Abstract 573: Metabolism as checkpoint: Induction of anti-tumor immune response with the novel glutamine antagonist JHU-083
Authors: Leone Robert D. , Englert Judson M. , Oh Min-Hee , Cheng Chih-Hsien , Rais Rana , Slusher Barbara , Powell Jonathan D. 
Published: July 2017

Abstract
The metabolic characteristics of the tumor microenvironment (eg, hypoxia, acidity, nutrient depletion, elevated adenosine) present a significant hurdle for immunotherapy. Dysregulated glutamine metabolism plays a crucial role in establishing this environment. We previously demonstrated that the novel glutamine antagonist, JHU-083, profoundly alters tumor metabolism and inhibits growth with minimal toxicity. Further studies have demonstrated that JHU-083 can reprogram the immune contexture of the TME leading to decreased regulatory T cells (Treg), increased CD8:Treg ratio, decreased MDSCs, suppressed adenosine, and decreased acidification and hypoxia. We now report that JHU-083 not only markedly enhances antitumor response to anti-PD-1 and adoptive cellular therapy (ACT) but also generates potent immune-mediated responses as a single agent. In an MC38 tumor model C57BL/6 mice treated from day 10 with concurrent JHU-083 and low-dose anti-PD-1 therapy showed robust antitumor activity with complete rejection and normal lifespan in 9/10 mice (vs. 0/10 complete responses with anti-PD-1 monotherapy). The combination regimen was well tolerated, causing only minimal, transient weight loss. In other studies, a therapeutic ACT model with OVA-expressing B16 melanoma cells was employed and showed that low-dose JHU-083 and adoptive transfer of activated OVA-specific T cells led to markedly suppressed tumor growth and increased survival versus vehicle treated controls. In the course of these studies we found that incrementally increasing the dose of single agent JHU-083 generated 100% complete response rates (5/5) with 60% of mice rejecting tumor upon rechallenge, strongly suggesting an immune-mediated rejection had been established. Indeed, subsequent tumor studies in WT and RAG-/- mice confirmed that anti-tumor response to single agent JHU-083 was critically dependent on the adaptive immune system. This was unexpected as glutamine is known to be essential for T cell expansion. To this end, we used a vaccinia-OVA model and found that low-dose JHU-083 administered in the peri-vaccination period had minimal suppressive effect on OVA-specific CD8 expansion, but importantly, promoted generation of robust memory T cells with higher T-Bet expression and increased mTORC1 activity upon rechallenge. These studies demonstrate that, while the dosing and schedule of JHU-083 employed can disrupt tumor metabolism and markedly inhibit tumor growth, these same doses can promote long-lived changes in T cells that enhance memory response. Overall, our studies indicate that glutamine antagonism within tumors ameliorates critical checkpoints to immune function, dissipating metabolic suppression of immune-mediated anti-tumor responses. As such, targeting tumor metabolism can “unleash” endogenous anti-tumor responses as monotherapy and can markedly enhance anti-PD1 checkpoint blockade and adoptive cellular therapy.
Citation Format: Robert D. Leone, Judson M. Englert, Min-Hee Oh, Chih-Hsien Cheng, Rana Rais, Barbara Slusher, Jonathan D. Powell. Metabolism as checkpoint: Induction of anti-tumor immune response with the novel glutamine antagonist JHU-083 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 573. doi:10.1158/1538-7445.AM2017-573