Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer

Abstract

The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine [encoding transgenes for prostate-specific antigen (PSA) and 3 costimulatory molecules] in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3-5 also received intraprostatic rF-GM-CSF. Cohort 5 received additional subcutaneous boosters with rF-PSA-TRICOM and rF-GM-CSF. Patients had pre- and post-treatment prostate biopsies, and analyses of peripheral and intraprostatic immune cells were performed. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. The most common grade 2 adverse events were fever (38%) and subcutaneous injection site reactions (33%); the single grade 3 toxicity was transient fever. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4+ (p = 0.0002) and CD8+ (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Clinical trials examining clinical end points are warranted.

Complex interplay between tumor microenvironment and cancer therapy

“…Preclinical studies indicated that intratumoral subcutaneous priming and intratumoral boosting was obtained with the delivery of recombinant vaccinia virus expressing TAA [136,137]. Several clinical trials are undergoing and support the advantages of intratumoral poxviruses expressing TAA [138,139]. In summary, the studies indicate that oncolytic viruses can be used as tools to modify the immunological components of the TME to improve the outcomes of cancer therapy.…”

Oncolytic viruses: focusing on the tumor microenvironment

“…The finding of increased inflammatory and T-cell infiltration in both local and distant lesions after intratumoral treatment with Newcastle disease virus, and subsequent systemic response to CTLA-4 blockade, shows the critical role that the inflammatory mileu induced by oncolytic virus itself likely plays in attracting anti-tumor T lymphocytes. 22 Clinical studies support the advantages of intratumoral poxviruses expressing TAA, including ongoing clinical trials of intraprostatic poxviruses expressing prostate-specific antigen in patients with prostate cancer 23,24 and our recently concluded phase I trial of intratumoral Panvac in patients with locally advanced pancreatic cancer. 25 Recombinant oncolytic viruses, expressing both TAA and immune stimulatory cytokines represent a powerful tool for transforming the tumor microenvironment to support an improved antigen presentation and generation of systemic immune …”

Integrating Immunotherapies in Prostate Cancer

“…To overcome possible immunosupression in the tumor microenvironment, this trial is also evaluating low dose cyclophosphamide in combination with sipuleucel-T and CT-011 as low dose cyclophosphamide has been shown to selectively reduce CD4+ CD25+FoxP3+ T regs leading to improved immune responses when combined with vaccine therapies [54,55]. Evidence of a local immune response in tumor tissue is not limited to sipulecuel-T. A phase I study of intraprostatic prostvac for locally recurrent prostate cancer found a marked increase in CD4+ (P=0.0002) and CD8+ (P=0.0002) T cells in tumor biopsies following therapy [41].…”

“…Of the 104 patients studied, 57 % had a greater than twofold increase in their PSA specific T cells (measured by IFN-γ ELISPOT assay) [40•]. A separate phase I study of intraprostatic prostvac in locally recurrent prostate cancer found a peripheral immune response to PSA or NGEP in 44 % of evaluated patients [41]. Prostvac's immune effect is likely not limited to effector T cells.…”