Abstract 6552: Intratumoral (ITu) delivery of mRNA-2752 encoding human OX40L/IL-23/IL-36γ in combination with durvalumab induces an immunostimulatory effect within the tumor microenvironment (TME) of patients with advanced solid tumors
Authors: Abadier Michael , Sullivan Ryan J. , Chow Jacky , Sehgal Vasudha , Sweis Randy F. , Daud Adil , Shapira-Frommer Ronnie , Perets Ruth , Kummar Shivaani , McKean Meredith , Geva Ravit , Patel Manish R. , Khattak Adnan , Fernandez-Peñas Pablo , Zacharek Sima , Wahl Natalia , Walker Russell M. , Van Linh , Aanur Praveen , Ward Jim , Do Khanh T. , Long Georgina V. 
Published: March 2024

Abstract
Background mRNA-2752 is a first-in-class ITu therapy composed of mRNA encoding human OX40L/IL-23/IL-36γ in a lipid nanoparticle. The combination of T cell costimulation and proinflammatory cytokines were developed to modulate the TME and allow a more robust immune response. Here we show evidence of the pharmacodynamic effect of ITu administration of mRNA-2752 in combination with PD-L1 antibody.
Methods In this ongoing phase 1 study (NCT03739931), patients (pts) with advanced solid tumors received 0.25-8 mg mRNA-2752 alone (Arm A) or in combination with 1500 mg IV durvalumab (Arm B)1,2. Pre and on-treatment peripheral and tumor samples were collected to monitor changes in cytokines by ligand binding assays, gene signatures by RNA sequencing, and T cell infiltration by immunohistochemistry. Tumor biopsies were taken at baseline, 24h, 15 and 28 days post treatment.
Results mRNA-2752 administration in combination with durvalumab revealed ≥2-fold plasma level increases of IL-23 (34/40, 85%) and IFN-γ (50/65, 77%) at 24h after first injection; exposure was induced in a dose-dependent manner. We observed induction of CD8 T cell abundance (20/49, 41%) and proliferation (23/49, 47%), and OX40L protein expression (28/49, 57%) in pts with evaluable post-treatment injected lesion biopsies. CD8 T cell abundance increased in 2 pts with evaluable post-treatment un-injected lesion biopsies. A positive correlation was observed between T cell abundance and T cell effector genes. All three mRNA (IL-23, IL-36γ, and OX40L) encoded genes were detected post treatment in tumor samples from 43 evaluable patients. In 18 pts with injected lesion biopsy samples at baseline and day 28 samples, the genes related to cytotoxic function (IFNG, GZMB, PRF1), T cell migration (CCL21, CCR7, KLF2), T cell activation/memory phenotype (TCF7, CD69, ITGAE), and conventional type 1 dendritic cells (CLEC9A, XCR1) were induced 28 days post-treatment in pts with complete/partial response or stable disease (CR/PR/SD, n=7) compared to progressive disease (PD, n=11) pts. RNA-Seq transcriptome analysis showed increases in the immune inflamed gene signatures related to antitumor activity in 24/43 (56%) pts post-treatment, and the pre-existing immune inflamed phenotype within the TME was associated with clinical benefit.
Conclusions mRNA-2752 ITu injection induced a systemic immunomodulatory effect by elevating effector cytokines. This was associated with pharmacodynamic changes within the TME, including increases in T cell abundance and proliferation, and upregulation of immune gene signatures that correlate with antitumor response.
References 1. Patel M. J ImmunoTherap. 2021;9:Abs569 2. Olson D, et al. J ImmunoTherap. 2022;10:Abs767
Study support: Moderna, Inc.
Citation Format: Michael Abadier, Ryan J. Sullivan, Jacky Chow, Vasudha Sehgal, Randy F. Sweis, Adil Daud, Ronnie Shapira-Frommer, Ruth Perets, Shivaani Kummar, Meredith McKean, Ravit Geva, Manish R. Patel, Adnan Khattak, Pablo Fernandez-Peñas, Sima Zacharek, Natalia Wahl, Russell M. Walker, Linh Van, Praveen Aanur, Jim Ward, Khanh T. Do, Georgina V. Long. Intratumoral (ITu) delivery of mRNA-2752 encoding human OX40L/IL-23/IL-36γ in combination with durvalumab induces an immunostimulatory effect within the tumor microenvironment (TME) of patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6552.