Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931.