Intratumoral mRNA-2416 monotherapy appears safe for patients with solid tumors
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Intratumoral mRNA-2416, a lipid nanoparticle therapeutic agent expressing the wild-type human OX40L, appeared safe among a cohort of patients with locally advanced, recurrent or metastatic solid tumors, according to results of a phase 1/2 first-in-human study presented at the virtual American Association for Cancer Research Annual Meeting.
Post-treatment tumor analyses showed increased OX40L protein expression, elevated PD-L1 levels and pro-inflammatory activity, researchers noted.
“Of note, the majority of patients with ovarian cancer included in the study achieved a best overall response of stable disease along with noted clinical observation of tumor regression in injected as well as uninjected lesions, which supports further investigation of this tumor type,” Antonio Jimeno, MD, PhD, professor in the department of medical oncology at University of Colorado Anschutz Medical Campus, said during a presentation.
Previous research has shown in vivo antitumor activity of a murine mRNA-2416 surrogate and synergy with anti-PD-L1 antibodies in syngeneic cancer models, according to study background.
Jimeno and colleagues assessed the safety and efficacy of mRNA-2416 (Moderna Therapeutics) monotherapy administered intratumorally every 2 weeks in doses ranging from 1 mg to 8 mg among 39 patients with solid tumors and accessible lesions.
Researchers collected tumor biopsies before and after treatment. They used quantitative immunofluorescence to evaluate tumor biopsies, and RNA sequencing to characterize OX40L expression and immune response after treatment.
Six patients experienced grade 3 treatment-associated adverse events. Of the 14 patients with best overall response of stable disease by RECIST, six achieved stable disease for 14 weeks or longer and four patients experienced tumor shrinkage. Of note, four out of six patients with ovarian cancer experienced stable disease.
Overall, two patients experienced tumor shrinkage in both injected and uninjected tumor sites. Two patients with ovarian cancer experienced tumor shrinkage in injected lesions only, and three patients experienced tumor shrinkage in uninjected lesions only.
“This shows that mRNA-2416 is able to induce a direct immune response, as well as a systemic distant effect,” Jimeno said.
After treatment, researchers observed increased OX4OL protein expression in five of nine patients in analyses of paired biopsies from injected lesions by quantitative immunofluorescence.
“The case of the most marked disease was observed in a patient with ovarian cancer in which post-treatment biopsy was collected on cycle one, day 2,” Jimeno added. “The patient’s OX40L score went from 558 to 7,047 within 24 hours post-injection.”
Researchers also observed activation of a pro-inflammatory gene expression response after treatment among most patients, including an increase in cytolytic activity scores, elevated PD-L1 expression and stimulation of a T cell-inflamed gene expression profile predictive of anti-PD-1/PD-L1 response. Researchers noted that they observed these findings among patients with long duration on study or tumor shrinkage.
“The observation of broad pro-inflammatory activity and beneficial changes in the [tumor microenvironment] with upregulation of PD-L1 support the evaluation of combination intratumoral mRNA-2416 with the anti-PD-L1 inhibitor durvalumab [Imfinzi, AstraZeneca] in solid tumors, which is ongoing in part B of this study with a focus on advanced ovarian carcinoma,” Jimeno said. – by Jennifer Southall
Reference:
Jimeno A, et al. Abstract CT032. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Perspective
Back to TopIgnacio Melero, MD
The bad news is that as a monotherapy, the clinical efficacy of this agent is very modest.
Let us not forget that the main objective of intratumoral therapy is to treat not only the directly injected tumor but also tumors elsewhere in the body, such as micrometastatic disease. There is good preclinical evidence of this approach and, in fact, it can achieve monotherapy activity in an immunogenic transplanted tumor model. For us to observe this activity in a less-immunogenic transplanted model, the agent needs to be combined with a systemic antibody targeting PD-L1.
What is missing here is the effect on concomitant distant noninjected tumors. From a clinical perspective, the effect on tumor shrinkage is modest and limited to one case of ovarian cancer with lymph node metastases in which injection led to shrinkage of the injected tumor mass and perhaps to limited progression of other tumor nodules in this same lymphatic chain.
The good news is that this agent is very safe. I am looking forward to seeing this agent in combination with durvalumab in part B of this trial. Perhaps OX40L is not the best of transgenes, as there have been unsuccessful experiences with agonist anti-OX40 antibodies. I am excited to see the results of the ongoing trials with scIL-12 [single-chain interleukin-12] mRNA. We can dream of this as a new platform for cancer immunotherapy.
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