Abstract 3209: CRLX101, an investigational nanoparticle-drug conjugate of camptothecin, demonstrates synergy with immunotherapy agents in preclinical models
Authors: Lazarus Douglas , Peters Christian , Stockmann Adam , Eliasof Scott , Jayaraman Lata 
Published: July 2016

CRLX101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. CRLX101 has been shown preclinically to be active in many different tumor types as a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α (HIF-1α). It has a long circulation half-life and has been shown pre-clinically to release camptothecin in a slow and prolonged manner in tumors. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of CRLX101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way.

Recent publications have suggested that tumor expression of the immune-suppressive molecule PD-L1 is controlled by HIF-1α. Since CRLX101 is a potent inhibitor of HIF-1α, it is possible that CRLX101 behaves as an inhibitor of the PD-1/PD-L1 axis in vivo. We therefore hypothesized that a combination of CRLX101 with agents that are being investigated in combination with the anti PD-1 antibody would lead to increased efficacy. Indole diamine oxygenase (IDO) inhibitors are a new class of drugs that decrease tumor-induced immune suppression and are currently being evaluated in the clinic with anti-PD-1 antibodies. Using syngeneic tumor models, we tested the combination of CRLX101 with three different IDO inhibitors. Treatment of the B16.F10 melanoma model with IDO inhibitors NLG919, INCB024360 or indoximod had no effect on tumor growth while CRLX101 as monotherapy showed moderate anti-tumor activity. When CRLX101 was combined with any of the three IDO inhibitors, the anti-tumor activity was greatly improved compared to monotherapy. Similar results were noted in other syngeneic tumor models. This improved combination response was not observed in IDO inhibitor combinations with the clinically approved topoisomerase inhibitor irinotecan, suggesting that CRLX101 provides a unique advantage in this context. Interestingly, CRLX101/IDO inhibitor combination was also superior to the combination of anti-PD-1 antibody and IDO inhibitor. These data suggest that CRLX101 in combination with IDO inhibitors can successfully block host-mediated immune-suppression to enhance anti-tumor immunity, and this combination may therefore show improved therapeutic activity in the clinic. We therefore plan to explore the immune-specific effects of CRLX101 as well as the mechanistic basis for the observed combination response, and use that information to guide CRLX101 clinical strategy in the setting of chemo-immunotherapy regimens.

Citation Format: Douglas Lazarus, Christian Peters, Adam Stockmann, Scott Eliasof, Lata Jayaraman. CRLX101, an investigational nanoparticle-drug conjugate of camptothecin, demonstrates synergy with immunotherapy agents in preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3209.