Abstract 3856: Antitumor activity of ABI-009 (<i>nab</i>-rapamycin) in combination with anti-PD1 antibody in a syngeneic mouse model of B16 melanoma
Authors: Shihe Hou, Berta Grigorian, Anita Schmid, Neil Desai
Journal: Cancer Research (2018)

Abstract Background: mTOR pathway has been implicated in cell survival and proliferation and is an attractive target for cancer therapy. Loss of PTEN, a negative regulator of mTOR pathway, is frequently observed in multiple cancer types. Recent studies indicate that loss of PTEN promotes resistance to T cell-mediated immunotherapy. Since PTEN loss can result in downstream mTOR activation, we investigated the safety and efficacy of ABI-009 (nab-rapamycin, a novel mTOR inhibitor) in combination with anti-PD1 antibody in a syngeneic mouse model of B16 melanoma. ABI-009 (nab-rapamycin) is a nanoparticle form of human albumin-bound rapamycin with a mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound (nab®) technology. ABI-009 is currently in phase 1 and 2 clinical studies for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), severe pulmonary arterial hypertension (PAH), nonmuscle-invasive bladder cancer, soft-tissue sarcomas, and various childhood cancers. Methods: Syngeneic B16 melanoma tumors were implanted in immunocompetent C57BL/6 mice. ABI-009 was administered IV at 5 mg/kg 3 times weekly. Monoclonal anti-mouse PD-1 antibody (RMP1-14, BioXcell, West Lebanon, NH, USA) was administered IP at 250 μg every 2 days for 3 times. The study drugs were either administered as single agent or in combination with 3 different dosing schedules: concurrent (A), ABI-009 one week before anti-PD1 (B), or anti-PD1 one week before ABI-009 (C). Results: Overall, all treatments were well tolerated with no significant body weight loss in any group. All treatment groups showed significant antitumor effect and longer survival compared with the saline control. Addition of ABI-009 simultaneously or after anti-PD1 significantly improved tumor growth suppression and survival compared with anti-PD1 alone. Tumor volumes were reduced 35.5% for group A and 44.8% for group C when compared with anti-PD1 alone (p &amp;lt; 0.05). Median survival was 26 days for group A and 26 days for group C vs. 20 days for anti-PD1 alone (p &amp;lt; 0.05). On the other hand, group B failed to significantly improve antitumor effect and survival over anti-PD1 alone. The combination treatment regimen of anti-PD1 given before ABI-009 (group C) was the best schedule among the 3 schedules tested. Conclusions: The combination of ABI-009 and anti-PD1 antibody was well tolerated. Results from this study support the treatment regimens of anti-PD1 immunotherapy, concurrent or followed by ABI-009. Pretreatment with ABI-009 followed by anti-PD1 is not recommended. A phase 1b investigation of safety/efficacy of nivolumab and ABI-009 in patients with advanced sarcoma has been initiated. Citation Format: Shihe Hou, Berta Grigorian, Anita Schmid, Neil Desai. Antitumor activity of ABI-009 (nab-rapamycin) in combination with anti-PD1 antibody in a syngeneic mouse model of B16 melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3856.