198 Combination intratumoral treatment with INTASYL™ self-delivering RNAi targeting TIGIT and PD-1/PD-L1 improves tumor control compared to monotherapy in a CT26 model of murine colorectal cancer. (10th December 2020)

• Record Type: Journal Article
• Authors: Cuiffo, Benjamin; Maxwell, Melissa; Yan, Dingxue; Jedinak, Andrej; Cardia, James; Fricker, Simon
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A116
• Page End: A117
• Publication Date: 2020-12-10
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0198
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Despite clinical successes of immune checkpoint blockade (ICB) antibodies blocking the inhibitory receptors CTLA-4, PD-1, or PD-L1, substantial challenges remain. Many patients do not respond, and ICB treatment is associated with serious immune-related adverse effects (irAEs) which are exacerbated by combination therapies. TIGIT blockade has been demonstrated to provide tumor control in pre-clinical studies, sparking ongoing clinical trials, including those targeting TIGIT in combination with anti-PD-1 or anti-PD-L1. The INTASYL™ platform is a self-delivering RNAi technology that (1) provides efficient delivery into target cells bypassing the need for specialized formulations, mechanical perturbation, or drug delivery systems; and (2) specifically and durably silence target gene expression when administered intratumorally (IT), providing in vivo tumor control. IT administration restricts pharmacokinetics to the tumor; an attractive strategy for mitigating ICB-mediated systemic irAEs. Additionally, using INTASYL, multiple targets can be silenced in combination. Here we demonstrate the in vivo efficacy of INTASYL specifically targeting TIGIT (PH-804), PD-1 (PH-762), PD-L1 (PH-790) alone or in combination in a CT26 model of murine colorectal carcinoma. Methods: To assess silencing activity, activated human pan-T cells were incubated in vitro with INTASYL compounds either alone or in combination and mRNA silencing was determined by qRT-PCR and protein silencing by flow cytometry. To assess in vivo tumor efficacy CT-26 cells were implanted subcutaneously into BALB/c mice. INTASYL compounds were administered IT at 1 mg/dose on Days 1, 3, 7, and 10 either as single agents (mPH-804, mPH-762, mPH-790) or in combination (mPH-804 + mPH-762 or mPH-804 + mPH-790). Controls consisted of PBS (vehicle; (IT)), and anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies (0.2 mg/dose) administered via intraperitoneal injection (IP). Tumor volumes and body weight were recorded throughout the study. Tumors were taken at the end of the study for analysis. Results: Single and combination knockdown of target molecules was validated at the mRNA level (=90%) by qRT-PCR and at the protein level (=80%) in activated human pan-T cells. In vivo, combination treatment with mPH-804 + mPH-762 or mPH-790 improved tumor control compared to individual monotherapies providing evidence of potential synergy. All treatments were well tolerated. Conclusions: n/a Acknowledgements: We demonstrate the potential of INTASYL-mediated combination therapy targeting TIGIT and PD-1/PD-L1. These findings indicate that combination of TIGIT + PD-1/PD-L1 silencing improves tumor control compared to monotherapy. As INTASYL IT is efficacious and may mitigate irAEs caused by antibody ICB, INTASYL combination therapies including PH-804, PH-762 and PH-790 warrant further investigation in patients.