B7-H3/CD276, a protein belonging to the B7 superfamily, is significantly expressed in prostate cancer and linked with a rapid recurrence of biochemical markers and early spread of cancer cells to other parts of the body. It has a potential binding site with androgen receptors, indicating possible interaction with the androgen axis. Enoblituzumab, an experimental antibody, is a humanized and Fc-optimized antibody that specifically targets B7-H3. It induces antibody-dependent cellular cytotoxicity, a process that enhances the immune system's ability to destroy cancer cells.
A recent Phase II study conducted by researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy has found that enoblituzumab shows promise as a potential therapy for prostate cancer (Nat Med 2023; https://doi.org/10.1038/s41591-023-02284-w).
In the Phase II, single-arm, biomarker-rich, neoadjuvant trial (NCT02923180), 32 men with operable intermediate- and high-risk localized prostate cancer (Grade Groups 3-5) were enrolled to assess the safety, anti-tumor efficacy, and immunogenicity of enoblituzumab when administered prior to prostatectomy. Patients received six weekly infusions of enoblituzumab (15 mg/kg IV) before surgery, and prostate glands were harvested for examination 2 weeks after the last dose to evaluate pathologic and immunologic endpoints.
The trial co-primary outcomes included safety and undetectable prostate-specific antigen (PSA) level (PSA0) at 1-year post-prostatectomy. Pre-planned secondary outcomes included PSA and Gleason grade group change from biopsy to prostatectomy. The aim of the trial was to obtain a precise estimate of PSA0 for evaluation of the drug's efficacy and safety.
The median age of the participants in the study was 64 years, with an age range of 48-74 years. Nearly half of the participants (47%) had a PSA level greater than 10 ng/mL at the time of diagnosis, which is considered abnormally high, and 50 percent had Gleason grade Group 5 at biopsy, indicating highly aggressive disease. Patients were enrolled in the study from February 2017 to June 2019. After surgery, prostate samples were examined, confirming that enoblituzumab was able to penetrate into prostate tumors and bind to B7-H3 in the majority of participants.
The study found that 12 percent of patients experienced Grade 3 adverse events, with no Grade 4 events occurring. One patient had a Grade 3 infusion reaction, and one experienced immune myocarditis that improved with steroids. Post-prostatectomy, 31 percent of patients showed a decline of >10 percent in PSA levels, and 66 percent had an undetectable PSA level at 1 year after surgery. Gleason grade group changes were significantly associated with enoblituzumab treatment. Tumor microenvironment profiling revealed upregulation of CD8+ T cells, PD-1/PD-L1 expression, and immune activation post-treatment. CD8+ T-cell increases were correlated with Gleason grade group declines. No safety concerns were found in first-in-human antigen spread profiling. Overall, enoblituzumab was well-tolerated with mild side effects such as fatigue, neurological symptoms, and flu-like or cold symptoms.
For expert analysis and additional insights on the study involving enoblituzumab, Oncology Times interviewed Eugene Shenderov, MD, DPhil, FACP, Assistant Professor of Oncology and Cancer Research Immunology at Johns Hopkins University School of Medicine, Member of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and Co-Director of the Prostate Cancer Multidisciplinary Clinic at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
Oncology Times: What are the potential implications of enoblituzumab as a treatment option for patients with high-risk localized prostate cancer?
Shenderov: "If randomized clinical trial(s) confirm enoblituzumab's efficacy in reducing the risk of prostate cancer recurrence following curative intent localized therapy in patients with high-risk localized prostate cancer, potentially the number of patients who die of prostate cancer would be reduced. High-risk patients are the ones that are most likely to progress to metastatic disease and eventually die from prostate cancer. As prostate cancer is the most common cancer in males, even a small percentage increase in men who do not recur following curative intent local radiation or surgery would mean many men would have the chance to live out the rest of their lives with their loved ones."
Oncology Times: How did enoblituzumab affect Gleason grade group change from biopsy to prostatectomy in the trial?
Shenderov: "Enoblituzumab therapy appeared to have reduced the Gleason grade group characterization in some men from biopsy to prostatectomy. This finding is preliminary and could be real or due to small sample size and differences inherent in comparing biopsy and prostatectomy tissues. Larger trials are required to help us understand the finding."
Oncology Times: How does enoblituzumab compare to other immunotherapy agents currently used in prostate cancer treatment?
Shenderov: "Enoblituzumab targets B7-H3, [which is] is a molecule expressed on virtually all prostate cancer cells and may prevent the immune system from eliminating the prostate cancer cells. Enoblituzumab is an antibody that binds to B7-H3. By latching onto the prostate cancer cell expressed B7-H3, enoblituzumab may allow the immune system to start to recognize the prostate cancer cell. Additionally, enoblituzumab is engineered to activate immune cells to kill cells through another immune mechanism called antibody-dependent cellular cytotoxicity, which may provide another route for the immune system to kill the cancer cells expressing B7-H3 and bound by enoblituzumab."
Oncology Times: What are the next steps in the clinical development of enoblituzumab for prostate cancer treatment, and what further research is needed to fully understand its potential benefits and limitations?
Shenderov: "Significant research is still ongoing in the laboratory to understand exactly how enoblituzumab drove the immune response seen in patients who appear to have responded to treatment compared to patients who did not. To tease out the full clinical efficacy and utility of enoblituzumab to be certain the findings seen in this small trial are reproducible will require randomized trials with control groups of patients not receiving enoblituzumab treatment. A larger randomized trial is being planned by Johns Hopkins in Baltimore."
Dibash Kumar Das is a contributing writer.