemotherapy The CTLA-4 inhibitor tremelimumab in combination with weekly gemcitabine demonstrated preliminary efficacy and tolerability with the most common grade 3–4 toxicities being asthenia (11.8%) and nausea (8.8%) in a phase Ib trial enrolling treatment-naïve metastatic pancreatic cancer patients [48]. IV intravenous, GVAX allogeneic pancreatic tumor cells transfected with granulocyte–macrophage colony-stimulating factor (GM-CSF) gene, SD stable disease, OS overall survival, CI confidence interval, HR hazard ratio, PR partial response, D day, MTD maximum-tolerated dose, PFS progression-free survival, NR not reported, PD-1 programmed cell death protein 1 receptor, PARP poly (ADP-ribose) polymerase, G gemcitabine, N nab-paclitaxel, X capecitabine, RT radiation therapy, Gy gray, AE adverse event, TGFβ transforming growth factor beta, DCR disease control rate due to futility [50]. A maximum-tolerated dose (MTD) was not reached at the highest dose level of 20 mg/kg every 2 weeks (Table 2)

Findings

Discussion

Conclusion