Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients

Abstract

Background: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT 01502293). Patients and methods: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre-and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Results: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. Conclusions: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/ distal lesions, adaptive immune resistance limited the response.

Electroporation as the Immunotherapy Strategy for Cancer in Veterinary Medicine: State of the Art in Latin America

“…In several animal models, the capability of achieving a systemic response using GET alone has been demonstrated [ 99 , 100 , 101 ]. Similar results were obtained in human patients, where promising results were reported [ 65 , 66 ], and many clinical trials are going in this direction.…”

“…The first one in 2008, was a phase I study performed on human patients with metastatic melanoma, where 10% of the patients had a complete response of distant untreated lesions and 42% showed disease stabilization or partial response [ 65 ]. In 2020 the results of the phase II study performed on human patients using the same plasmid were published, where 46% of the patients showed some degree of systemic response, and 75% of the treated patients remained alive after a 6-year follow-up period [ 66 ]. These results are not only due to the IL-12 but also to the GET procedure itself, as it increases the immunogenicity of DNA vaccines as compared with DNA injection alone [ 67 ].…”

Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma

“… 11 In the current study, our data extend on initial characterization to show the potential for therapeutic efficacy when locally administered. Although this is an appealing avenue for tumors that are easily accessible for local delivery, an approach currently in clinical trials for other therapeutic platforms, 32 future studies will determine trafficking, recruitment, and efficacy of systemically injected GEMs for tumors that may be impossible to access, diffuse, multifocal, or metastatic.…”

Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma

“…To potentially overcome these poor responses, studies are being conducted to determine the potential of combining IL-15 or IL-15/IL-15Rα with other immune modifiers, including checkpoint inhibitors [ 40 , 41 , 42 ]. Interestingly, in the pIL-12 clinical trials, patients who had a poor response were observed to have elevated tumor levels of PD-1 and PD-L1 [ 34 , 43 ]. A phase II clinical trial combining pIL-12 and anti-PD-1 in immunologically quiescent melanomas resulted in a higher than expected response rate [ 44 ], with a complete response rate (all tumors responding) of 36% [ 44 ].…”