Immunotherapy is a type of cancer treatment designed to boost the body’s natural defenses to fight the cancer. It uses substances either made by the body or in a laboratory to improve or restore immune system function, according to the American Society of Clinical Oncology. Currently, there are two main forms of cancer immunotherapies: immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. Other ways of cancer immunotherapies are emerging, including targeting tumor-infiltrating regulatory T cells, or TI-Tregs, but with limited success. Most Treg-targeting therapeutics eliminate both tumor and normal Tregs, which can induce autoimmune-like side effects.
University of Florida Health Cancer Center researchers have found a potential new way of targeting this population of immune-suppressive T cells that could possibly benefit a large population of cancer patients, including those who will not respond to other immunotherapies.
The researchers discovered that B-cell lymphoma extra-large, or BCL-XL, is a potential molecular target of TI-Tregs, which play an important role within tumors to promote an immunosuppressive microenvironment and inhibit anti-cancer immunity. BCL-XL is an important survival factor for tumor cells and TI-Tregs.
“We purposely developed therapeutics that target the BCL-XL protein to kill both tumor cells and TI-Tregs and improve anti-tumor immunity, as well as to enhance anti-tumor response to chemotherapy,” said Daohong Zhou, M.D., associate director for translation and drug development at the UF Health Cancer Center and a co-corresponding author on the study, which was published online today in Nature Communications.
The researchers developed a compound called DT2216, which is a molecule that degrades BCL-XL and triggers cell death in some tumor cells that depend on BCL-XL for survival and TI-Tregs, but not in Tregs outside of the tumor to avoid normal tissue damage and autoimmunity — as is the case in some of other immunotherapies.
“BCL-XL is also important for platelet survival. Small molecule BCL-XL inhibitors such as Navitoclax have not been able to be developed as anticancer drugs because they cause dose-limiting thrombocytopenia,” said Guangrong Zheng, Ph.D., an associate professor in the UF College of Pharmacy’s department of medicinal chemistry and a co-author on the study.
About six years ago, Zheng’s group collaborated with Zhou to use a new technology called proteolysis-targeting chimeras, or PROTAC, to target this BCL-XL protein for degradation in tumor cells, but not in platelets, to overcome the on-target toxicity of BCL-XL inhibitors, which led to the discovery of DT2216.
“We initially didn’t expect DT2216 to have important functions in cancer-related immune regulations,” said Weizhou Zhang, Ph.D., an associate professor in the UF College of Medicine’s department of pathology, immunology and laboratory medicine and a co-corresponding author on the study. “This is a one-stone-kills-two-birds type of potential anticancer drug — it targets BCL-XL to kill cancer cells, at the same time to eliminate TI-Tregs to increase anti-tumor immunity.”
This discovery, co-funded by the National Cancer Institute and the Congressionally Directed Medical Research Programs (CDMRP), was done in cell culture and in non-immunocompromised animal models. However, it remains to be determined if DT2216 can be proven useful for cancer treatment in humans through careful clinical studies.
“The BCL-XL-targeted therapy via PROTAC will hopefully benefit patients who cannot benefit from or develop resistance to current immunotherapy,” Zhang said. “This application has big potential for patients whose cancer progression is dependent on TI-Tregs.”
This study published in Nature Communications on Feb. 24, 2021. Along with Zhang, Zhou and Zheng, the research team includes co-lead authors Ryan Kolb, Ph.D., and Umasankar De, Ph.D., as well as contributing authors Sajid Khan, Ph.D., Yuewan Luo, Ph.D., Myung-Chul Kim, Ph.D., Haijun Yu, Ph.D., Chaoyan Wu, Ph.D., Jiao Mo, Ph.D., Xin Zhang, Ph.D., Peiyi Zhang, Xuan Zhang, Ph.D., Nicholas Borcherding, M.D., Ph.D., Daniel Koppel, Yang-Xin Fu, M.D., Ph.D., and Song Guo Zheng, M.D., Ph.D.