Journal
GASTROENTEROLOGY
Volume 143, Issue 5, Pages 1375-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.07.017
Keywords
Immunotherapy; Pancreatic Cancer; Adoptive Cell Therapy; Chimeric Antigen Receptor
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Funding
- Moross Cancer Center
- Israel Science Foundation
- EC HEALTH FP6 ATTACK Consortium
- Moross Cancer Center at The Weizmann Institute of Science
- Friends of Assaf Harofeh Medical Center
- Deutsche Forschungsgemeinschaft, Bonn
- Wilhelm Sander-Stiftung, Munich
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BACKGROUND & AIMS: Pancreatic adenocarcinoma (PAC) is often diagnosed at an advanced and inoperable stage, and standard systemic treatments are generally ineffective. We investigated the effects of adoptive transfer of tumor-specific T cells that express chimeric antibody-based receptors (CAR) to mice with primary and metastatic PAC xenografts. METHODS: Human effector T cells were genetically modified to express CAR against Her2/neu or CD24, a putative PAC stem cell antigen. The antitumor reactivity of the engineered T cells (T-bodies) was evaluated in SCID mice with different PAC xenografts. A total of 1 x 10(7) T-bodies were injected via the tail vein or directly administered to the subcutaneous tumor on 3 or 4 alternating days. Mice were then given twice-daily intraperitoneal injections of interleukin-2 for 10 days. RESULTS: Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. Intravenous injection of T-bodies reduced tumor size and prolonged survival of mice with orthotopically transplanted tumors; more than 50% of animals appeared to be disease-free more than 2 months later. Additional systemic administration of T-bodies 8 weeks after the initial injection eliminated primary tumors, along with liver and draining lymph node metastases. A single administration of the Her2/neuspecific T-bodies prolonged the survival of mice with tumors in which most of the cells expressed the target antigen. In contrast, the CD24-specific T-bodies prolonged survival of mice in which only a subpopulation of the tumor cells expressed the antigen. CONCLUSIONS: CAR-redirected T cells stop growth and metastasis of PAC xenografts in mice. T-bodies specific to CD24, a putative cancer stem cell antigen, were effective against PAC xenografts that had only a subset of antigen-expressing cells.
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