![Overcoming Resistance to Checkpoint Inhibitor Cancer Therapy]()
A drug targeting CTLA-4, a receptor protein on T-cells, was the first so-called immune checkpoint inhibitor approved for cancer immunotherapy. However, the majority of patients with cancer don’t respond to anti-CTLA-4 therapy. In a paper published online on May 6 in Nature Communications, Xingxing Zang, M.Med., Ph.D., and colleagues at Albert Einstein College of Medicine described a new mechanism for cancer resistance to anti-CTLA-4 therapy and also developed a new combination therapy that shows promise for overcoming that resistance.
The researchers analyzed 30 types of human cancers for the expression of B7x, a checkpoint protein on cancer cells that Dr. Zang had previously identified and that is associated with advanced disease and poorer clinical outcomes. Tumors expressing B7x were resistant to anti-CTLA-4 therapy and also contained large numbers of regulatory T-cells (Tregs), which are known to suppress the immune response against cancer. B7x, expressed on tumor cells or present as lone proteins, promoted the conversion of conventional T cells into Tregs. The findings suggested that B7x expression—by expanding the pool of Tregs in tumors—thwarts the effectiveness of anti-CTLA-4 therapy, which partially relies on depleting Tregs in tumors. Combining anti-B7x therapy with anti-CTLA-4 therapy in mouse models resistant to anti-CTLA-4 therapy led to successful treatment, suggesting that future clinical trials of cancer patients should assess the effectiveness of the new combination therapy. Related intellectual property and monoclonal antibody have been licensed to a drug company to develop medications targeting B7x.
Dr. Zang is professor of microbiology & immunology, of medicine, and of urology, the Louis Goldstein Swan Chair in Cancer Research at Einstein. The study’s first author is Peter John, a M.D./Ph.D. student in Dr. Zang’s laboratory.
Posted on: Friday, May 06, 2022