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Rodriguez-Garcia A , Sharma P , Poussin M , Boesteanu AC , Minutolo NG , Gitto SB , Omran DK , Robinson MK , Adams GP , Simpkins F , Powell DJ Jr
CAR T Cells Targeting MISIIR for the Treatment of Ovarian Cancer and Other Gynecologic Malignancies
Mol Ther. 2020 Feb 5;28(2) :548-560
PMID: 31870622 PMCID: PMC7001088 URL: https://www.ncbi.nlm.nih.gov/pubmed/31870622
AbstractThe prognosis of patients diagnosed with advanced ovarian or endometrial cancer remains poor, and effective therapeutic strategies are limited. The Mullerian inhibiting substance type 2 receptor (MISIIR) is a transforming growth factor beta (TGF-beta) receptor family member, overexpressed by most ovarian and endometrial cancers while absent in most normal tissues. Restricted tissue expression, coupled with an understanding that MISIIR ligation transmits apoptotic signals to cancer cells, makes MISIIR an attractive target for tumor-directed therapeutics. However, the development of clinical MISIIR-targeted agents has been challenging. Prompted by the responses achieved in patients with blood malignancies using chimeric antigen receptor (CAR) T cell therapy, we hypothesized that MISIIR targeting may be achieved using a CAR T cell approach. Herein, we describe the development and evaluation of a CAR that targets MISIIR. T cells expressing the MISIIR-specific CAR demonstrated antigen-specific reactivity in vitro and eliminated MISIIR-overexpressing tumors in vivo. MISIIR CAR T cells also recognized a panel of human ovarian and endometrial cancer cell lines, and they lysed a battery of patient-derived tumor specimens in vitro, without mediating cytotoxicity of a panel of normal primary human cells. In conclusion, these results indicate that MISIIR targeting for the treatment of ovarian cancer and other gynecologic malignancies is achievable using CAR technology.
Notes1525-0024 Rodriguez-Garcia, Alba Sharma, Prannda Poussin, Mathilde Boesteanu, Alina C Minutolo, Nicholas G Gitto, Sarah B Omran, Dalia K Robinson, Matthew K Adams, Gregory P Simpkins, Fiona Powell, Daniel J Jr Journal Article United States Mol Ther. 2020 Feb 5;28(2):548-560. doi: 10.1016/j.ymthe.2019.11.028. Epub 2019 Dec 6.