Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses

Cancer Immunol Res. 2020 Feb;8(2):246-254. doi: 10.1158/2326-6066.CIR-19-0359. Epub 2019 Dec 18.

Abstract

Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use
  • Antigens, Neoplasm / immunology
  • Biomarkers / blood
  • Biomarkers / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Electroporation / methods*
  • Humans
  • Immunity, Cellular / drug effects
  • Immunotherapy / methods
  • Interferon-gamma / immunology
  • Interleukin-12 / therapeutic use*
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / therapy*
  • Neoplasm Staging
  • Patient Safety
  • Plasmids / administration & dosage*
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / therapy*
  • Treatment Outcome
  • Tumor Microenvironment / immunology*

Substances

  • Adjuvants, Immunologic
  • Antigens, Neoplasm
  • Biomarkers
  • Interleukin-12
  • Interferon-gamma

Supplementary concepts

  • Melanoma, Cutaneous Malignant