Interleukin-12 electroporation may sensitize 'cold' melanomas to immunotherapies

May 06, 2020

Bottom Line: Combining intratumoral electroporation of interleukin-12 (IL-12) DNA (tavokinogene telseplasmid, or TAVO) with the immune checkpoint inhibitor pembrolizumab (Keytruda) led to clinical responses in patients with immunologically quiescent advanced melanoma, according to results from a phase II trial.

Journal in Which the Study was Published:Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: 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

Background: "Immune checkpoint inhibition has become a common first-line treatment for melanoma in recent years," said Daud. "However, approximately 40 percent 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." It is estimated that only 12 to 15 percent of "cold" melanomas respond to immune checkpoint inhibition, added Daud. "The big question in the field is how to turn these 'cold' melanomas into 'hot' ones that will respond to immune checkpoint inhibition."

How the Study was Conducted: In this single-arm phase II trial, Daud and colleagues examined the impact of treating patients with "cold" melanomas with a combination of the immune checkpoint inhibitor pembrolizumab and a DNA plasmid encoding IL-12 (TAVO). IL-12 is a cytokine that triggers the recruitment of immune cells. To help reduce toxicities associated with systemic IL-12 administration, Daud and colleagues used electroporation to deliver TAVO directly into melanoma lesions.

The trial enrolled 23 adult patients with unresectable or metastatic melanoma who had accessible lesions and who were predicted to respond poorly to pembrolizumab, based on the proportion of checkpoint-positive immune cells in their tumors. Patients underwent TAVO electroporation on days 1, 5, and 8 of every six-week cycle, and they received pembrolizumab every three weeks. Patients remained on treatment until confirmed disease progression, up to two years.

Results: Responses were observed in nine of 22 evaluable patients, for an objective response rate of 41 percent. Thirty-six percent of 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. In addition to regression of electroporated lesions, regression was also observed in 29.2 percent of untreated lesions. Responses in untreated lesions may be due to proliferation and circulation of cancer-specific immune cells throughout the body, explained Daud.

Grade 3 or higher adverse effects were limited and included pain, chills, sweats, and cellulitis, in addition to the toxicities typically observed with pembrolizumab alone, Daud noted.

By examining pre- and post-treatment tissue samples, Daud and colleagues found that the combination treatment increased the number of immune cells in the tumor microenvironment, compared with baseline levels. This increase was observed for both responders and nonresponders; however, nonresponders also had greater numbers of immunosuppressive cells. Gene expression analyses revealed that the combination treatment led to upregulation of immune-activating genes in patients' tumor cells. Furthermore, treatment enhanced the number of proliferating immune cells in peripheral blood of both responders and nonresponders, indicating activation of a systemic immune response.

Author's Comments: "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 Daud.

"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," Daud added.

Based on these findings, ongoing work from Daud and colleagues aims to understand how to induce responses in the patients who did not respond to the TAVO and pembrolizumab combination. Additionally, Daud and colleagues are currently conducting a phase II study of intratumoral TAVO plus pembrolizumab in patients who have progressed on pembrolizumab or nivolumab. Daud is also interested in examining the impact of the combination therapy for other "cold" tumor types, including breast cancer.

Study Limitations: "While our results are promising, a key limitation to this approach is that approximately 60 percent of patients still did not respond," explained Daud. An additional limitation is that electroporation would not be an option for patients with inaccessible lesions.
Funding & Disclosures: The study was supported by Merck and OncoSec Medical Inc. Daud has received research funding from Merck, Bristol Myers Squibb, Pfizer, Incyte, Genentech/Roche, OncoSec Medical Inc., the Parker Institute for Cancer Immunotherapy, and the Cook, Kelly, and Amoroso Funds at UCSF.

Follow us: Cancer Research Catalyst; Twitter; and Facebook

For AACR information, visit Fast Facts.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes 46,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 127 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 22,500 attendees. In addition, the AACR publishes nine prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit

American Association for Cancer Research

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to