Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen.
OBJECTIVE
Most patients diagnosed with ovarian cancer will ultimately die from their disease. For this reason, novel approaches to the treatment of this malignancy are needed. Adoptive transfer of a patient's own T cells, genetically modified ex vivo through the introduction of a gene encoding a chimeric antigen receptor (CAR) targeted to a tumor-associated antigen, is a novel approach to the treatment of ovarian cancer.


METHODS
We have generated several CARs targeted to the retained extracellular domain of MUC16, termed MUC-CD, an antigen expressed on most ovarian carcinomas. We investigate the in vitro biology of human T cells retrovirally transduced to express these CARs by coculture assays on artificial antigen-presenting cells as well as by cytotoxicity and cytokine release assays using the human MUC-CD(+) ovarian tumor cell lines and primary patient tumor cells. Further, we assess the in vivo antitumor efficacy of MUC-CD-targeted T cells in SCID-Beige mice bearing peritoneal human MUC-CD(+) tumor cell lines.


RESULTS
CAR-modified, MUC-CD-targeted T cells exhibited efficient MUC-CD-specific cytolytic activity against both human ovarian cell and primary ovarian carcinoma cells in vitro. Furthermore, expanded MUC-CD-targeted T cells infused through either i.p. injection or i.v. infusion into SCID-Beige mice bearing orthotopic human MUC-CD(+) ovarian carcinoma tumors either delayed progression or fully eradicated disease.


CONCLUSIONS
These promising preclinical studies justify further investigation of MUC-CD-targeted T cells as a potential therapeutic approach for patients with high-risk MUC16(+) ovarian carcinomas.
Chekmasova
Alena A
AA
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Rao
Thapi D
TD
Nikhamin
Yan
Y
Park
Kay J
KJ
Levine
Douglas A
DA
Spriggs
David R
DR
Brentjens
Renier J
RJ
D000818:Animals; D018394:CA-125 Antigen / Q000235:genetics / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins