期刊
CLINICAL CANCER RESEARCH
卷 21, 期 14, 页码 3241-3251出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-3197
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资金
- Department of Defense [BCRP W81XWH-11-1-0002, W81XWH-12-1-0223]
- Cancer Center Core Grant [CA16672, RO1 (CA124782), RO1 (CA120956, RO1 (CA141303), R33 (CA116127), P01 (CA148600)]
- Albert J. Ward Foundation
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- CLL Global Research Foundation
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy
- Fund for Leukemia Immunotherapy
- Institute of Personalized Cancer Therapy
- Leukemia and Lymphoma Society SCOR
- Lymphoma Research Foundation
- Miller Foundation
- MDACC Moon Shot
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- Production Assistance for Cellular Therapies (PACT)
- TeamConnor
- William Lawrence and Blanche Hughes Children's Foundation
Purpose: The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma. Experimental Design: Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR(+) T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR(+) T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model. Results: We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K+ AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env(+) tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env-specific CAR(+) T cells, we observed a significant antitumor effect. Conclusions: Adoptive cellular immunotherapy with HERV-K env-specific CAR(+) T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors. (C) 2015 AACR.
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