Utilizing B7-H3 Targeted Therapeutics to Prevent Lethal Prostate Cancer: The Help Elucidate & Attack Longitudinally (HEAL) Prostate Cancer Trial Cohort
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 targeted immunotherapy in men with high-risk localized prostate cancer, a pre-surgical, neoadjuvant, study (NCT02923180) was completed and recently presented at ASCO 2022. Patients underwent a pre-treatment prostate biopsy and then received 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. We have now designed a phase 2, randomized, neoadjuvant clinical trial in high-risk local prostate cancer patients that is powered to properly assess whether enoblituzumab truly has clinical efficacy seen in the small, underpowered, 32-patient trial. Novel pathologic and immunologic analyses, which are the focus of this proposal, are included as secondary endpoints in order to allow a thorough interrogation of the mechanisms underlying enoblituzumab’s putative antitumor effects and provide lethal prostate cancer evolution. We hypothesize that B7-H3 is central to prostate cancer development and metastatic potential and that the studies herein will help understand lethal prostate cancer as never before. Ultimate Applicability of the Research and Impact: The proposed research utilizes human clinically annotated samples from patients treated with enoblituzumab as described above. If the clinical trial is successful we will proceed to an FDA registrational trial and use the analyses herein to guide trial design. No neoadjuvant therapy is approved in prostate cancer and hence significant need exists. We believe that the outlined research can achieve a patient-related outcome within 3 years, as all insights will be done in parallel to patient accrual for this soon to be launched trial, and DOD support is crucial for the biomarker correlative studies proposed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310390
Entities
People
- Eugene Shenderov
Organizations
- Johns Hopkins University
- United States Army