Understanding Antitumor T Cell Immunity in High-Risk Localized Prostate Cancer After Neoadjuvant Treatment with an Antibody Targeting the B7-H3 Checkpoint
Abstract
Scientific Objective and Rationale: Prostate cancer is the most prevalent male cancer and the second most common cause of cancer-related death in men. Advances have been made in early detection and local therapy, but few treatments have been able to dramatically alter the course of disease once it becomes metastatic, i.e., spreads to other organs, such as bone. Immunotherapy. The use of a person’s own immune system to target and kill melanoma, lung, and colon cancer has resulted in unprecedented advances in treatment. Unfortunately, in prostate cancer, current immunotherapy strategies have yielded minimal objective responses, possibly due to targeting of non-optimal immune mechanisms that are involved in prostate cancer, suggesting the need for alternative immunological approaches. We are investigating B7-H3, a presumed immune checkpoint molecule (a protein that is thought to keep the immune system in check), and blocking it allows activation of the immune system, in this case against a person’s own cancer. It has been shown to modulate anti-tumor immune responses, and its expression has been shown to correlate with worse clinical outcomes in men with prostate cancer. Specifically, B7-H3 expression appears to be associated with biochemical progression (PSA rise) and clinical progression (visible disease on imaging scans) following local treatment. To determine the anti-tumor, immunological, and biological effects of B7-H3 inhibition in men with high-risk localized prostate cancer, a pre-surgical, Phase II study (NCT02923180) is nearing full accrual. Patients undergo a pretreatment prostate biopsy and then receive enoblituzumab, a humanized monoclonal antibody against B7-H3, prior to radical prostatectomy. They then undergo radical prostatectomy. The primary endpoints of this study are the safety and feasibility of enoblituzumab in the pre-surgical prostate cancer setting and the PSA0 Response (undetectable PSA level <0.1 ng/mL) at 12 months following radical prostatectomy. The secondary endpoints include evaluating anti-tumor responses in the prostatectomy samples. Exploratory immune analyses, which are the focus of this proposal, are planned using the initial tumor biopsy, the post-treatment prostate specimens, and serial blood samples pre-, intra-, and post-treatment to interrogate anti-tumor immune responses. We hypothesize that enoblituzumab therapy, by modifying the tumor microenvironment, will lead to significantly reduced biochemical recurrence in high-risk prostate cancer patients who undergo prostatectomy due to objective antitumor immune responses and eradication of hidden (micro-metastatic) disease. Ultimate Applicability of the Research: The proposed research utilizes human clinically annotated samples from patients treated with enoblituzumab, as described above. The immunologic data collected in this study will guide biomarker development and inform future clinical trials in prostate cancer by elucidating the biology of high-risk prostate patients and assessing the impact of the novel treatment being utilized. We will also try to understand how prostate cancer cells hide from the immune system. We believe that the outlined research can achieve a patient-related outcome within 4 years, as all insights will be based on clinically annotated patient samples from the above Institutional Review Board-approved NCT02923180 study. Principal Investigator’s (PI’s) Career Goals in Prostate Cancer Research and Patient Care: The PI is himself a survivor of cancer, having survived childhood acute lymphocytic leukemia. Consequently, he aims to conduct translational research in genitourinary oncology, with a focus on immuno-oncology, both to treat patients at the bedside and develop new treatments in the laboratory. The PI has a significant track record in the field of immuno-oncology, having completed a D.Phil in tumor immunology as a Rhodes Scholar in the joint “Ox-Cam” doctoral program of the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910511
Entities
People
- Eugene Shenderov
Organizations
- Johns Hopkins University
- United States Army