Multicenter phase I trial of a DNA vaccine encoding the androgen receptor ligand binding domain (pTVG-AR, MVI-118) in patients with metastatic prostate cancer

Abstract

Abstract Background Preclinical studies have demonstrated that a DNA vaccine encoding the androgen receptor ligand-binding domain (AR LBD) can elicit CD8+ T cells specific for the AR LBD, delay disease progression and prolong survival of prostate tumor-bearing animals. Vaccination of tumor-bearing mice treated with androgen deprivation (AD) led to a delay in the emergence of castration-resistant disease. This same DNA vaccine (pTVG-AR, MVI-118) was evaluated in a phase I clinical trial in men with metastatic prostate cancer (mPC) on AD therapy. Methods 40 patients with mPC, within 6 months of beginning standard AD therapy, were randomly assigned to receive pTVG-AR on one of two different treatment schedules, and with or without GM-CSF used as an adjuvant. Ten total vaccinations were given over 1 year, and patients were followed for 18 months. The primary objectives were safety and immune activity. Secondary objectives were to evaluate different schedules, the requirement for GM-CSF, and whether treatment was associated with PSA progression-free survival (PSA PFS). Results Between 2015 and 2017, 40 patients were enrolled at 3 centers. 27 patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event. No grade 3 or 4 adverse events were observed. Samples from 30 patients were available for immune analysis. 14/30 (47%) developed Th1 biased immunity to the AR LBD as determined by IFNγ or granzyme B ELISPOT that was detectable at least twice after beginning treatment. Differences in immune responses were observed with different schedules, but not with GM-CSF adjuvant. Patients who developed immunity had a significantly prolonged PSA PFS compared to patients without immunity (HR\xa0=\xa00.18, 95% CI: 0.04-0.92, p\xa0=\xa00.040). Conclusions This trial showed that pTVG-AR was safe and immunologically active in patients with mPC, and identified a preferred schedule of administration. Association between immunity and PSA PFS suggests treatment may delay the time to castration resistance, similar to observations in preclinical studies. Future studies will evaluate pTVG-AR in earlier stages of disease, and in combination with other agents. Clinical trial identification NCT02411786. Legal entity responsible for the study Douglas McNeel. Funding Madison Vaccines, Inc. Disclosure D.G. McNeel: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Madison Vaccines Inc; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck. R. Lesniewski: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Madison Vaccines Inc. B. Olson: Licensing / Royalties: Madison Vaccines Inc. C. Kyriakopoulos: Research grant / Funding (institution): Madison Vaccines Inc. All other authors have declared no conflicts of interest.