CAR T Cells Targeting MISIIR for the Treatment of Ovarian Cancer and Other Gynecologic Malignancies.
Animals
Cell Line, Tumor
Disease Models, Animal
Epitopes
/ genetics
Female
Genital Neoplasms, Female
/ immunology
Humans
Immunotherapy, Adoptive
Mice
Ovarian Neoplasms
/ immunology
Receptors, Chimeric Antigen
/ immunology
Receptors, Peptide
/ immunology
Receptors, Transforming Growth Factor beta
/ immunology
Single-Chain Antibodies
/ genetics
T-Lymphocytes
/ immunology
Xenograft Model Antitumor Assays
AMHR2
CAR T cell therapy
MISIIR
MISR2
MISRII
chimeric antigen receptor
immunotherapy
mullerian inhibiting substance type 2 receptor
ovarian cancer
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
08
06
2019
revised:
22
11
2019
accepted:
29
11
2019
pubmed:
25
12
2019
medline:
29
12
2020
entrez:
25
12
2019
Statut:
ppublish
Résumé
The prognosis of patients diagnosed with advanced ovarian or endometrial cancer remains poor, and effective therapeutic strategies are limited. The Müllerian inhibiting substance type 2 receptor (MISIIR) is a transforming growth factor β (TGF-β) 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.
Identifiants
pubmed: 31870622
pii: S1525-0016(19)30554-4
doi: 10.1016/j.ymthe.2019.11.028
pmc: PMC7001088
pii:
doi:
Substances chimiques
Epitopes
0
Receptors, Chimeric Antigen
0
Receptors, Peptide
0
Receptors, Transforming Growth Factor beta
0
Single-Chain Antibodies
0
anti-Mullerian hormone receptor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
548-560Informations de copyright
Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
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