708 MEDI1191 (IL-12 mRNA) induces peripheral and intratumoral immunostimulatory effect in patients with cutaneous or subcutaneous (C/SC) lesions

Background

MEDI1191 is an investigational therapy composed of mRNA encoding bioactive interleukin-12 (IL-12p70) in a lipid nanoparticle optimized for intratumoral injection. We hypothesized that intratumoral injection of MEDI1191 will reprogram the immunosuppressed tumor microenvironment (TME) and increase cytotoxic T-cell recruitment, proliferation and activation.

Methods

In an ongoing phase 1 dose escalation study (NCT03946800), patients with C/SC lesions received 0.1-12µg MEDI1191 sequentially (Part 1A) or concurrently (Part 1B) with intravenous durvalumab (1500 mg).¹ Clinical samples were collected to monitor changes in peripheral cytokines, circulating tumor (ct) DNA, peripheral and tumoral gene signatures and T cell infiltration.

Results

Peripheral blood cytokine analysis revealed increased serum IL-12 levels in 27/29 (93%) patients post first injection and was associated with ≥2-fold increase in serum IFN-γ in 24/29 (83%) patients. The IFN-inducible chemokines (CXCL9, CXCL10 and CXCL11) in periphery were detected at the protein and transcriptomic levels. In 11 patients whose blood samples underwent bulk RNA sequencing, markers of activated peripheral T cells were detectable over time with increased mean fold change of GZMB, IFNG and IL12RB1 gene expression in patients with partial response (PR, n=1) or stable disease (SD, n=5) patients. Pre-treatment expression of the genes encoding key mediators of cytotoxic T-cell function were potential predictors of response as observed by significantly higher expressions of peripheral IL12RB1 and IFNG genes at baseline in PR/SD patients. Using immunohistochemistry (IHC), we observed ≥ 2-fold increase in CD8 T cells (8/17, 47%) and Ki-67+CD3+ T-cells (7/17, 41%) in tumor biopsies 15 days post first injection. Patients with increased intratumoral CD8 T cells by IHC and RNA sequencing showed higher tumoral GZMB and IFNG gene expression. In 9 patients with evaluable tumor biopsies at baseline and post-treatment, we observed an increase in antitumor gene signatures, including activated CD8 (7/9, 78%), activated NK (7/9, 78%), M1 macrophages (7/9, 78%) and IFN-γ signaling (8/9, 89%). Consistent with IL-12’s role as a central mediator of Th1 cell development, we observed an increase in Th1 signature and STAT4 gene (6/9, 67%). Analysis of ctDNA in plasma of 17 patients demonstrated >50% reduction in mutant allele frequency in 2/3 patients who developed PR.

Conclusions

Intratumoral injection of MEDI1191 induces pharmacodynamic changes within the TME such as increase in activated T cell infiltration and upregulation of anti-tumor gene signatures. There was an associated immunomodulatory effect in the periphery, including elevated IL-12, IFN-γ and activated T-cells.

Trial Registration

NCT03946800

Reference

[1] Benedito A Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, Omid Hamid. First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT183.

Ethics Approval

The IRB/IEC responsible for each site reviewed and approved the final study protocol, including the final version of the ICF and any other written information and/or materials to be provided to the subjects. Institutional Review Boards, Mount Sinai Health System, New York (Board Number 19-00279).