Study Suggests Way to Boost Immunotherapy Against Breast Cancer, Other Solid Tumors

Boosting immune system T cells to effectively attack solid tumors, such as breast cancers, can be achieved by adding a small molecule to a treatment procedure via chimeric antigen receptor (CAR) T-cell therapy, according to a study by researchers at the UNC Lineberger Comprehensive Cancer Center. The boost helps recruit more immune cells into battle at the tumor site, as noted in the findings published in the Journal of Experimental Medicine.

CAR T immunotherapy, in which T cells are modified in the laboratory to express CARs that in turn target surface proteins on cancer cells, has been most effective in the treatment of patients with B-cell leukemia or lymphoma. However, this study points to the potential for using CAR T-cell therapy effectively against solid tumors, as well, according to the authors.

"We know that CAR T cells are safe for patients with solid tumors but so far they have not been able to cause significant tumor regression in the overwhelming majority of people treated," said Jonathan S. Serody, MD, the Elizabeth Thomas Professor of Medicine, Microbiology and Immunology and director of the Immunotherapy Program at UNC Lineberger, in a press release. "Now we may have a new approach to make CAR T cells work in solid tumors, which we think could be a game-changer for therapies aimed at an appreciable number of cancers."

For CAR T-cell therapy to be effective, T cells infused back into patients have to be able to migrate to the site of the tumor. In patients with non-solid tumors, such as lymphomas, CAR-T cells home in on bone marrow and other organs that make up the lymphatic system. For solid tumors, however, this is not the case, since they do not persist and expand well there due to the nature of the microenvironment surrounding such tumors, according to the study.

The research team focused on Th17 and Tc17 cells, which are known to have longer persistence in the micro-environment that surrounds a tumor, in part due to better survival capabilities. To boost accumulation of Th17 and Tc17 cells near solid tumors, the researchers turned to 2 small molecules that can activate an immune response: the stimulator of interferon genes agonists (STING) DMXAA and cGAMP.

DMXAA, which worked well in the investigators’ mouse studies, has not provided benefit in human clinical trials, as it does not activate human STING, according to the study authors. The other STING agonist however, cGAMP, does activate human STING and is known to boost the human immune system.

In the research teams’ experiments, mice injected with cGAMP exhibited an enhanced proliferation of T cells, as those cells migrated to the tumor site. The end result was a significant decrease in tumor growth and enhanced survival.

"We hope to be able to study cGAMP in humans fairly soon," Serody said in a press release. "We will look to see if we can produce improvements in the treatment of head and neck cancers first, and if that proves promising, move into other forms of cancer by using CAR T cells generated by one of our colleagues here at UNC."

REFERENCE

Study points the way to boost immunotherapy against breast cancer, other solid tumors. EurekAlert! https://www.eurekalert.org/pub_releases/2020-12/ulcc-spt122920.php. Published December 31, 2020. Accessed January 5, 2021.