Intratumoral electroporation of plasmid interleukin-12: efficacy and biomarker analyses from a phase 2 study in melanoma (OMS-I100)

Background

Recent data from immune checkpoint studies, including studies of anti-PD1 and anti-PDL1 antibodies, suggest that an inflammatory intratumoral milieu is required for an optimal response to immune therapy. Serial biopsy analyses from a phase 1 study demonstrate that transformation of tumor cells with electroporation (EP) of plasmid interleukin-12 (pIL-12) promotes this inflammatory immune milieu. Here we present clinical response data for 30 advanced melanoma patients (pts) treated with pIL-12 EP in a phase 2 trial (OMS-I100). We also present additional safety and more detailed biomarker data demonstrating the promotion of pro-inflammatory genes with pIL-12 EP therapy.

Methods

Thirty patients with stage IIIB-IV melanoma received up to 4 cycles of pIL-12 EP into superficial cutaneous, subcutaneous, and nodal lesions on days 1, 5 and 8 of each 12-week cycle. Tumor responses were evaluated using modified RECIST criteria for cutaneous lesions. Adverse events (AEs) were assessed using CTCAE version 4. Alterations in transcription were assessed by comparing pre- and post-treatment biopsies from treated lesions using NanostringTM technology to identify pharmacodynamic markers of downstream pathway activation and to characterize cellular infiltration.

Results

The best overall response rate (BORR) by modified RECIST in 29 evaluable pts was 31% (9/29), with 10% (3/29) of pts achieving a CR. Regression of at least one non-treated lesion was seen in 54% (13/24) of pts with evaluable lesions. The most common treatment-related adverse event (AE) reported was transient Grade 1/2 pain at the treatment site, reported in 87% (26/30) of pts. Grade 3 adverse events were rare and included only 1 report of Grade 3 pain at the injection site. No grade 4 or higher adverse events were observed. Analysis of tissue samples from patients treated with pIL-12 EP showed a gene expression pattern consistent with downstream activation of NK cells and interferon-γ-dependent genes, including key genes responsible for tumor inflammation, antigen processing and presentation (APM).

Conclusions

pIL-12 EP monotherapy induces objective tumor responses in a significant proportion of patients (BORR 31%) and treatment was well tolerated. pIL-12 EP promotes the expression of pro-inflammatory genes including genes required for antigen processing and presentation. Regression of non-treated lesions suggests successful induction of systemic anti-tumor immune-mediated effects. Based on these data, further investigation of pIL-12 EP both as a single agent, and in combination with other therapies such as anti-PD1/PD-L1, is warranted.