Abstract CT032: A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies
Authors: Jimeno Antonio , Gupta Shilpa , Sullivan Ryan , Do Khanh T. , Akerley Wallace L. , Wang Ding , Teoh Deanna , Schalper Kurt , Zacharek Sima J. , Sun Jing , Laino Andressa S. , Frederick Joshua , Zhou Honghong , Randolph William , Pascarella Stephanie , Johansen Lisa , Cohen Pamela S. , MEEHAN ROBERT S. , Bauer Todd M. 
Published: September 2020

Abstract
Background: While PD-1/L1 blockade is an effective therapeutic approach for many patients with solid and hematologic malignancies, it is not sufficient to induce tumor regressions in the majority of patients. Optimal T cell responses require T cell receptor activation and co-stimulation, which can be provided via ligation of tumor necrosis factor receptor family members, such as OX40. Binding of OX40 by OX40L in the presence of a recognized antigen promotes CD4+ and CD8+ T cell expansion, enhances memory responses and inhibits regulatory T cell function. mRNA-2416 is a novel mRNA-based lipid nanoparticle therapeutic agent that expresses the wild type human OX40L. Preclinical in vivo anti-tumor activity of a murine mRNA-2416 surrogate and synergy with anti-PD-L1 antibodies in syngeneic cancer models are observed (unpublished). Here we present the findings of a first-in-human study of mRNA-2416 monotherapy delivered intratumorally in solid tumor patients with accessible lesions.
Methods: This study tested the safety and efficacy of mRNA-2416 administered every 2 weeks for up to 12 doses in a standard 3+3 phase 1 dose escalation in patients with locally advanced, recurrent or metastatic solid malignancy or lymphoma. Tumor biopsies were collected pre- and post-treatment and evaluated by quantitative immunofluorescence (QIF) and RNA sequencing to characterize OX40L expression and immune response following treatment.
Results: As of November 13, 2019, 39 patients have been treated at 4 dose levels from 1-8 mg. mRNA-2416 was generally well-tolerated with no DLTs. 6 out of 39 patients experienced grade 3 treatment related AEs. Out of 14 patients with best overall response of stable disease by RECIST, 6 had stable disease for ≥ 14 weeks, and 4 had tumor shrinkage in the injected lesions. Analyses of paired biopsies from injected lesions by QIF showed increased OX40L protein expression as well as elevated T cell scores post-treatment. Activation of a pro-inflammatory gene expression response post-treatment was observed in many cases, including increased cytolytic activity scores, elevated PD-L1 expression, and stimulation of a T cell-inflamed gene expression profile predictive of anti-PD-1/L1 response. These findings were observed in patients with long duration on study or tumor shrinkage.
Conclusion: Intratumoral mRNA-2416 is tolerable at all dose levels studied when given as monotherapy and analyses of tumor post-treatment demonstrate increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity. Taken together with the observation of preclinical in vivo synergy with PD-L1 blockade, these data support the evaluation of a combination of intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab in solid tumors, which is ongoing in part B of this study.
Citation Format: Antonio Jimeno, Shilpa Gupta, Ryan Sullivan, Khanh T. Do, Wallace L. Akerley, Ding Wang, Deanna Teoh, Kurt Schalper, Sima J. Zacharek, Jing Sun, Andressa S. Laino, Joshua Frederick, Honghong Zhou, William Randolph, Stephanie Pascarella, Lisa Johansen, Pamela S. Cohen, ROBERT S. MEEHAN, Todd M. Bauer. A phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT032.