Combining immune checkpoint inhibition and dendritic cell vaccination in advanced pleural and peritoneal mesothelioma: The phase 1b MESOVAX trial.

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2548 Background: Mesothelioma (M) remains a rare malignancy with limited therapeutic options. While immunotherapy combinations have recently become the standard of care for non-epithelioid subtypes, further strategies are required to enhance clinical outcomes. Dendritic cell vaccines (DCvax) have demonstrated preliminary activity and a favorable safety profile in M. Preclinical data suggest that DCvax induces PD-L1 expression on tumor cells; therefore, combining DCvax with Pembrolizumab (P) may sensitize patients (pts) to PD-1 blockade. Methods: MESOVAX is a proof-of-concept, Phase Ib, study evaluating the safety of P 200 mg combined with an autologous anti-tumor DCvax administered every 3 weeks (Q3W) for 6 cycles, followed by P monotherapy until disease progression or up to 2 years. Subcutaneous IL-2 (3 MU) was administered for 5 days following each vaccination. The primary endpoint was safety. Secondary endpoints included: changes in PD-L1 expression evaluated in pre- and post-therapy tumor samples by immunohistochemistry (IHC); immunological efficacy evaluated in vivo by DTH test and ex vivo measuring the immune response against selected tumor antigens (i.e MESOTHELIN, WT1, 5T4, TWIST-1, KRT-18, THBS2) by Interferon gamma (IFNγ) Enzyme-Linked Immunosorbent Spot (ELISpot) Assay; and treatment activity (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], and overall survival [OS]). Results: As of 28/11/2025, 9 pts (median follow-up: 32.5 months (mths)) were evaluable for safety and efficacy. Median age was 62 years; 89% (n = 8) were male, and all had epithelioid histology. Treatment-related adverse events (TRAEs) of any grade occurred in all 9 pts, with the most frequent being injection site reactions, asthenia, and fever. No grade 3–4 TRAEs were reported. Regarding treatment exposure, 4 pts received 6 cycles of P+DC, 6 pts received maintenance P, and one pt completed the maintenance phase. Best overall responses included 1 partial response (PR), 4 stable diseases (SD), and 4 progressive diseases (PD), with a median PFS of 5.3 mths (95% CI 1.8–17.3). Notably, one pt with prolonged SD (duration 9 mths) exhibited a PD-L1 conversion in the tumor tissue (from negative to positive) following treatment. Regarding the immunological activity, 4 pts experienced a positive DTH test during treatment, and interestingly for 3 of them we were able to measure a concomitant increase of the ex vivo antitumoral immune response against the tested antigens. Conclusions: The combination of DCvax and P is safe and demonstrates encouraging clinical activity in pretreated epithelioid M. The observed PD-L1 induction at the tumor site supports the synergistic potential of this combinatorial immunotherapeutic strategy. This trial is supported in part by a research grant from Investigator-Initiated Studies Program of MSD Italia S.r.l. Clinical trial information: NCT03546426 .

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