Abstract | PURPOSE: 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.
|
Authors | 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 |
Journal | Clinical 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 |
PMID | 25829402
(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
|