title: IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumorsin 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-16ectoantigen, 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 MUC16ectoCAR and IL-12 (4H11-28z/IL-12).In vitro, 4H11-28z/IL-12 CAR T cells show enhanced proliferation and robust IFNγ 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 IFNγ. 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 on-target toxicity.
authors.affiliation: Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York, NY, USA.
authors.forename: Mythili
authors.initials: M
authors.lastname: Koneru
authors.affiliation: Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York, NY, USA.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Purdon
authors.affiliation: Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Spriggs
authors.affiliation: Rutgers School of Public Health ; Newark, NJ USA.
authors.forename: Susmith
authors.initials: S
authors.lastname: Koneru
authors.affiliation: Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York, NY, USA.
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
keywords: AAPCs, artificial antigen presenting cells; ADCC, antibody-dependent cellular cytotoxicity; ALL, acute lymphocytic leukemia; CAR, chimeric antigen receptor; EGFRt, truncated epidermal growth factor; EOC, epithelial ovarian cancer; i.p., intraperitoneal; IL-12, interleukin-12; i.v., intravenous; MDSC, myeloid-derived suppressor cells; PBL, peripheral blood leukocytes; PBMCs, peripheral blood mononuclear cells; scFv, single-chain fragment antibody; TAA, tumor-associated antigen; TCR, T cell receptor; TIL, tumor-infiltrating lymphocytes; Tregs, regulatory T cells.; IL-12; MUC16; chimeric antigen receptors; human ovarian cancer; tumor microenvironment