[HTML][HTML] Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy

P Jayaprakash, M Ai, A Liu, P Budhani… - The Journal of …, 2018 - Am Soc Clin Investig
P Jayaprakash, M Ai, A Liu, P Budhani, T Bartkowiak, J Sheng, C Ager, C Nicholas…
The Journal of clinical investigation, 2018Am Soc Clin Investig
Despite the success of immune checkpoint blockade against melanoma, many “cold” tumors
like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent
across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-
4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces
or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and
checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic …
Despite the success of immune checkpoint blockade against melanoma, many “cold” tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate–derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc–/–Smad4pc–/– mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.
The Journal of Clinical Investigation