دورية أكاديمية
Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA-Transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy.
| العنوان: | Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA-Transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy. |
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| المؤلفون: | Hung CF; 1 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.; 2 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore, Maryland., Xu X; 1 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland., Li L; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Ma Y; 1 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland., Jin Q; 1 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland., Viley A; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Allen C; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Natarajan P; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Shivakumar R; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Peshwa MV; 3 MaxCyte, Inc. , Gaithersburg, Maryland., Emens LA; 2 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore, Maryland.; 4 Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy , Baltimore, Maryland. |
| المصدر: | Human gene therapy [Hum Gene Ther] 2018 May; Vol. 29 (5), pp. 614-625. Date of Electronic Publication: 2018 Apr 02. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: M.A. Liebert Country of Publication: United States NLM ID: 9008950 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7422 (Electronic) Linking ISSN: 10430342 NLM ISO Abbreviation: Hum Gene Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York : M.A. Liebert, c1990- |
| مواضيع طبية MeSH: | GPI-Linked Proteins/*immunology , Natural Killer T-Cells/*transplantation , Ovarian Neoplasms/*therapy , Receptors, Antigen, T-Cell/*therapeutic use, Animals ; Cell Line, Tumor ; Female ; GPI-Linked Proteins/antagonists & inhibitors ; GPI-Linked Proteins/therapeutic use ; Humans ; Immunotherapy, Adoptive ; Lymphocytes/immunology ; Mesothelin ; Mice ; Natural Killer T-Cells/immunology ; Ovarian Neoplasms/immunology ; RNA, Messenger/genetics ; RNA, Messenger/therapeutic use ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/therapeutic use ; Xenograft Model Antitumor Assays |
| مستخلص: | CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to "on-target off-tumor" toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK cells may permit prospective control of "on-target off-tumor" toxicity. To develop a commercial product for solid tumors, mesothelin was selected as an antigen target based on its association with poor prognosis and overexpression in multiple solid cancers. It was hypothesized that selecting, activating, and expanding cells ex vivo prior to mRNA CAR transfection would not be necessary, thus simplifying the complexity and cost of manufacturing. Now, the development of anti-human mesothelin mRNA CAR transfected peripheral blood lymphocytes (CARMA-hMeso) is reported, demonstrating the manufacture and cryopreservation of multiple cell aliquots for repeat administrations from a single human leukapheresis. A rapid, automated, closed system for cGMP-compliant transfection of mRNA CAR in up to 20 × 10 9 peripheral blood lymphocytes was developed. Here we show that CARMA-hMeso cells recognize and lyse tumor cells in a mesothelin-specific manner. Expression of CAR was detectable over approximately 7 days in vitro, with a progressive decline of CAR expression that appears to correlate with in vitro cell expansion. In a murine ovarian cancer model, a single intraperitoneal injection of CARMA-hMeso resulted in the dose-dependent inhibition of tumor growth and improved survival of mice. Furthermore, repeat weekly intraperitoneal administrations of the optimal CARMA-hMeso dose further prolonged disease control and survival. No significant off-target toxicities were observed. These data support further investigation of CARMA-hMeso as a potential treatment for ovarian cancer and other mesothelin-expressing cancers. |
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| معلومات مُعتمدة: | P30 CA006973 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: cell therapy; chimeric antigen receptor (CAR); immunotherapy; mesothelin; ovarian cancer |
| المشرفين على المادة: | 0 (CD19-specific chimeric antigen receptor) 0 (GPI-Linked Proteins) 0 (Msln protein, mouse) 0 (RNA, Messenger) 0 (Receptors, Antigen, T-Cell) 0 (Receptors, Chimeric Antigen) J27WDC343N (Mesothelin) |
| تواريخ الأحداث: | Date Created: 20180117 Date Completed: 20190517 Latest Revision: 20230607 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5930796 |
| DOI: | 10.1089/hum.2017.080 |
| PMID: | 29334771 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-7422 |
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| DOI: | 10.1089/hum.2017.080 |