Lipid nanoparticle–encapsulated mRNA-2752 encoding human OX40L, IL-23, and IL-36γ plus durvalumab induces an immunostimulatory effect within the tumor microenvironment in patients with advanced solid tumors
Author Identifier (ORCID)
Abstract
Purpose: Messenger RNA (mRNA)-2752, a lipid nanoparticle– encapsulated, mRNA-based therapeutic encoding OX40L, interleukin 36γ (IL-36γ), and IL-23, has demonstrated modulation of the tumor microenvironment (TME) and antitumor efficacy in combination with immune checkpoint inhibitors (CPI) in CPIresistant models.
Patients and Methods: In this phase I study (NCT03739931) of intratumoral mRNA-2752 monotherapy (arm A) or mRNA2752 plus durvalumab (arm B) in advanced solid tumors, the primary objectives were safety, tolerability, determination of maximum tolerated dose (MTD), and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors version 1.1 in CPI-resistant melanoma (arm B only).
Results: Among 134 patients (arm A, n = 19 and arm B, n = 115), the MTD was not reached; a recommended dose for expansion of ≤8 mg was selected. Dose-limiting toxicities included two grade II cytokine-release syndrome events in arm B. Treatment-related adverse events (AE) were mostly grade I/II; grade III mRNA-2752–related AEs occurred in 1 patient (5.3%) in arm A and 29 patients (25.2%) in arm B. In the CPIresistant melanoma cohort (n = 28), across doses, the confirmed ORR was 17.9% (95% CI, 6.1%–36.9%), and the disease control rate was 42.9% (95% CI, 24.5%–62.8%). Increased peripheral cytokine levels and sustained inflammatory responses in the TME were observed, particularly in patients with an objective response.
Conclusions: mRNA-2752 monotherapy or in combination with durvalumab demonstrated antitumor activity with manageable safety in patients with heavily pretreated, relapsed, or resistant solid tumors, particularly in patients with CPI-resistant melanoma. In addition, biomarker analyses demonstrated a sustained inflammatory response within the TME. Together, these findings support the investigation of mRNA-based therapeutics for patients with advanced cancer.
Keywords
mRNA-2752, immunotherapy, solid tumors, melanoma, tumor microenvironment, durvalumab
Document Type
Journal Article
Date of Publication
8-15-2026
E-ISSN
15573265
ISSN
10780432
Volume
32
Issue
16
PubMed ID
42149124
Publication Title
Clinical Cancer Research
Publisher
American Association for Cancer Research
School
School of Medical and Health Sciences
Copyright
subscription content
First Page
3493
Last Page
3505
Recommended Citation
Sweis, R. F., Long, G. V., Daud, A., Stemmer, S. M., Jimeno, A., Perets, R., Kummar, S., Patel, M. R., Khattak, A., Abadier, M., Van, L., Guo, R., T, K., DO, & Sullivan, R. J. (2026). Lipid nanoparticle–encapsulated mRNA-2752 encoding human OX40L, IL-23, and IL-36Γ plus durvalumab induces an immunostimulatory effect within the tumor microenvironment in patients with advanced solid tumors. Clinical Cancer Research, 32(16), 3493–3505. https://doi.org/10.1158/1078-0432.CCR-25-4643