Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC.

Abstract

INTRODUCTION:

Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.

METHODS AND RESULTS:

Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti-PD-L1/anti-PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10.

CONCLUSIONS:

Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.

• Authors: Triparna Sen, Carminia M Della Corte, Snezana Milutinovic, Robert J Cardnell, Lixia Diao, Kavya Ramkumar, Carl M Gay, C Allison Stewart, Youhong Fan, Li Shen, Ryan J Hansen, Bryan Strouse, Michael P Hedrick, Christian A Hassig, John V Heymach, Jing Wang, Lauren A Byers
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 14 Issue 12 Pg. 2152-2163 (12 2019) ISSN: 1556-1380 [Electronic] United States
• PMID: 31470128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• Programmed Cell Death 1 Receptor
• SRA737
• Deoxycytidine
• Gemcitabine

Topics

• Administration, Oral
• Animals
• Combined Modality Therapy (methods)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Female
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Immunotherapy (methods)
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Small Cell Lung Carcinoma (drug therapy, pathology)
• Tumor Microenvironment (immunology)
• Xenograft Model Antitumor Assays
• Gemcitabine