In a phase II trial published in Clinical Cancer Research, the combination of intratumoral plasmid IL-12 (tavokinogene telseplasmid; tavo) and pembrolizumab (Keytruda) was associated with a higher than anticipated response rate in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).

Researchers suggested that this approach may help to induce remissions in patients who are clinically refractory to anti-PD-1 therapies. 

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

The primary endpoint for the study was objective response rate (ORR) by RECIST, and secondary endpoints included duration of response, overall survival, and progression-free survival. Additionally, toxicity was evaluated by the CTCAE v4. 

Patients who were ≥18 years old, anti-PD-1 antibody experienced, and naïve with metastatic or unresectable melanoma with accessible lesions were eligible for the study. Tavo was administered to patients on days 1, 5, and 8 every 6 weeks, while 200 mg of pembrolizumab was administered every 3 weeks. Treatment was continued for up to 2 years if individuals had stable disease or better and continued to benefit from treatment. Moreover, patients with unconfirmed disease were allowed to continue on treatment until disease progression was confirmed.

Overall, the trial enrolled 23 adult patients and responses were observed in 9 of 22 evaluable patients, for an ORR of 41%,36% of which were complete responses. 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 electroplated lesions, regression was also seen in 29.2% of untreated lesions. Daud explained that responses in untreated lesions may be caused by proliferation and circulation of cancer-specific immune cells throughout the body. 

The combination of tavo and pembrolizumab was found to be well tolerated, with adverse events (AEs) observed being similar to those previously reported with pembrolizumab alone. Grade 3 or higher ES were limited and included pain, chills, sweats, and cellulitis. 

Further, correlative analysis demonstrated that the combination enhanced immune infiltration and sustained the IL-12/IFNy feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased tumor infiltrating lymphocytes, emerging T-cell receptor clones and, ultimately, systemic cellular immune responses. 

“While our results are promising, a key limitation to this approach is that approximately 60 percent of patients still did not respond,” Daud explained. In addition, the researchers noted that electroporation would not be an option for patients with inaccessible lesions. 

Based on the presented findings, ongoing work from Daud and his colleagues aims to understand how to induce responses in patients who did respond to the combination of tavo and pembrolizumab. Even further, Daud and his colleagues are also currently conducting a phase II study of intratumoral tavo plus pembrolizumab in patients who have progressed on pembrolizumab or nivolumab. 

References:

1. Algazi AP, 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. doi:10.1158/1078-0432.CCR-19.2217.

2. Interleukin-12 Electroporation May Sensitize Immunologically “Cold” Melanomas to Immune Checkpoint Inhibition [news release]. Philadelphia. Published May 6, 2020. Accessed May 8, 2020. 



Source link