IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo Journal Article

Authors: Koneru, M.; Purdon, T. J.; Spriggs, D.; Koneru, S.; Brentjens, R. J.
Article Title: IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo
Abstract: A novel approach for the treatment of ovarian cancer includes immunotherapy with genetically engineered T cells targeted to ovarian cancer cell antigens. Using retroviral transduction, T cells can be created that express an artificial T cell receptor (TCR) termed a chimeric antigen receptor (CAR). We have generated a CAR, 4H11-28z, specific to MUC- 16ecto antigen, which is the over-expressed on a majority of ovarian tumor cells and is the retained portion of MUC-16 after cleavage of CA-125. We previously demonstrated that T cells modified to express the 4H11-28z CAR eradicate orthotopic human ovarian cancer xenografts in SCID-Beige mice. However, despite the ability of CAR T cells to localize to tumors, their activation in the clinical setting can be inhibited by the tumor microenvironment, as is commonly seen for endogenous antitumor immune response. To potentially overcome this limitation, we have recently developed a construct that co-expresses both MUC16ecto CAR and IL-12 (4H11-28z/IL-12). In vitro, 4H11-28z/IL-12 CAR T cells show enhanced proliferation and robust IFNg secretion compared to 4H11-28z CAR T cells. In SCID-Beige mice with human ovarian cancer xenografts, IL-12 secreting CAR T cells exhibit enhanced antitumor efficacy as determined by increased survival, prolonged persistence of T cells, and higher systemic IFNg. Furthermore, in anticipation of translating these results into a phase I clinical trial which will be the first to study IL-12 secreting CAR T cells in ovarian cancer, an elimination gene has been included to allow for deletion of CAR T cells in the context of unforeseen or off-tumor ontarget toxicity. © 2015 Taylor & Francis Group, LLC.
Keywords: tumor microenvironment; muc16; il-12; chimeric antigen receptors; human ovarian cancer
Journal Title: OncoImmunology
Volume: 4
Issue: 3
ISSN: 2162-4011
Publisher: Landes Bioscience  
Date Published: 2015-03-01
Start Page: e994446
Language: English
DOI: 10.4161/2162402x.2014.994446
PROVIDER: scopus
PMCID: PMC4404840
PUBMED: 25949921
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Renier J Brentjens
    280 Brentjens
  2. David R Spriggs
    325 Spriggs
  3. Mythili Koneru
    6 Koneru
  4. Terence John Purdon
    60 Purdon