First-in-Human Study of mRNA-2416 Shows Promise in Advanced Solid Tumors and Ovarian Cancer
核心洞察
mRNA-2416, a novel lipid nanoparticle-encapsulated mRNA encoding human OX40L (搜索) for intratumoral injection, demonstrated acceptable safety and tolerability in a first-in-human phase I/II study with 61 patients receiving treatment.
The study showed proof-of-concept for mRNA-based immunotherapy, with tumor biopsies demonstrating increased OX40L (搜索) protein expression, elevated PD-L1 (搜索), and proinflammatory responses following treatment.
While predefined primary efficacy endpoints were not met in the ovarian cancer (搜索) expansion cohort, tumor shrinkage was observed in both injected and non-injected tumors, supporting systemic immune activation.
A first-in-human phase I/II study of mRNA-2416, a novel lipid nanoparticle-encapsulated messenger RNA encoding human OX40 (搜索) ligand (OX40L (搜索)), has demonstrated acceptable safety and provided proof-of-concept for intratumoral mRNA-based immunotherapy in patients with advanced solid tumors (搜索) and ovarian cancer (搜索).
The multicenter, open-label study enrolled 79 patients from August 2017 to August 2021, with 61 patients receiving treatment across two arms: mRNA-2416 alone (arm A, n=39) or in combination with durvalumab (arm B, n=22), including 16 patients in an ovarian cancer (搜索) expansion cohort.
Safety Profile and Dosing
The maximum tolerated dose (MTD) was not reached across all tested dose levels (1.0 mg to 8.0 mg), with no dose-limiting toxicities observed. Treatment-related adverse events were predominantly grade 1/2 in severity, with only 8 grade 3 events and no grade 4/5 events reported.
In arm A, the most frequent mRNA-2416-related treatment-emergent adverse events occurring in ≥10% of patients included injection site pain (28%), flushing (26%), pyrexia (23%), fatigue (21%), and injection site erythema (21%). In arm B, pyrexia (46%), injection site pain (41%), nausea (32%), and fatigue (27%) were the most common mRNA-2416-related adverse events.
"mRNA-2416 was tolerable at all doses assessed—the MTD was not reached—and was associated with increased OX40L (搜索) protein expression in injected tumors," the researchers reported.
Clinical Activity and Response
Based on RECIST v1.1 criteria, objective response rates were 0.0% (95% CI: 0.0 to 11.9%) for arm A and 5.3% (95% CI: 0.1 to 26.0%) for arm B. In arm B, one patient with ovarian cancer (搜索) achieved a partial response at the 4.0 mg dose level, though this was unconfirmed due to the absence of a confirmatory scan.
Stable disease was observed in 31% of patients in arm A and 11% in arm B. Median progression-free survival was 60 days (95% CI: 50 to 108 days) for arm A and 50 days (95% CI: 38 to 55 days) for arm B.
Notably, tumor shrinkage occurred in both injected and surrounding non-injected tumors in several patients. One 63-year-old patient with serous fallopian/ovarian cancer (搜索) who had received 13 prior lines of systemic therapy showed regression of the injected lesion to near resolution after four injections, with surrounding non-injected lesions visibly flattening by cycle 4.
Mechanism of Action Validation
The study provided compelling evidence for mRNA-2416's mechanism of action through comprehensive biomarker analyses. Tumor biopsies demonstrated increased OX40L (搜索) protein expression in injected tumors, with confirmed increases observed in 4/4 biopsies evaluated 24-48 hours post-treatment in combination therapy patients.
Pharmacodynamic effects included increased T-cell presence in the tumor microenvironment, activation of proinflammatory gene expression responses, and upregulation of T-cell-inflamed signature genes in 6/9 monotherapy patients assessed. PD-L1 (搜索) expression, an interferon-inducible gene, was also elevated after treatment, with effects most pronounced in injected tumors.
Patients receiving combination therapy demonstrated more extensive systemic cytokine responses, including elevated levels of interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Peak IFNγ was observed at 24 hours and was elevated in 24/26 patients assessed 24 hours post-treatment.
Ovarian Cancer Focus
The study included a specific expansion cohort in patients with platinum-resistant ovarian cancer (搜索), a population with limited response to immune checkpoint inhibitor monotherapy (response rates <15%). While predefined primary efficacy endpoints were not met in this exploratory cohort, the researchers noted evidence of immune modulation and tumor shrinkage.
"Despite preclinical data suggesting that immunotherapy should be effective in epithelial ovarian cancer (搜索), clinical successes with immune-based therapies have been modest," the authors noted, highlighting the continued need for novel approaches in this challenging indication.
Pharmacokinetic Profile
Pharmacokinetic analyses revealed that median time to peak concentration (tmax) for mRNA-2416 was 14 hours (range: 3-26 hours) at the 2.0 and 4.0 mg dose levels. Both peak and total systemic exposure of mRNA-2416 were sub-proportional to dose levels over the 1.0 to 8.0 mg range. Total and peak serum mRNA-2416 exposures were higher when administered in combination with durvalumab compared with monotherapy.
Future Directions
The researchers emphasized that while predefined primary efficacy endpoints were not met, the pharmacodynamic analyses support continued research into mRNA-based therapeutics. They noted several study limitations, including constraints on injection volume based on lesion size and the heavily pretreated patient population, with patients receiving a median of 4 prior lines of therapy.
"Additional research is needed to further elucidate biomarkers of response and identification of the subset of patients most likely to benefit," the authors concluded. They suggested that future studies should evaluate alternative administration schedules, including serial versus concurrent administration of immune checkpoint inhibitors, and noted that a phase I study of mRNA-2752 (encoding OX40L (搜索)/IL-23/IL-36γ) is currently underway to further explore this therapeutic approach.