Researchers at The University of Texas MD Anderson Cancer Center have discovered that a combination of immune checkpoint blockade and targeted therapies that block normal DNA damage repair (DDR) achieved significant tumor regression in mouse models of small cell lung cancer (SCLC), suggesting a promising new approach for treating patients with this aggressive cancer.

The preclinical research, published today in Cancer Discovery, suggest that the PARP inhibitor olaparib and other DDR inhibitors induce a rapid immune response and sensitize SCLC cells to immunotherapy, to which they were previously resistant.

Small cell lung cancer, one of the most aggressive types of cancer, makes up about 15 percent of all lung cancers diagnosed in the U.S., representing about 30,000 patients each year, explained Lauren Averett Byers, M.D., associate professor of Thoracic/Head & Neck Medical Oncology and corresponding author on the study.

Standard treatment for advanced SCLC is chemotherapy, but recurrence is common and the average survival is only about 12 months, according to Byers. For about 30 years, there were no changes to this approach, but recently the use of immunotherapy in combination with chemotherapy has become a new standard. However, the benefits are minimal for patients.

"While the use of immunotherapy has revolutionized the way we treat lung cancer, we find that small cell lung cancers can escape the immune system very effectively, so we see a much lower response rate," said Byers. "However, we want to do a lot better for our patients, and we think there's a lot of room for further improvement."

Previously, Byers discovered that DDR pathways were highly active in SCLC and blocking these pathways with drugs, such as PARP and CHK1 inhibitors, was effective in treating SCLC in the lab. Additionally, cancers with extensive amounts of DNA damage have been shown to respond better to immunotherapy.

"Therefore, we predicted that if we combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, we might see a much greater response to the immune therapy," said Byers. "We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumors. In fact, in some cases, the tumors disappeared completely."

Combining the CHK1 inhibitor, prexasertib, or the PARP inhibitor, olaparib, together with an immune checkpoint inhibitor against PD-L1 resulted in significant tumor regression in SCLC mouse models, whereas immunotherapy alone had no effect.

The combination of PARP inhibitor and immunotherapy resulted in complete regression in all treated mice in as little as one week, leaving no tumors available for further analysis. The CHK1 combination treatment led to complete regression in 60 percent of treated mice.

The researchers discovered that DDR inhibitors activated an immune response in the mice, leading to an increase in cancer-killing immune cells in the tumors. This process was controlled by the STING pathway, which normally works to detect signals of a viral or bacterial infection. In this case, the STING pathway responded to DNA damage to activate the immune system, thus making SCLC cells susceptible to immunotherapy treatment.

"I think the results from this study are really compelling because of the dramatic activity that we saw with the combination of adding a targeted therapy to immune therapy," said Byers. "I think our findings can be rapidly translated into the clinic for our patients and also to other cancer types."

Clinical trials testing PARP inhibitors or immunotherapies for patients with SCLC are ongoing. Byers and colleagues hope to launch clinical trials to investigate the combination approach later this year, and expect this may also be effective in other cancer types defined by increased DNA damage, such as BRCA-mutant breast and ovarian cancers.

This study was supported by the Lung Cancer Moon Shot™, part of MD Anderson's Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

"The support of the Moon Shot really helped us to jumpstart the work in the lab and generate a great deal of the preliminary data that showed us this was a promising approach," said Byers. "That allowed us then to pursue additional funding to expand this work and advance it toward the clinic."

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This work also was supported by the National Cancer Institute (U01-CA213273, R01-CA207295, P30-CA016672), the Lung Cancer Research Foundation, the University of Texas Southwestern Medical Center and MD Anderson Lung SPORE (5 P50 CA070907), the MD Anderson Small Cell Lung Cancer Working Group, the Abell-Hanger Foundation Distinguished Professorship, the MD Anderson Physician Scientist Award, the R. Lee Clark Fellowship funded by the Estate of Jeanne F. Shelby, the Rexanna's Foundation for Fighting Lung Cancer, and the Elsa U. Pardee Foundation.

A full disclosure of conflicts of interest can be found with the full study.

In addition to Byers, MD Anderson authors include: Triparna Sen, Ph.D., Leticia Rodriguez, Ph.D., Limo Chen, Ph.D., Carminia Della Corte, M.D., Naoto Morikawa, M.D., Youhong Fan, Yongbin Yang, M.D., Ph.D., and Bonnie Glisson, M.D., all of Thoracic/Head & Neck Medical Oncology; Junya Fujimoto, M.D., Ph.D., and Ignacio Wistuba, M.D., both of Translational Molecular Pathology; Lixia Diao, Ph.D., Lerong Li, Ph.D., and Jing Wang, Ph.D., all of Bioinformatics and Computational Biology; John V. Heymach, M.D., Ph.D., Thoracic/Head & Neck Medical Oncology and Cancer Biology; and Don L. Gibbons, M.D., Ph.D., Thoracic/Head & Neck Medical Oncology and Molecular and Cellular Oncology. Additional authors include: Sandra Cristea, Thuyen Nguyen, and Julien Sage, Ph.D., all of Stanford University, Stanford, CA.