Posted September 1, 2023

Johann de Bono, M.D., Ph.D., The Institute of Cancer Research, London, United Kingdom
Andrea Alimonti, MD., Ph.D., Institute of Oncology Research, Switzerland
Michael Shen, Ph.D., Columbia University Medical Center

In recent years, successful biological treatments targeting the immune system (immunotherapy) have come to the forefront of cancer care. In prostate cancer, however, immunotherapy has been largely ineffective, likely due to the immune-suppressive nature of the environment surrounding prostate tumors. B7-H3 is an immune-regulating protein with high expression on prostate tumor cells. Recent studies indicate that B7-H3 may play a role in suppressing the antitumor immune response thereby promoting prostate cancer tumor growth. There is now emerging evidence for drugs targeting B7-H3 in prostate cancer as well as other cancer types, but the function and expression profile of this protein in prostate cancer, over time, remains unclear. With support from a fiscal year 2020 Translational Science Award – Partnering PI Option, Dr. Johann de Bono, Dr. Andrea Alimonti, and Dr. Michael Shen will assess the expression of B7-H3 in prostate cancer.

Through evaluation of B7-H3 and its receptor in biopsies from patients with lethal prostate cancer and assessing the protein’s association with immune cells in the tumor microenvironment, tumor genetics, and clinical outcomes, the team aims to determine approaches to precisely target B7-H3. To date, the team has evaluated B7-H3 expression in two data sets of gene expression in lethal prostate cancers. They found that, of all immune genes evaluated, the one coding for B7-H3 was among the most highly expressed in prostate cancer and was predominantly expressed on tumor cells, and not on normal tissue, indicating the potential to be a therapeutic target.

Assessment of biopsy samples from patients with metastatic castration-resistant prostate cancer — that is, cancer that is resistant to common hormone therapy — and pre-treatment tumor biopsy collected at the time of cancer diagnosis from the same patient revealed no significant change in B7-H3 protein expression on the cancer cell from early- to late-stage disease. These findings indicate that in patients with aggressive prostate cancer B7-H3 protein increased early in tumor development. Interestingly, the team also found that B7-H3 expression was higher in tumors with certain genetic changes that are associated with worse patient outcomes. Evaluating immune cell populations, the team found that tumors with high B7-H3 expression were infiltrated by fewer white blood cells with the ability to recognize and kill cancer cells. Additional experiments are needed to further assess impact on the immune system and validate these findings.

The team plans to determine the antitumor activity of targeting B7-H3 and to correlate response to tumor genetics and expression of the protein. They aim to develop biomarkers to indicate response to treatment and determine potential drug combinations. Thus far, the team has assessed a B7-H3 antibody drug conjugate (ADC). ADCs are an emerging treatment option that pair a cancer-treating drug with an antibody targeting a cancer-specific protein, in this case B7-H3. The team has treated prostate cancer cell lines, as well as tumors derived from patient biopsies grown as tiny 3D structures in the dish (also known as organoids) and implanted in mice with the B7-H3 ADC. Tumors with and without B7-H3 expression were used. The team showed that tumors expressing B7-H3 shrank in response to the B7-H3 ADC, whereas antitumor effects were not observed in tumors lacking B7-H3 expression. However, the antitumor activities varied across different tumor models indicating that B7-H3 was necessary for the antitumor effects but additional factors impacted response.

Dr. de Bono, Dr. Shen, Dr. Alimonti, and their collaborators are laying the framework for additional studies to better understand the role of B7-H3 in prostate cancer and its effect on immune cells. B7-H3 targeting drugs are currently being studied in other cancers, so the knowledge gained from this study could help other researchers understand the potential mechanisms of resistance. In addition, the team has shown the antitumor effects of B7-H3 ADCs that could be combined with other treatment options for prostate cancer and address issues of treatment resistance. Clinical trials with novel anticancer drugs targeting B7-H3 are now serving men suffering from advanced prostate cancer.

Publication:
Guo C, Figueiredo I, Gurel B, et al. 2023. B7-H3 as a therapeutic target in advanced prostate cancer. European Urology 83(3):224-238

Link:
Public and Technical Abstracts: B7-H3 (CD276) as a Therapeutic Target in Lethal Prostate Cancers

Top of Page