Genetic engineering of T cells to target HERV-K, an ancient retrovirus on melanoma

Janani 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

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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%ofgenetically 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.

Original languageEnglish (US)
Pages (from-to)3241-3251
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Krishnamurthy, J., Rabinovich, B. A., Mi, T., Switzer, K. C., Olivares, S., Maiti, S. N., Plummer, J. B., Singh, H., Kumaresan, P. R., Huls, H. M., Wang-Johanning, F., & Cooper, L. J. N. (2015). Genetic engineering of T cells to target HERV-K, an ancient retrovirus on melanoma. Clinical Cancer Research, 21(14), 3241-3251. https://doi.org/10.1158/1078-0432.CCR-14-3197