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Updated: May 19, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Lipid Nanoparticle-Encapsulated mRNA-2752 Encoding Human OX40L, IL-23, and IL-36γ plus Durvalumab Induces an
Randy F Sweis1, Georgina V Long2, Adil Daud3
1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
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 CPI-resistant models.
Patients And Methods:
In this phase I study (NCT03739931) of intratumoral mRNA-2752 monotherapy (arm A) or mRNA-2752 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 CPI-resistant 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.
Insights
mRNA-2752, a novel immunotherapy, showed antitumor activity in patients with advanced cancers, particularly in those resistant to immune checkpoint inhibitors. The treatment demonstrated a manageable safety profile and modulated the tumor microenvironment, supporting further investigation.
Area of Science:
- Oncology
- Immunotherapy
- mRNA Therapeutics
Background:
- mRNA-2752 is a novel lipid nanoparticle (LNP)-encapsulated mRNA therapeutic encoding OX40L, IL-36γ, and IL-23.
- It has shown potential in modulating the tumor microenvironment (TME) and exhibiting antitumor effects, especially when combined with immune checkpoint inhibitors (CPI).
- This study investigates its efficacy in CPI-resistant models.
Purpose of the Study:
- To evaluate the safety, tolerability, and objective response rate (ORR) of intratumoral mRNA-2752 as monotherapy or in combination with durvalumab.
- To determine the maximum tolerated dose (MTD) and recommended dose for expansion.
- To assess efficacy in patients with advanced solid tumors, particularly those with CPI-resistant melanoma.
Main Methods:
- A Phase 1 clinical study (NCT03739931) involving patients with advanced solid tumors.
- Intratumoral administration of mRNA-2752 monotherapy (Arm A) or mRNA-2752 plus durvalumab (Arm B).
- Primary objectives included safety, tolerability, MTD, and ORR per RECIST v1.1 in CPI-resistant melanoma (Arm B only).
Main Results:
- The MTD was not reached; a recommended dose of ≤8 mg was selected.
- Grade 3 treatment-related adverse events occurred in 5.3% (Arm A) and 25.2% (Arm B) of patients.
- In CPI-resistant melanoma (n=28), confirmed ORR was 17.9% and disease control rate was 42.9%.
- Increased peripheral cytokine levels and sustained TME inflammatory responses were observed, particularly in responders.
Conclusions:
- mRNA-2752, as monotherapy or combined with durvalumab, demonstrated antitumor activity and a manageable safety profile in heavily pretreated patients.
- The therapy was particularly effective in CPI-resistant melanoma.
- Biomarker analyses confirmed sustained TME inflammation, supporting the investigation of mRNA-based therapeutics in advanced cancer.
