1620P - Immune correlates of intratumoral IL-12 electroporation

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Cancer Immunology and Immunotherapy
Translational Research
Presenter Robert Pierce
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors R.H. Pierce1, K.T. Takamura1, S.A. Shirley2, S.E. Chan3, J. Lewis3, J.S. Campbell4, L. Fong3, R. Heller2, T.T. Diep1, A. Daud5
  • 1Clinical Development, OncoSec Medical Inc., 92121 - San Diego/US
  • 2Frank Reidy Research Center For Bioelectrics, Old Dominion University, 23508 - Norfolk/US
  • 3Department Of Hematology/oncology, University of California, San Francisco, 94143 - San Francisco/US
  • 4Research And Development, OncoSec Medical Inc., 92121 - San Diego/US
  • 5Department Of Hematology/oncology, University of California, San Francisco, San Francisco/US

Abstract

Aim

Intratumoral (IT) electroporation (EP) of plasmid IL-12 promotes systemic anti-tumor immunity and is being evaluated in Phase 2 trials. In patients (pts) with advanced melanoma (MEL) treated with IL-12 EP, regression of non-injected lesions was seen in 4/19 pts in the Phase I study and 13/21 pts in the ongoing Phase 2 study. This study explores systemic efficacy and immune correlates in clinical samples and in a bilateral MEL model, utilizing the poorly immunogenic B16 cell line, to test the hypothesis that intratumoral IL-12 EP can enhance tumor immunogenicity.

Methods

Pre- and post-treatment biopsies and blood were collected from MEL trial pts. A B16 2-tumor MEL model was developed in mice. Tumors treated with IL-12 EP were compared to untreated tumors in the same animal. mRNA was evaluated by NanoString and leukocyte populations by IHC and flow cytometry.

Results

Analyses of clinical samples indicated a doubling of NK cells in the treated tumor as well as increased frequency in activated NK cells in circulation. In the B16 model, complete regression was seen in 20/20 treated tumors at post-treatment day 7 and 4/10 untreated tumors at day 18 or 22. Regression in untreated tumors was accompanied by a TIL infiltrate and transcriptional profile consistent with increased NK, CD8, CD4 and Tregs. In addition, the infiltrate was associated with increased mRNA for PD-1, PD-L1, IFNg and IFNg-inducible genes involved in antigen presentation and processing.

Conclusions

IL-12 EP results in regression of untreated lesions in pts and mice. Analysis of IL-12 EP-treated tumors showed a pattern consistent with NK cell infiltration, IFNg expression and upregulation of IFNg-driven genes, including ones involved in antigen processing and presentation. In mice, where untreated tumors were systematically analyzed, a TIL infiltrate and transcriptional IFNg-program was identified consistent with enhanced B16 immunogenicity. This model provides insights into the immune reactions in both the electroporated tumor and in untreated lesions. Although preliminary, data from the B16 model and IL-12-treated pts support the hypothesis that augmentation of immunogenicity is a component of IL-12's systemic anti-tumor effects.

Disclosure

R.H. Pierce: I have a leadership position as Chief Medical Officer and stock/other ownership in OncoSec Medical Inc. to disclose; K.T. Takamura: I have an employment position at OncoSec Medical Inc. to disclose; J.S. Campbell: I have a leadership position as Executive Director of Research and Development with OncoSec Medical Inc. to disclose; L. Fong: I have research funding with OncoSec Medical Inc. to disclose; R. Heller: I have research funding with OncoSec Medical Inc. to disclose; T.T. Diep: I have a leadership position as Executive Director Clinical Development and stock/other ownership in OncoSec Medical Inc. to disclose; A.I. Daud: I have a leadership position as Chief Clinical Strategist and research funding with OncoSec Medical Inc. to disclose. All other authors have declared no conflicts of interest.