Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma

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.

Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs

“…In humans, it is well-established that only certain types of cancers are responsive to ICIs alone [41]. Therefore, various combination immunotherapies against cancer have been proposed [42][43][44]. One of the many modalities tested in combination with ICIs is the highly potent immune-activating cytokine interleukin 12 (IL-12) [44,45].…”

“…Therefore, various combination immunotherapies against cancer have been proposed [42][43][44]. One of the many modalities tested in combination with ICIs is the highly potent immune-activating cytokine interleukin 12 (IL-12) [44,45]. Human IL-12 is cross functional on dog immune cells and has been tested as electrogenetherapy [46] as immunocytokine (NHS-IL-12 [47]) or armed oncolytic virus [48] in dogs.…”

Localized Interleukin-12 for Cancer Immunotherapy

“…Finally, a recent Phase II study of i.t. pIL-12+EP and systemic pembrolizumab in patients with non-infiltrated melanomas resulted in a 41% objective response rate with 36% complete responses (397). Correlative studies demonstrated increased antigen cross-presentation along with enhance T cell infiltration and activity leading to higher than expected clinical responses (397).…”

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

“…Alternatively, intratumoral electroporation of tavo (IL-12) was found to be safe in a Phase I clinical trial, demonstrated preliminary efficacy by increasing intratumoral IL-12 and IFN-γ, and led to remission in several patients ( 74 ). Two recent Phase II clinical trials of tavo (IL-12) electroporation found that this treatment leads to an increase in NK cell and cDC1-related transcripts in the tumor, an increase in CD8 + T cells in the tumor, and activation of systemic immune responses in treated patients ( 72 , 73 ). In these studies, it was proposed that intratumoral electroporation of tavo (IL-12) appears to boost NK cell abundance in the tumor, which leads to an increase in abundance of protective cDC1s, increased T cell responses, and, in some patients, durable responses to treatment ( 72 ).…”