Abstract 2244: DeepIL-15 primed T cells synergize with PD-L1 blockade to overcome resistance to checkpoint immunotherapy
Authors: Geretti Elena , Liang Xiaoyan , Lyons Jesse , Bardwell Philip , Caruso Santina , Hewes Becker , Fitzgerald Jonathan , Sauer Karsten , Andresen Thomas 
Published: August 2019

Introduction Interleukin-15 (IL-15) activates and expands both CD8+T cells and NK cells but not immunosuppressive Tregcells. While IL-15 is an attractive asset for cancer immunotherapy, its systemic administration is limited by toxicities. To limit IL-15 systemic exposure, we have developed DeepTM IL-15, a multimer of chemically crosslinked IL-15/IL-15 Rα/Fc heterodimers (IL15-Fc). Deep IL-15 is surface anchored to tumor reactive T cells prior to adoptive cell transfer (ACT). This novel therapeutic approach enables Deep IL-15 loading onto cells at concentrations unachievable with systemic IL15-Fc, causes autocrine T cell activation and expansion, yet limits systemic exposure and associated toxicities. The anti-tumor activity of T cell therapies has been limited by insufficient T cell expansion and by checkpoint immunosuppression. Here, we combined Deep IL-15 primed T cells with PD-L1 blockade to overcome these limitations.

Methods Deep IL-15 was synthesized by incubation of IL15-Fc with a crosslinker. PMEL CD8+T cells (PMEL) were isolated from B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J mice,activated, expanded, and Deep IL-15 was anchored to PMEL to generate Deep IL-15 Primed PMEL (Deep-15 PMEL). B16-F10 tumor-bearing mice were treated with cyclophosphamide (4 mg/mouse) one day prior to injection of 107Deep-15 PMEL (carrying ~ 58 ug of IL15-Fc)± anti-PD-L1 antibody (10 mg/kg q2w). We monitored mouse weight, tumor volumes, transferred and endogenous T cells, IL15-Fc systemic exposure, and cytokine release.

Results Deep-15 PMEL showed significantly improved expansion and anti-tumor activity compared to PMEL, and provided long-term protection against tumor re-challenge. Importantly, the toxicity profile of Deep-15 PMEL was better than that of IL15-Fc co-injection with PMEL, yielding lower systemic exposure to IL15-Fc, less IFN-γinduction and no expansion of endogenous CD8+T and NK cells. Deep-15 PMEL resulted in 2/10 partial regressions and a statistically significant tumor growth inhibition compared to both vehicle and PD-L1 blockade alone. Co-administration of anti-PD-L1 further improved the anti-tumor activity of Deep-15 PMEL, resulting in 10/10 Complete Regressions (CR) and 6/10 Tumor Free Survivors. Conclusions By loading tumor-reactive T cells with Deep IL-15 before ACT, Torque's proprietary Deep Priming technology leverages the immune-stimulating power of IL-15 while avoiding immunotoxicity. Deep IL-15 Priming promotes engrafted T cell-specific activation and proliferation, and a favorable toxicity profile. In vivo transfer of Deep-15 PMEL combined with checkpoint inhibition was well tolerated and elicited remarkable anti-tumor activity in the PD-L1 refractory B16-F10 model, with 10/10 CRs. Torque is initiating a Phase I trial for TRQ15-01 (Deep IL-15 Primed multi-targeted human T cells) and planning a combination arm with checkpoint blockade in solid tumors.

Citation Format: Elena Geretti, Xiaoyan Liang, Jesse Lyons, Philip Bardwell, Santina Caruso, Becker Hewes, Jonathan Fitzgerald, Karsten Sauer, Thomas Andresen. DeepIL-15 primed T cells synergize with PD-L1 blockade to overcome resistance to checkpoint immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2244.