This study is a prospective, open label, single arm phase II trial. A total of 22 patients will be treated with atezolizumab, PROSTVAC, and pre-operative MVA-BN-Brachyury to confirm the efficacy of prostatic combination immunotherapy and to measure the relative change in the number of tumor infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.
Here we propose to use a combination of both checkpoint therapy with dual vaccine therapy. Patients will be treated with an intraprostatic injection of MVA-BN-Brachyury and subcutaneous PROSTVAC therapy. MVA-BN-Brachyury is a replication-deficient, attenuated vaccinia virus (Ankara strain) expressing both a CD8+ T-cell epitope from the brachyury protein and a triad of T-cell co-stimulatory molecules (B7.1, ICAM-1 and LFA-3). MVA-brachury-TRICOM, upon infection of cells, causes innate and then adaptive immune responses, antigen cascade, and improved T cell trafficking to the tumor. Vaccine therapy is one strategy that might increase immune infiltration into the tumor microenvironment. Prostate cancer is known to have minimal lymphocyte infiltration within the microenvironment. This vaccine strategy of direct injection into the tumor in combination with checkpoint inhibitors has previously been performed in early phase clinical trials.6 Furthermore, this approach of potent vaccine vector use can induce systemic effects as seen in a recent clinical trial of 12 patients with metastatic melanoma.12 In that study, responses were also observed in non-target lesions. In this case, MVA-BN-Brachyury is preferred as in intralesional injection agent over other vaccines due to the increased immunogenicity of MVA compared with fowlpox and improved safety profile for direct injection when compared with vaccinia, due to replication incompetence. In the prior study with MVA-BN-Brachyury no patients were observed to have replication of the virus. T cell mediated tumor cell killing is dependent on specific T cell recognition of a tumor target antigen, localization of those specific T cells to the tumor, and those T cells properly functioning within the tumor microenvironment. We hypothesize that these three primary issues comprise the major causes of most patients receiving no benefit from checkpoint inhibitor therapy or with vaccine monotherapy. We hypothesize that these issues can be addressed with an active intratumoral virus administration approach combined with the use of a subcutaneously administered vaccine (PROSTVAC) to induce PSA-specific T cell activation in combination with a checkpoint inhibitor. Combination viral based vaccine plus immune checkpoint inhibitor therapy will result in exposure of cancer specific antigens and induce inflammation at the site of the cancer ultimately resulting in significant clinical antitumor effect. Additionally, we hypothesize that the concurrent administration of anti-PD-1 moncolonal antibody therapy is necessary to allow those active T cells to achieve tumor cell killing, and significant overall clinical efficacy. The addition of atezolizumab is likely to provide additional efficacy over vaccine therapy alone. This is suggested by the induction of PD-1+ T-cells with vaccines.17 Additionally, PD-1 inhibition with nivolumab18 and pembrolizumab19 have shown clinical activity in metastatic prostate cancer. We suggest that the combination will provide even greater efficacy. Multiple studies have demonstrated a strong correlation between density of lymphocytes and prognosis, including overall survival.13-16 Given the very low density of infiltrating lymphocytes historically in prostate cancer, (Kaur HB, Hum Path 2019) we suggest that the primary endpoint of the change in CD8+ density is a reasonable pharmacodynamic endpoint for this exploratory, hypothesis generating study. However, as this study will be the first to date of the treatment combination, safety will also serve as a co-primary endpoint. The secondary objectives of PSA responses will help confirm the clinical utility of this approach in this target population.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Cycle= 21 days. Neoadjuvant Therapy: Treatment will be given for 2 neoadjuvant cycles. MVA-BN-Brachyury will be administered as intratumoral injection on Day 1 of each of 2 neoadjuvant cycles. PROSTVAC-V will be administered as a subq injection on Day 1 of Cycle 1 (the first neoadjuvant cycle) and PROSTVAC-F will be administered as a subq injection on Day 1 of Cycle 2 (the second neoadjuvant cycle). Atezolizumab will be given as an infusion on Day 1 of each 2 neoadjuvant cycles. MVA-BN-Brachyury will be injected intratumorally into the prostate. Injections will target PI-RADS 4 and 5 lesions. Surgery: Patients will undergo SOC radical prostatectomy Adjuvant Therapy: Systemic treatment with atezolizumab and PROSTVAC-F will be reinitiated between 3 to 8 weeks after surgery and will continue for an additional 6 cycles. PROSTVAC-F will be given as a subq injection on Day 1 of each cycle. Atezolizumab will be given as an infusion on Day 1 of each cycle.
Huntsman Cancer Institute
Salt Lake City, Utah, United States
To measure the relative change in the number of infiltrating CD8+ lymphocytes within the prostate tissue between the paired biopsy and radical prostatectomy specimens.
CD8+ lymphocytes in diagnostic biopsy and prostatectomy tissue samples will be quantified by immunohistochemistry (IHC) and analyzed using digital quantification. The relative change will be reported.
Time frame: Within 8 weeks after cycle2 day 1 visit
To assess the safety of combination immunotherapy in localized prostate cancer through evaluation of Adverse Events (AEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs)
Adverse Events (AEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs) as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v5.0), timing, seriousness, and relationship to study treatment will be documented.
Time frame: Lead-in safety evaluation for first 6 subjects is the time from Cycle 1 Day 1 until the start Cycle 3 Day 1(about 63 days) then continuing through completion of the study. From enrollment through completion of the study for the remaining participants
To assess the undetectable PSA rate
Undetectable PSA rates at 6 months and 12 months post-prostatectomy. This will be compared with Huntsman Cancer Institute (HCI) historical controls. Matching will be based on NCCN risk categories, age and follow up time.
Time frame: 6 and 12 months
Assess clinical activity of perioperative combination immunotherapy.
PSA evaluation will occur every 90 days after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy. PSA progression will be defined based on Prostate Cancer Working Group 3 (PCWG3) criteria.
Time frame: PSA evaluation will occur every 3 months after completion of the adjuvant treatment period. PSA relapse-free survival will be calculated and compared to HCI matched historical controls. Patients will be followed for 2 years after prostatectomy.
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