Naslov
COMBINATORIAL THERAPEUTIC APPROACHES WITH PD-1 INHIBITION IN PROSTATE CANCER

Autori
Benjamin Benzon, Stephanie Glavaris, Brian Simons, Robert Hughes, Kamyar Ghabili, Patrick Mullane, Rebecca Miller, Katriana Nugent, Brian Shinder, Jeffrey Tosoian, Richard Blosser, Ephraim Fuchs, Phuoc Tran, Paula Hurley, Milena Vuica-Ross, Edward Schaeffer, Charles Drake, and Ashley Ross

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Journal of Urology / - , 2016

Skup
American Urological Association (AUA) 2016 Annual Meeting

Mjesto i datum
San Diego (CA), Sjedinjene Američke Države, 06.05.2016. - 10.05.2016

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
prostate cancer, immunotherapy

Sažetak
INTRODUCTION AND OBJECTIVES Checkpoint blockade targeting PD-1 or CTLA-4 works by fundamentally different mechanisms (with CTLA-4 inhibition acting at secondary lymphoid organs for activation of naïve T cells, and PD-1 interactions being regulated at the tissue / tumor level to effect T cells already exposed to antigen). The efficacy and toxicity profile of anti-PD-1/PD-L1 and anti-CTLA-4 therapies also differ greatly, with PD-1/PD-L1 therapy having relatively low toxicity. In both humans and animal models, PD-1 directed therapy for prostate cancer had not been shown to be efficacious. Here we investigate combinatorial strategies to augment the effect of PD-1 therapy in a mouse model. METHODS Immuno-competent FVB mice were bilaterally implanted with Myc-CAP cells to form isogenic grafts. Four weeks after tumor introduction tumors were treated with either 10mg/kg of anti-PD-1 therapy alone or in combination with cryotherapy to one tumor. In a separate experiment, the same paradigm was followed but mice were pre-treated with 25mg/kg of Degarelix after palpable tumors were seen (followed by cryotherapy and anti-PD1). Finally, we performed a similar set of experiments but in the presence or absence of pretreatment with epigenetic modifiers (5-azaccytidine and Entinostat). RESULTS Therapy with anti-PD1 or anti-PD1 combined with cryotherapy marginally and insignificantly increased mouse survival and time to logarithmic tumor growth. Addition of neoadjuvant androgen deprivation significantly increased median survival (from 40 days to 60 days, p<0.001). Pre- treatment with epigenetic modifiers did not significantly increase mouse survival or time to logarithmic tumor growth. In addition, mice receiving epigenetic modifiers showed clinical signs of distress and experienced one treatment related death. CONCLUSIONS Combinatorial strategies including anti-PD-1, androgen deprivation, and tumor ablation at one metastatic site appear promising in a mouse model of prostate cancer. Addition of epigenetic treatments increased toxicity with marginal increase in efficacy. These results have formed the basis of a recently opened trial in men with low volume metastatic disease (NCT02489357).

Izvorni jezik
Engleski

POVEZANOST RADA