Intratumoral delivery of electroporated plasmid IL-12 yields systemic immune responses in metastatic melanoma patients
Menée sur 30 patients atteints d'un mélanome métastatique (durée médiane de suivi : 29,7 mois), cette étude évalue l'efficacité, du point de vue de la réponse du système immunitaire, de la survie sans progression et de la survie globale, de l'injection intratumorale d'un plasmide exprimant l'interleukine IL-12 en combinaison avec une électroporation des lésions cancéreuses
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 (tavokinogene telseplasmid, TAVO™) in advanced melanoma patients (NCT 01502293). Patients and Methods : Patients with stage III/IV melanoma were treated intratumorally with plasmid IL-12, 0.5 mg/mL followed by electroporation (6 pulses, 1500 v/cm) on days 1,5,8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for PDL-1, flow cytometry to assess changes in immune cell subsets and analysis immune-related gene expression were performed 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 CTCAEv3. 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. 46% of patient 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 upregulated but there was also increased adaptive immune resistance. Conclusions : Intratumoral pIL-12 was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration was observed in treated as well as untreated/distal lesions, adaptive immune resistance limited response.