Enhanced Tumor Trafficking of GD2 Chimeric Antigen Receptor T Cells by Expression of the Chemokine Receptor CCR2b
- 1 October 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Immunotherapy
- Vol. 33 (8), 780-788
- https://doi.org/10.1097/cji.0b013e3181ee6675
Abstract
For adoptive T-cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced coexpression of the chemokine receptor CCR2b, as this receptor directs migration toward CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from 6 patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared with CCR2-negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater antitumor activity in vivo.Keywords
This publication has 39 references indexed in Scilit:
- Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigenBlood, 2009
- T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor modelBlood, 2009
- Vα24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophagesJCI Insight, 2009
- Monocyte Chemoattractant Protein-1 (MCP-1): An OverviewJournal of Interferon & Cytokine Research, 2009
- Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastomaNature Medicine, 2008
- Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cellsPublished by American Society of Hematology ,2008
- Orchestrating the orchestrators: chemokines in control of T cell trafficNature Immunology, 2008
- Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastomaJCI Insight, 2007
- T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cellsBlood, 2006
- A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian CancerClinical Cancer Research, 2006