CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma

To investigate whether CEACAM7 represents a novel therapeutic target for treating pancreatic ductal adenocarcinoma (PDAC) and to generate CEACAM7-targeting CAR T cells to test this hypothesis. We identified CEACAM7 (CGM2), a member of the CEA family of proteins with expression restricted to the colo...

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Bibliographic Details
Published in:Clinical cancer research 2021-03, Vol.27 (5), p.1538-1552
Main Authors: Raj, Deepak, Nikolaidi, Maria, Garces, Irene, Lorizio, Daniela, Castro, Natalia M, Caiafa, Sabrina G, Moore, Kate, Brown, Nicholas F, Kocher, Hemant M, Duan, Xiaobo, Nelson, Brad H, Lemoine, Nicholas R, Marshall, John F
Format: Article
Language:English
Subjects:
Animals
Antigens, Neoplasm - immunology
Apoptosis
Carcinoembryonic Antigen
Carcinoma, Pancreatic Ductal - immunology
Carcinoma, Pancreatic Ductal - pathology
Carcinoma, Pancreatic Ductal - therapy
Cell Proliferation
GPI-Linked Proteins - antagonists & inhibitors
Humans
Immunotherapy, Adoptive - methods
Mice
Pancreatic Neoplasms
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - therapy
Prognosis
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:To investigate whether CEACAM7 represents a novel therapeutic target for treating pancreatic ductal adenocarcinoma (PDAC) and to generate CEACAM7-targeting CAR T cells to test this hypothesis. We identified CEACAM7 (CGM2), a member of the CEA family of proteins with expression restricted to the colon and pancreas, as a potential CAR T-cell target for PDAC. We probed a panel of PDAC tumor sections as well as patient-derived PDAC cell cultures for CEACAM7 expression. We generated CAR-targeting CEACAM7, and assessed antitumor efficacy of CEACAM7 CAR T cells using and models. We show here that CEACAM7 is expressed in a large subset of PDAC tumors, with low to undetectable expression in all normal tissues tested. CEACAM7 is also expressed in primary PDAC cultures isolated from patient-derived tumors, with high expression within the cancer stem cell-enriched subset. CAR T cells targeting CEACAM7 are capable of targeting antigen-expressing tumor cells, and mediate remission in patient-derived xenograft tumors. We identify CEACAM7 as a potential therapeutic target in PDAC and describe the development of CEACAM7-targeted CAR T cells with efficacy against PDAC.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-19-2163