Prostate cancer: Enoblituzumab a monoclonal antibody that targets the immune checkpoint protein

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Enoblituzumab in Localized Prostate Cancer: A Promising Immunotherapy Approach

Prostate cancer is the second most commonly diagnosed cancer in men worldwide, with an estimated 1.4 million new cases in 2020 alone. Despite advances in treatment options such as surgery, radiation therapy, and androgen deprivation therapy, some patients with localized prostate cancer may experience disease progression, recurrence, and metastasis.

Therefore, there is a need for new treatment options that can improve patient outcomes and quality of life. Immunotherapy has emerged as a promising approach for the treatment of prostate cancer, and enoblituzumab, a B7-H3-targeting antibody, is one such immunotherapeutic agent that is being studied in clinical trials.

B7-H3 (CD276) is a transmembrane protein that belongs to the B7 family of immune checkpoint molecules. It is expressed on the surface of various cancer cells, including prostate cancer, and has been shown to be associated with tumor progression and poor prognosis.

B7-H3 can act as both a co-stimulatory and co-inhibitory molecule, modulating T cell function and immune responses. B7-H3 overexpression in prostate cancer cells can also promote cancer cell proliferation, migration, and invasion, highlighting its role in tumorigenesis and metastasis.

Enoblituzumab is a humanized, Fc-engineered monoclonal antibody that specifically targets B7-H3 on tumor cells. It mediates antibody-dependent cellular cytotoxicity (ADCC), a process by which immune cells such as natural killer (NK) cells and macrophages are activated to target and kill cancer cells that express the target antigen. Enoblituzumab has shown promising preclinical activity in prostate cancer models, and clinical trials are underway to evaluate its safety, efficacy, and immunogenicity in patients with prostate cancer.

A phase 2, biomarker-rich neoadjuvant trial of enoblituzumab in patients with localized prostate cancer was conducted to assess the safety and efficacy of this immunotherapeutic agent. The trial enrolled 32 biological males with operable intermediate to high-risk localized prostate cancer to receive enoblituzumab before prostatectomy.

The primary endpoints were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA0 with reasonable precision.

The results of the trial showed that enoblituzumab was well-tolerated with no notable unexpected surgical or medical complications or surgical delay. The primary safety endpoint was met, with no grade 4 adverse events observed. The primary efficacy endpoint of PSA0 rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%), suggesting potential clinical activity of enoblituzumab in prostate cancer. Moreover, patients who achieved PSA0 had a higher frequency of B7-H3-specific T cells in their peripheral blood, indicating a potential immune response to enoblituzumab treatment.

The study results validate B7-H3 as a rational target for therapy development in prostate cancer, and larger studies are planned to further evaluate the safety and efficacy of enoblituzumab in this patient population. The trial also highlights the potential of neoadjuvant immunotherapy to enhance the immune response against cancer and improve patient outcomes.

The use of enoblituzumab as an immunotherapeutic agent in prostate cancer is supported by the growing understanding of the role of B7-H3 in cancer pathogenesis and immune regulation. By specifically targeting B7-H3 on tumor cells, enoblituzumab can activate immune cells to recognize and eliminate cancer cell.

Potential Limitations and Future Directions

The present study has several potential limitations. Firstly, the small sample size and lack of a control arm limit the ability to draw definitive conclusions about the clinical activity of enoblituzumab in localized PCa. Larger randomized controlled trials are needed to further investigate the safety and efficacy of B7-H3–targeted immunotherapy in this patient population.

Secondly, the neoadjuvant design of the trial only allowed for evaluation of short-term outcomes, and longer follow-up is needed to assess the impact of enoblituzumab on disease recurrence and survival. Lastly, the study did not include patients with low-risk PCa, and the safety and efficacy of enoblituzumab in this population remain unknown.

In future studies, it will be important to investigate potential biomarkers of response to B7-H3–targeted immunotherapy, as well as to evaluate the optimal dosing and scheduling of enoblituzumab. Additionally, combining enoblituzumab with other immune checkpoint inhibitors or conventional therapies may enhance its therapeutic efficacy.

Conclusion

Enoblituzumab is a promising B7-H3–targeted immunotherapy that has demonstrated safety and preliminary clinical activity in the neoadjuvant treatment of localized PCa. The results of this phase 2 trial support further investigation of enoblituzumab in larger randomized controlled trials, and validate B7-H3 as a rational target for therapy development in PCa. As the field of immuno-oncology continues to evolve, B7-H3 represents a promising target for novel immunotherapeutic strategies in PCa and other cancers.

Data Availability

TRV-β-seq of tumor and peripheral T cells, as the project ‘Neoadjuvant B7H3 Trial in Prostate Cancer’, is available in the immuneACCESS free public database at https://clients.adaptivebiotech.com/immuneaccess. The authors deferred trial participant raw genomic data deposition to national or international public repositories to avoid compromising privacy of the research participants. A summary of patient whole-exome sequence alterations of clinical significance is provided in Supplementary Data Table 4. Aggregate patient-related information has been made available on ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/results/NCT02923180). Additional requests for raw and analyzed data can be referred to the corresponding author (E.S.) and will be reviewed promptly as part of a data transfer agreement per Johns Hopkins’ institutional policies, to determine whether the request is subject to any clinical trial patient confidentiality or intellectual property requirements. Source data are provided with this paper.

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