Universität zu Köln

Maliar, Amit, Servais, Charlotte, Waks, Tova, Chmielewski, Markus, Lavy, Ron, Altevogt, Peter, Abken, Hinrich and Eshhar, Zelig (2012). Redirected T Cells That Target Pancreatic Adenocarcinoma Antigens Eliminate Tumors and Metastases in Mice. Gastroenterology, 143 (5). S. 1375 - 1390. PHILADELPHIA: W B SAUNDERS CO-ELSEVIER INC. ISSN 1528-0012

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Maliar, Amit UNSPECIFIED UNSPECIFIED UNSPECIFIED Servais, Charlotte UNSPECIFIED UNSPECIFIED UNSPECIFIED Waks, Tova UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Lavy, Ron UNSPECIFIED UNSPECIFIED UNSPECIFIED Altevogt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Eshhar, Zelig UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-479858
DOI:	10.1053/j.gastro.2012.07.017
Journal or Publication Title:	Gastroenterology
Volume:	143
Number:	5
Page Range:	S. 1375 - 1390
Date:	2012
Publisher:	W B SAUNDERS CO-ELSEVIER INC
Place of Publication:	PHILADELPHIA
ISSN:	1528-0012
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADOPTIVE IMMUNOTHERAPY; RECEPTOR; EXPRESSION; IMMUNOGLOBULIN; LYMPHOCYTES; AFFINITY; DOMAINS; CD24; OVEREXPRESSION; AMPLIFICATION Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47985