ASCO GU 2017: Keynote Lecture: Immunology of Prostate Cancer - Session Highlights
Early studies of PC treatment with programmed death-1/programmed dealth-ligand-1 (PD-1/PD-L1) blockade (heretofore referred to as PD-1 inhibition/blockade) did not demonstrate efficacy. From a cellular standpoint, this makes sense, as there are inherently fewer T cells infiltrating PC tumors than with other solid tumors. Genetically, PC also has a smaller mutational load than other tumors that have shown more activity with PD-1 blockade. That being said, tumors with more defects in DNA-repair genes,which certain PC tumors have been shown to have, may present more surface neoantigens and, therefore, may cause more T-cell infiltration that would have therapeutic consequences.
CTLA-4 is another part of the checkpoint signaling pathway that allows regulatory CD4 T cells to suppress cytotoxic CD8 T cells. For that reason,, CTLA-4 blockade can block CD8 T-cell suppression and has been shown to have good biological activity in various tumors. CTLA-4 blockade has already been studied in the postchemotherapy setting for patients with mCRPC. In one study, there was a trend toward improvement in survival, which was not significant, though one could argue that this had to do with the addition of those with visceral metastatic disease (usually not included in these studies).
An intriguing hypothesis that arose when studying the biological activity of these agents is that tumors may become sensitized to PD-1 inhibition. Graff and colleagues recently showed that patients with mCRPC who responded, then failed, enzalutamide treatment might subsequently become sensitized via various pathways to respond to PD-1 monotherapy. This is a fascinating finding as it demonstrates that sequential treatments may have additive or synergistic effects.
While sequential therapy options are enticing, combined/concurrent treatment is also proving to be an important treatment strategy. In animal models, researchers have demonstrated a strong synergistic function of combined PD-1 and CTLA-4 blockade. Clinically, this combined blockade has shown dramatic results in melanoma and is now U.S. Food and Drug Administration-approved for metastatic melanoma therapy.Piggybacking off these successes, investigators are evaluating the efficacy of combined blockade in mCRPC patients with AR-V7 expression in an ongoing trial (STARVE-PC). Data are likely to be available in 2018.
Cancer vaccination is another immunologic treatment option being widely investigated. Vaccines provide antigens that manipulate dendritic cells to activate CD8 T cells, which then turn against tumors. Unfortunately, when tumors detect the interferon-gamma secreted by these cytotoxic T cells, they upregulate PD-L1 in defense against incoming immune cells. To block this “adaptive resistance,” vaccines may be more effective when combined with PD-1 blockade.
In a similar vein, there are other ways to “heat up” the immune system to actively target tumors. There are promising data suggesting that bone-directed radiation (Radium-223) upregulates cytotoxic T cells and can be used in combination with PD-1 blockade. Other promising data suggest that prostate cryotherapy combined with PD-1 blockade and androgen deprivation therapy works against PC. Cryotherapy of the prostate induces necrosis, which causes a T-cell influx into the prostate and promotes immunologic antitumor activity with the assistance of PD-1 inhibition. There is currently a pilot clinical trial underway for men with oligometastatic disease using this treatment paradigm.
Dr. Drake specifically highlighted a paper by Liu and colleagues in Cancer Discovery 2016. In mice with metastatic breast cancer, researchers used neoadjuvant immunotherapy teamed with surgery and, surprisingly, found dramatic activity against metastatic disease in these animals. Indeed, the combined therapy worked significantly better than surgery alone or surgery followed by adjuvant immunotherapy. Dr. Drake is hopeful that this may be a treatment strategy that will show activity against other metastatic solid tumors and specifically PC.
In summary, there are many adjuvant checkpoint inhibitor trials currently in progress, both alone and in combination with other PC agents. There are also several vaccine trials underway also in combination with immunotherapy and other antitumor agents.
Indeed, this is a very exciting time in immunologic therapy for PC, and a series of ongoing clinical trials will highlight the way forward. As is the case in many other solid tumors, we should be thrilled about the mounting evidence promoting the efficacy of PC immunotherapy.
Speaker: Charles G. Drake, MD, PhD, Columbia University
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA