Interleukin-12 Electroporation May Help 'Cold' Melanomas Respond to Immunotherapies

The combination of intratumoral electroporation of interleukin-12 (IL-12) DNA (TAVO) and pembrolizumab (Keytruda, Merck) resulted in clinical responses in patients with immunologically quiescent advanced melanoma, according to a study published in Clinical Cancer Research.1

“Immune checkpoint inhibition has become a common first-line treatment for melanoma in recent years,” said Adil 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, in a press release. “However, approximately 40% of melanomas are considered to be ‘cold,’ meaning that they lack sufficient infiltration of immune cells within the tumor and therefore have poor responses to this therapy.”2

However, an estimated 12% to 15% of these “cold” melanomas did respond to immune checkpoint inhibition, Daud explained.2

“The big question in the field is how to turn these ‘cold’ melanomas into ‘hot’ ones that will respond to immune checkpoint inhibition,” Daud said.2

In this single-arm phase 2 trial, the researchers assessed the effects of treating patients with “cold” melanomas with a combination of the immune checkpoint inhibitor pembrolizumab and TAVO. IL-12, a cytokine that urges the recruitment of immune cells, has associated toxicities with its administration, so electroporation was used to deliver TAVO directly into melanoma lesions in order to reduce those toxicities.1

In the trial, 23 adult patients were enrolled. All of these patients had unresectable or metastatic melanoma with accessible lesions and were predicted to respond poorly to pembrolizumab, based on the number of checkpoint-positive immune cells within their tumors.1

The patients received pembrolizumab every 3 weeks and had TAVO electroporation on days 1, 5, and 8 within a 6-week cycle. The patients continued this treatment regimen until there was confirmed disease progression, which occurred up to a 2-year period.1

Treatment responses were seen in 9 of 22 evaluable patients, for an objective response rate of 41%. A complete response to treatment was experienced by 36% of patients.1

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. Additionally, regression was observed in 29.2% of untreated lesions. According to Daud, the responses in untreated lesions may be caused by the proliferation and circulation of cancer-specific immune cells within the body.2

Grade 3 or higher adverse effects (AEs) to the combination treatment included pain, chills, sweats, and cellulitis. These AEs are in addition to those toxicities that are typical of pembrolizumab alone, Daud explained in a press release.2

The researchers found that by examining pre- and post-treatment tissue samples, the combination of the two treatments increased the number of immune cells in the tumor microenvironment, compared with levels at baseline. Although this increase was seen in responders and nonresponders, nonresponders alone had more immunosuppressive cells present.1

Furthermore, the analyses of the gene expression showed that the combination treatment caused an upregulation of immune-activating genes in tumor cells. Additionally, the treatment increased the proliferation of immune cells in the peripheral blood of responders and nonresponders, demonstrating the treatment activated a systemic immune response.1

“Combining pembrolizumab with TAVO electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition,” Daud said in a press release. “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.”2

Based on the results of this study, the researchers plan to investigate the induced responses in those patients who did not respond to the TAVO and pembrolizumab combination. Daud and his colleagues have also begun to conduct a phase 2 study of intratumoral TAVO plus pembrolizumab in patients who have progressed on pembrolizumab or nivolumab.2

Daud hopes in the future to examine the effects of the combination therapy on other “cold” tumor types, including breast cancer.2

REFERENCES

  1. Algazi A, Twitty CG, Tsai KK, et al. Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma. Clinical Cancer Research. 2020. doi: 10.1158/1078-0432.CCR-19-2217.
  2. Interleukin-12 Electroporation May Sensitize Immunologically “Cold” Melanomas to Immune Checkpoint Inhibition [news release]. Philadelphia, PA: American Association for Cancer Research; May 6, 2020. aacr.org/about-the-aacr/newsroom/news-releases/interleukin-12-electroporation-may-sensitize-immunologically-cold-melanomas-to-immune-checkpoint-inhibition/. Accessed May 6, 2020.



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