NEW YORK — Intratumoral plasmid interleukin-12 electroporation was associated with local necrosis and increased tumor infiltrating lymphocytes and can lead to systemic tumor regression in melanoma, according to study results presented at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
These benefits warrant the study of plasmid interleukin (IL)-12 electroporation in combination with anti-programmed cell death-1 (PD-1) monoclonal antibodies, Alain Algazi, MD, of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, said during his presentation.
“IL-12 is a key cytokine, and might be really important in terms of stimulating an anti-tumor immune response, but if you give it systemically, it is toxic,” Algazi said. “This is a way that you can give a concentrated amount of IL-12 into the tumor, with a focal intervention that is more tolerable.”
Algazi and colleagues developed a platform for treatment where researchers inject plasma DNA into the tumor and then give an electric current to the site in order to make holes in the tumor cells. The tumor can then take up the plasma and start expressing IL-12.
“This is a platform that can be used for any variety of things you’d want to express, but IL-12 is a particularly appropriate focal intervention that might cause the tumor inflammation we’re looking for to get an anti-tumor immune response,” Algazi said.
Algazi and colleagues conducted a phase 1 study evaluating plasmid IL-12 electroporation in 24 patients. Patients received intratumoral plasmid IL-12 electroporation on days 1, 5 and 8. Using biopsy samples from two patients, researchers noted dense tumor infiltrating lymphocyte (TIL) populations by 22 days, and by 18 months there were no residual melanoma cells, Algazi said.
Overall, two patients achieved a complete response — one which lasted longer than 16 months and the other longer than 20 months — and six patients achieved stable disease that ranged from 4 months to 6 months.
Based on these data, researchers conducted a phase 2 trial in 30 patients (median age 67 years, 53.3% male). Patients had unresectable stage IIIB/C melanoma or stage IV melanoma, and 55.2% had received prior immunotherapy.
Overall, treatment was well tolerated, Algazi said. The most common adverse event was pain (87%), the median duration of which was 1 minute. The median pain score was 3 immediately after treatment, but 5 minutes later the pain score decreased to 0.
Four patients achieved a complete response, five achieved a partial response and five patients achieved stable disease. The overall response rate was 31% and the disease control rate was 48%.
The median duration of response was 3.2 months (range, 2.1-16.6) and the median duration of disease control was 5.9 months (range, 2.7-16.6).
Intratumoral plasmid IL-12 electroporation promoted local and systemic anti-tumor immunity, Algazi said. Of 26 evaluable patients, 50% had distant lesion regression.
Median PFS was 3.1 months.
“You can get objective responses with single-agent plasmid IL-12 electroporation, and it appears to be well tolerated except for the pain associated with treatment,” Algazi said. “Preliminary data suggest we’re getting inflammation in the tumor, which is part one of the two-part immune response. We need inflammation in the tumor and we need immune cell infiltration and cytokine elaboration, and that might be what we really need to synergize with the PD-1/PD-L1 antibody checkpoint inhibitor.”
Researchers plan to open a study evaluating the combination of pembrolizumab (Keytruda, Merck) and intratumoral plasmid IL-12 electroporation this year, Algazi said. — by Alexandra Todak
For more information:
Algazi A. Plasmid Il-12 electroporation in melanoma. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.
Disclosure: Algazi reports research funding from GlaxoSmithKline and Merck.