T Cells That Target Carcinoembryonic Antigen Eradicate Orthotopic Pancreatic Carcinomas Without Inducing Autoimmune Colitis in Mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 143; no. 4; pp. 1095 - 1107.e2
• Main Authors: Chmielewski, Markus, Hahn, Olga, Rappl, Gunter, Nowak, Michael, Schmidt–Wolf, Ingo H, Hombach, Andreas A, Abken, Hinrich
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2012
• Subjects: Adoptive Cell Therapy; Animals; Autoimmune Diseases - etiology; Carcinoembryonic Antigen - immunology; Carcinoembryonic Antigen - metabolism; Carcinoma - metabolism; Carcinoma - therapy; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; CEA; Chimeric Antigen Receptor; Colitis - immunology; Fibrosarcoma - metabolism; Fibrosarcoma - therapy; Gastroenterology and Hepatology; Immune Cell Therapy; Immunotherapy, Adoptive - adverse effects; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - therapy; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - transplantation; click beetle luciferase; TCR; carcinoembryonic antigen; IL; transforming growth factor−β; myeloperoxidase; MPO; mAb; Adoptive Cell Therapy; T-cell receptor; GLuc; Immune Cell Therapy; tg; CBLuc; CAR; Chimeric Antigen Receptor; Gaussia luciferase; TGF-β; transgenic; interleukin; monoclonal antibody; CEA
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2012.06.037

Background & Aims New treatment approaches are needed for patients with pancreatic adenocarcinoma. Carcinoembryonic antigen (CEA) is highly expressed on the surface of pancreatic adenocarcinoma cells; we investigated the effects of cytolytic T cells that recognize CEA in a mouse model of pancreatic carcinoma. Methods Immune-competent mice that expressed the CEA transgene (CEAtg) in the intestinal and pulmonary tracts were given intrapancreatic injections of Panc02 CEA+ cells (express CEA and click beetle luciferase) and tumors were grown for 10 days. Mice were then given single intravenous injections of T cells engineered to express a chimeric antigen receptor (CAR) with high specificity, but moderate affinity, for CEA and a luminescence marker. Results Injection of the anti-CEA CAR T cells reduced the size of pancreatic tumors to below the limit of detection in all mice and produced long-term tumor eradication in 67% of mice. T cells also eradicated CEA+ fibrosarcoma cells injected 45 days later. Bioluminescence imaging revealed the accumulation and persistence of the T cells at the tumor site. The efficacy of the T cells did not require lymphodepletion and was not reduced by soluble CEA. Mice developed some noninflammatory infiltrations of CAR+ T cells in intestine and lung, but there was no evidence of destruction of CEA+ healthy tissues. Conclusions Injection of T cells that target CEA can eradicate tumors grown from CEA+ pancreatic carcinoma cells in the pancreas of CEAtg mice without autoimmune effects.