In a phase II clinical trial, patients with stage III/IV melanoma were treated with intratumoral injections of tavokinogene telseplasmid (Tavo) – a plasmid encoding IL-12 – followed by electroporation. Tavo was well tolerated. Best ORR in 28 evaluable patients was 36% (18% CR) and median OS was not reached at a median follow-up of 30 months. Best ORR in treated and untreated lesions were 44% and 25%, respectively. Tavo increased TILs, T cell and NK cell activation, antigen presentation, and T cell trafficking, leading to systemic response. Tavo also increased PD-L1 expression, and 6 of 8 patients progressing on Tavo responded to subsequent pembrolizumab.
Contributed by Anna Scherer
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 (NCT01502293). 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.
Author Info: (1) Department of Medicine, University of California, San Francisco, San Francisco, USA. (2) Department of Medicine, University of Washington, Seattle, USA. (3) St. Luke's Cancer C
Author Info: (1) Department of Medicine, University of California, San Francisco, San Francisco, USA. (2) Department of Medicine, University of Washington, Seattle, USA. (3) St. Luke's Cancer Center, Bethlehem, USA. (4) Lakeland Health Medical Center, Lakeland, USA. (5) University of Colorado Cancer Center - Anschutz, Denver, USA. (6) Providence John Wayne Cancer Institute, Santa Monica, USA. (7) Department of Medicine, University of California, San Francisco, San Francisco, USA. (8) Department of Medicine, University of California, San Francisco, San Francisco, USA. (9) Department of Medicine, University of California, San Francisco, San Francisco, USA. (10) Department of Medicine, University of California, San Francisco, San Francisco, USA. (11) Earle A. Chiles Research Institute at Providence Portland Medical Center, Portland, USA. (12) Earle A. Chiles Research Institute at Providence Portland Medical Center, Portland, USA. (13) Earle A. Chiles Research Institute at Providence Portland Medical Center, Portland, USA. (14) OncoSec Medical Incorporated, San Diego, USA. (15) OncoSec Medical Incorporated, San Diego, USA. (16) OncoSec Medical Incorporated, San Diego, USA. (17) OncoSec Medical Incorporated, San Diego, USA. (18) OncoSec Medical Incorporated, San Diego, USA. (19) OncoSec Medical Incorporated, San Diego, USA. (20) Department of Medicine, University of California, San Francisco, San Francisco, USA. (21) OncoSec Medical Incorporated, San Diego, USA. (22) Department of Medicine, University of California, San Francisco, San Francisco, USA. Electronic address: Adil.daud@ucsf.edu.
