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Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma.

AbstractPURPOSE:
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.
AuthorsJanani Krishnamurthy, Brian A Rabinovich, Tiejuan Mi, Kirsten C Switzer, Simon Olivares, Sourindra N Maiti, Joshua B Plummer, Harjeet Singh, Pappanaicken R Kumaresan, Helen M Huls, Feng Wang-Johanning, Laurence J N Cooper
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 14 Pg. 3241-51 (Jul 15 2015) ISSN: 1557-3265 [Electronic] United States
PMID25829402 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright©2015 American Association for Cancer Research.
Chemical References
  • HERV-K cORF protein, Human endogenous retrovirus K
  • Receptors, Antigen, T-Cell
  • Viral Proteins
Topics
  • Animals
  • Genetic Engineering (methods)
  • Genetic Therapy (methods)
  • Humans
  • Immunohistochemistry
  • Immunotherapy, Adoptive (methods)
  • Melanoma (immunology, virology)
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell (genetics)
  • T-Lymphocytes (transplantation)
  • Viral Proteins (immunology)
  • Xenograft Model Antitumor Assays

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