Combining Pembrolizumab With IL-12 Electroporation May Improve Clinical Response in Patients With Immunologically 'Cold' Melanoma

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Patients with non–immune-infiltrated “cold” tumors have low frequencies of intratumoral tumor-reactive, checkpoint-positive cytotoxic lymphocytes, making them less responsive to checkpoint blockage than patients with immune-infiltrated “hot” tumors. A phase II study by Alain P. Algazi, MD, and colleagues investigated whether combining intratumoral plasmid interleukin-12 (IL-12) (tavokinogene telseplasmid [TAVO]) with pembrolizumab could turn patients’ cold melanoma tumors into hot ones that will respond to immune checkpoint inhibition. They found that the therapy altered the tumor microenvironment, improving the response rate in these patients. According to the study authors, this combination therapy may help to induce remissions in patients who are clinically refractory to anti–programmed cell death protein 1 (PD-1) therapies. The study was published in Clinical Cancer Research.

Alain P. Algazi, MD

Alain P. Algazi, MD

Study Methodology

The researchers enrolled 23 adult patients with unresectable or metastatic non–immune-infiltrated melanoma with accessible lesions. The patients received TAVO electroporation intratumorally on days 1, 5, and 8 every 6 weeks, and pembrolizumab every 3 weeks.

The primary endpoint was objective response rate as determined by RECIST. Secondary endpoints included duration of response, overall survival, and progression-free survival. Toxicity was evaluated by the common terminology criteria for adverse events (CTCAE) v4.

The patients remained on the combination treatment until confirmed disease progression for up to 2 years.

Study Results

The combination of TAVO and pembrolizumab was well tolerated. Grade 3 or higher adverse effects were limited and included pain, chills, sweats, and cellulitis, and those adverse events were similar to adverse events seen with pembrolizumab alone.

Responses were observed in 9 of 22 evaluable patients, for an objective response rate of 41%. Thirty-six percent of the patients experienced a complete response. The median progression-free survival was 5.6 months, and the median overall survival was not reached after a median follow-up of 19.6 months.


  • Combining intratumoral electroporation of interleukin-12 with pembrolizumab in patients with cold melanoma tumors altered the tumor microenvironment and resulted in encouraging clinical responses.
  • This combination therapy may help to induce remissions in patients who are clinically refractory to anti–PD-1 therapies.

In addition to regression of electroporated lesions, regression was also observed in 29.2% of untreated lesions. Responses in untreated lesions may be due to the proliferation and circulation of cancer-specific immune cells throughout the body.

Correlative analysis showed that the combination therapy enhanced immune infiltration and sustained the IL-12/IFN-γ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased tumor-infiltrating lymphocytes, emerging T-cell receptor clones, and systemic cellular immune responses.

“The combination of TAVO and pembrolizumab was associated with a higher-than-expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T-cell infiltration with enhanced immunity paralleling the clinical activity in [tumors with] low checkpoint-positive cytotoxic lymphocytes,” concluded the study authors.

Translational Significance

In patients with cold melanoma tumors, the combination therapy productively altered the tumor microenvironment and was associated with encouraging clinical responses.

“Combining pembrolizumab with TAVO electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition,” said principal study investigator Adil I. Daud, MD, Clinical Professor at the University of California, San Francisco (UCSF) and Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center. “By using electroporation to deliver TAVO locally, we were able to avoid many of the toxicities associated with systemic IL-12 administration, while still attaining clinical responses and inducing immune-cell infiltration in treated and untreated melanoma lesions.”

Dr. Daud is the corresponding author of this study.

Disclosure: Funding for this study was provided by Merck and OncoSec Medical Inc. For full disclosures of the study authors, visit

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