Newswise — The immune checkpoint protein B7-H3 may be a promising new target for immunotherapy in treatment-resistant prostate cancers, according to two new studies led by researchers at Johns Hopkins Kimmel Cancer Center. The studies were recently presented at the ESMO 2021 Congress.
says Eugene Shendorf, MD, PhD, lead author of both studies and assistant professor of oncology at Johns Hopkins. However, prostate cancer cells do not express much PD-L1, a protein targeted by FDA-approved immunotherapy agents used to treat melanoma, non-small cell lung cancer, bladder and kidney cancer, among others, which may explain the response These treatments are less powerful for prostate cancer patients.
Immunotherapy agents known as “checkpoint inhibitors” unlock certain molecules that act as cuffs that prevent the body’s natural immune system from fighting cancer cells. When these restrictions are lifted, the T cells of the immune system can wake up and attack the cancer cells.
Study 1 (Abstract #627) was a phase II trial of anti-B7-H3 enoblituzumab antibody in 32 patients with localized prostate cancer who were scheduled to undergo prostatectomy. Patients received six weekly infusions of inuplituzumab prior to surgery. The investigators then compared biopsy samples taken at diagnosis with the removed prostate to study changes in tumor tissue. Some patients had significantly lower prostate-specific antigen (PSA) levels, a measure of cancer severity, and there were more functional immune cells seen after treatment with enoblituzumab, indicating a change in the tumor microenvironment.
The second study (summary number 620) was a phase I study – a study aimed at determining toxicity associated with a new drug treatment – evaluating an experimental agent called MGC018 in solid tumors. The drug contains an anti-B7-H3 antibody along with an anti-cancer agent called duocarmycin, which allows the drug to deliver a duocarmycin payload directly to cancer cells that express B7-H3. Among the patients studied were 39 with metastatic castration-resistant prostate cancer who had already received prior treatment with chemotherapy and hormonal therapies. They received increasing doses of the treatment every three weeks. Of the 39 patients evaluated by the study poster deadline, 21 (54%) had a PSA decrease of more than 50% from baseline, and four of 16 patients evaluated radiographic response had a partial response, Which means their cancer has partially responded to treatment. Prostate cancer cells secrete PSA and its presence is used as a biomarker of disease burden. More than half of the studied patients experienced severe or life-threatening (grade III or higher) adverse events, suggesting the need to reduce toxicity in further drug development. This included patients with non-small cell lung cancer, melanoma, triple negative breast cancer, and head and neck squamous cell carcinoma.
“Everything seems to point to the fact that B7-H3 is likely to be an important therapeutic target in the prostate cancer setting,” says Shendroff. He and his colleagues plan to conduct a clinical trial to study combination therapies that target B7-H3 to determine whether it enhances the immune response.
The research was supported by Conquer Cancer, Macrogenics, the Prostate Cancer Foundation, and the Congressional-administered Department of Defense Medical Research Programs.
Shenderov is the founder and CEO of LifeImmune Inc. She has received institutional research funding for clinical trials from Macrogenics, and has served as a consultant for First Thinkt.io and Guidepoint Global. Johns Hopkins University manages these relationships in accordance with its conflict of interest policies. Macrogenics was a sponsor of the MGC018 study.