CAR T Cells Targeting MISIIR for the Treatment of Ovarian Cancer and Other Gynecologic Malignancies

被引:31
|
作者
Rodriguez-Garcia, Alba [1 ,2 ,3 ]
Sharma, Prannda [1 ,2 ,3 ]
Poussin, Mathilde [1 ,2 ,3 ]
Boesteanu, Alina C. [3 ]
Minutolo, Nicholas G. [1 ,2 ,3 ]
Gitto, Sarah B. [1 ,2 ,3 ]
Omran, Dalia K. [1 ]
Robinson, Matthew K. [4 ,6 ]
Adams, Gregory P. [4 ,7 ]
Simpkins, Fiona [5 ]
Powell, Daniel J., Jr. [1 ,2 ,3 ]
机构
[1] Univ Penn, Perelman Sch Med, Ovarian Canc Res Ctr, Dept Obstet & Gynecol, 3400 Civ Ctr Blvd,Bldg 421,TRC Room 8-103, Philadelphia, PA 19104 USA
[2] Univ Penn, Abramson Canc Ctr, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Abramson Canc Ctr, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA
[4] Fox Chase Canc Ctr, Dev Therapeut Program, Philadelphia, PA 19111 USA
[5] Univ Penn, Ovarian Canc Res Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Philadelphia, PA 19104 USA
[6] Immunome, Exton, PA 19341 USA
[7] Elucida Oncol, Monmouth Jct, NJ 08852 USA
关键词
MULLERIAN-INHIBITING SUBSTANCE; CHIMERIC ANTIGEN RECEPTOR; II RECEPTOR; IN-VITRO; ANTITUMOR-ACTIVITY; HORMONE-RECEPTOR; SURVIVAL; GROWTH; LINES; EXPRESSION;
D O I
10.1016/j.ymthe.2019.11.028
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The 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.
引用
收藏
页码:548 / 560
页数:13
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