A study published in Lancet oncology demonstrated that anti-CTLA-4 (Ipilimumab) + radiation therapy in castration resistant prostate cancer (CRPC) did not show a statistically significant cancer specific survival benefit (Figure 1).1 There are some critical issues for further clinical development. These include:
1. What are the cellular and molecular mechanisms involved in the anti-tumor effect? Toxicities?
2. Can we identify predictive, prognostic of pharmacodynamic biomarkers?
3. What are the best standard of care therapies to combine with immune checkpoint blockade and how do we combine these agents?
4. Can we identify new targets to help improve the numbers of patients who benefit?
5. And most importantly, why do some patients respond and some don’t
There are additional inhibitory pathways in prostate tumor microenvironment, aside from CTLA-4. These include STAT1, ICOS, STAT4, JAK2, PD-L2, JAK1, PD-L1, VISTA, PD-1, and LAG-3. It has been shown that PD-L1 expression in prostate cancer increases after treatment with Ipilimumab. This has also been shown with VISTA expression in prostate cancer. VISTA and PD-1/PD-L1 have been shown to be potent inhibitor of human T cell responses.
Targeting multiple immune checkpoints in a murine prostate tumor model has been demonstrated to be more beneficial than targeting a single immune checkpoint (Figure 2). Ipilimuab-enhanced T-cell responses to conventional prostate cancer antigens and neoantigens (PSA, PSMA, PAP).
In summary, immune checkpoint therapy has joined the ranks of surgery, radiation and chemotherapy as a pillar of cancer treatment, but has not yet demonstrated clear clinical benefit for patients with prostate cancer. Prostate cancer is poorly infiltrated by T cells but an increase in T cell infiltration into prostate tumors may lead to expression of compensatory inhibitory pathways (PD1/PD-L1,VISTA) that suppress anti-tumor immune responses. Multiple immune checkpoints exists and are dynamic in their expression; therefore, they should be evaluated in both pre- and on-treatment human tumor samples to guide therapeutic decisions. T-cells from patients with prostate cancer are capable of recognizing mutated antigens expressed by prostate tumors. Ongoing studies will help to determine whether neoantigen-specific T cell responses correlate with anti tumor responses. Combination therapy will be necessary to improve anti-tumor immune responses with potential clinical benefit in patients with prostate cancer. Lastly, there is a plethora of novel immunotherapy targets that still need to be explored (Figure 3).
Figure 1: Ipilimumab +radiation therapy in castration resistant prostate cancer:
Figure 2: Targetting multiple immune checkpoint in a murine prostate tumor model:
Figure 3 – Novel immunotherapy targets:
Presented by: Padmanee Sharma, MD Anderson Cancer Center
Written by: : Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
References:
Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. The Lancet Oncology; 15(7): 700-12.