Phase I study of hV01, a recombinant human IL-21-expressing oncolytic vaccinia virus, as monotherapy in advanced solid tumors.

Abstract

2570 Background: Oncolytic viruses have shown an excellent safety profile and can initiate antitumour immunity through in-situ tumor lysis and systemic immune response, thereby gaining significant attention in cancer immunotherapy. Here, we conducted a phase I study of hV01, a genetically engineered oncolytic vaccinia virus expressing IL-21, in patients with advanced malignant solid tumors. Methods: This open-label, single-dose escalation study evaluated four dosing levels (range, 1×10^7 - 8×10^8 PFU) of intratumoral (i.t) injection of hV01, with a 28-day treatment cycle (NCT05914376). The primary aims were to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs) and safety. Treatment response was evaluated by RECIST v1.1 criteria on day 28 using a CT scan.Peripheral blood samples were analyzed for immune cell phenotypes with FACS and viral shedding with Q-PCR after the hV01 regimen. Results: Thirteen patients with advanced solid tumors were enrolled; most had failed multiple prior therapies. Twelve patients completed at least one treatment cycle, with three in each dosing cohort. Six of the twelve patients (6/12, 50%) achieved stable disease (SD), while the rest had progressive disease (PD), evaluated at the end of the first treatment cycle. Among the six patients with SD, one patient with pulmonary spindle cell carcinoma in the 1×10^7 PFU cohort had progression-free survival (PFS) for 138 days, and one patient with dedifferentiated liposarcoma in the 6.0×10^8 PFU cohort had a PFS for 206 days. One patient with nasopharynx cancer in the 8.0×10^8 PFU cohort achieved a partial response (PR) after four treatment cycles. No DLTs occurred during the observation period of this study. The most commonly treatment-related adverse events (TRAE) were fever and anemia, which were reported as grade 1-2 events in eleven patients (11/13, 84.6%) and six patients (6/13, 46.2%), respectively. The only grade 3 event was decreased lymphocyte count in one patient in the 6.0×10^8 PFU cohort. FACS analysis found a decrease in T cells and natural killer (NK) cells in the peripheral blood in all patients on the day following hV01 administration, and later, the levels of T cells and NK cells gradually rebounded. Notably, four patients had significantly higher (more than doubled or tripled) levels of NK cells compared to their baseline on day 15 after the hV01 regimen. Conclusions: Single-dosing of hV01 per treatment cycle was well tolerated and safe. hV01 i.t. injection demonstrated primary efficacy in patients with advanced tumors. The data support further study of multiple-dosing regimens and future trials evaluating the benefits of combining hV01 with other antitumor therapies. Clinical trial information: NCT05914376 .