Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells
Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02268/full |
| _version_ | 1819027498623565824 |
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| author | John P. Murad John P. Murad Anna K. Kozlowska Anna K. Kozlowska Hee Jun Lee Maya Ramamurthy Wen-Chung Chang Paul Yazaki David Colcher John Shively Mihaela Cristea Stephen J. Forman Stephen J. Forman Saul J. Priceman Saul J. Priceman |
| author_facet | John P. Murad John P. Murad Anna K. Kozlowska Anna K. Kozlowska Hee Jun Lee Maya Ramamurthy Wen-Chung Chang Paul Yazaki David Colcher John Shively Mihaela Cristea Stephen J. Forman Stephen J. Forman Saul J. Priceman Saul J. Priceman |
| author_sort | John P. Murad |
| collection | DOAJ |
| description | Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor-associated glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72-CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease. |
| first_indexed | 2024-12-21T05:43:26Z |
| format | Article |
| id | doaj.art-03ff7a9430ab4c70be8c4bbe6027d5ef |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T05:43:26Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-03ff7a9430ab4c70be8c4bbe6027d5ef2022-12-21T19:14:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02268411924Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T CellsJohn P. Murad0John P. Murad1Anna K. Kozlowska2Anna K. Kozlowska3Hee Jun Lee4Maya Ramamurthy5Wen-Chung Chang6Paul Yazaki7David Colcher8John Shively9Mihaela Cristea10Stephen J. Forman11Stephen J. Forman12Saul J. Priceman13Saul J. Priceman14Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesIrell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesChair of Medical Biotechnology, Poznan University Medical Sciences, Poznań, PolandDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesDepartment of Molecular Imaging & Therapy, Diabetes Metabolism Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Molecular Imaging & Therapy, Diabetes Metabolism Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Molecular Imaging & Therapy, Diabetes Metabolism Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesDepartment of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesDepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, United StatesDepartment of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United StatesImpressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor-associated glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72-CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease.https://www.frontiersin.org/article/10.3389/fimmu.2018.02268/fullchimeric antigen receptorovarian cancerregional intraperitoneal deliveryTAG72tumor-associated glycoproteinsadoptive cellular immunotherapy |
| spellingShingle | John P. Murad John P. Murad Anna K. Kozlowska Anna K. Kozlowska Hee Jun Lee Maya Ramamurthy Wen-Chung Chang Paul Yazaki David Colcher John Shively Mihaela Cristea Stephen J. Forman Stephen J. Forman Saul J. Priceman Saul J. Priceman Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells Frontiers in Immunology chimeric antigen receptor ovarian cancer regional intraperitoneal delivery TAG72 tumor-associated glycoproteins adoptive cellular immunotherapy |
| title | Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells |
| title_full | Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells |
| title_fullStr | Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells |
| title_full_unstemmed | Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells |
| title_short | Effective Targeting of TAG72+ Peritoneal Ovarian Tumors via Regional Delivery of CAR-Engineered T Cells |
| title_sort | effective targeting of tag72 peritoneal ovarian tumors via regional delivery of car engineered t cells |
| topic | chimeric antigen receptor ovarian cancer regional intraperitoneal delivery TAG72 tumor-associated glycoproteins adoptive cellular immunotherapy |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02268/full |
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