In renal cell and bladder cancers, inflamed tumor with the presence of T cells uses PD-L1 blockade to release the brakes on T cells and cause tumor cell lysis. In prostate cancers, tumor cells tend to be “non-inflamed”. It has been theorized that the use of vaccine with PDL1 inhibition will release those breaks on the T cells to initiate tumor destruction.
Currently, in prostate cancer, only one approved immunotherapy exists, Sipuleucel-T, for patients with minimally symptomatic or asymptomatic metastatic castrate resistant prostate cancer. However, the Society for Immunotherapy of Cancer Consensus (SITC) statement warns physicians to not expect a PSA decrease or objective response. Prostvac-VF is presently being investigated in clinical trials with the hope of induction of tumor specific immune responses. In a phase II trial, overall survival was 25.1 months vs 16.6 months in the control arm (HR 0.56, 95% CI 0.37-0.85). A phase II trial was then conducted randomizing asymptotic or minimally symptomatic mCRPC patients to Prostvac-vf + GM-CSF, Prostvac-vf or a vector placebo and followed for 5 years. Median survival in all groups was 33.9 months, however, on subgroup analysis, it did not meet endpoints. Prostvac did have an impact on PSA response. On a separate study, prostvac was shown to increase intra- and peri-tumoral immune infiltrate in patients with localized prostate cancer when given in the neoadjuvant setting and examined after radical prostatectomy.
PD1/PDL1 inhibition has been shown to demonstrate a rapid, deep, durable response across a wide range of tumors in a subset of patients. An ongoing trial is using Prostvac + Ipilimumab + Nivolumab (NCT02933255) in mCRPC patients who have not undergone prior chemotherapy. Two of four patients have demonstrated significant PSA response. A separate marker, TGF-B, has been associated with T cell exclusion and a lower overall response rate to PDL1 blockade. Multiple open trials for prostate cancer using combination therapy at the National Cancer Institute are underway.
In kidney cancer, previously published work by George et al demonstrated that CD8+ T cell density identifies a group of patients with prolonged disease-free survival with sunitinib treatment.
Shifting focus to bladder cancer, BCG is a live attenuated strain of mycobacterium bovis that was first described for use in urothelial carcinoma in 1976 and approved for non-muscle invasive disease in 1990. One of the earliest effective immunotherapies, physiologic mechanism of action incudes inflammatory response with induction of type 1 cytokines and should be utilized for intermediate or high-risk patient. Mainly in the metastatic setting, multiple studies have looked at various checkpoint inhibitors in either both the cisplatin eligible and ineligible populations. On May 18, 2018, the FDA released a statement that PDL1 negative patients do worse if treated with PD1/PDL1 blockade that cisplatin in eligible patients.
Multiple phase III checkpoint inhibitor trials are underway in the adjuvant setting. Dr. Gulley explained the schema of the PURE-01 study, a phase II single arm open label study of pembrolizumab in the neoadjuvant setting. Pathologic compete response was 39% in all patients and 48% in PD-L1 positive patients, compared to ddMVAC of 28%.
Dr. Gulley stated that the future of immunotherapy in the realms of bladder, kidney and prostate cancers has an exciting future.
Presented By: James L. Gulley, MD, PhD, National Cancer Institute
Written by: David B. Cahn, DO, MBS Fox Chase Cancer Center Philadelphia, PA Twitter: @dbcahn at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA