Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma.

Abstract

Chimeric antigen receptor (CAR) therapy has begun to demonstrate success as a novel treatment modality for hematologic malignancies. The success observed thus far has been with T cells permanently engineered to express chimeric receptors. T cells engineered using RNA electroporation represent an alternative with the potential for similar efficacy and greater safety when initially targeting novel antigens. Neuroblastoma is a common pediatric solid tumor with the potential to be targeted using immunotherapy. We performed xenograft studies in NSG mice in which we assessed the efficacy of both permanently modified and transiently modified CAR T cells directed against the neuroblastoma antigen GD2 in both local and disseminated disease models. Disease response was monitored by tumor volume measurement and histologic examination, as well as in vivo bioluminescence. RNA-modified GD2 CAR T cells mediated rapid tumor destruction when delivered locally. A single infusion of lentivirally modified GD2 CAR T cells resulted in long-term control of disseminated disease. Multiple infusions of RNA GD2 CAR T cells slowed the progression of disseminated disease and improved survival, but did not result in long-term disease control. Histologic examination revealed that the transiently modified cells were unable to significantly penetrate the tumor environment when delivered systemically, despite multiple infusions of CAR T cells. Thus, we demonstrate that RNA-modified GD2 CAR T cells can mediate effective antitumor responses in vivo, and permanently modified cells are able to control disseminated neuroblastoma in xenograft mice. Lack of long-term disease control by RNA-engineered cells resulted from an inability to penetrate the tumor microenvironment.

• Authors: Nathan Singh, Xiaojun Liu, Jessica Hulitt, Shuguang Jiang, Carl H June, Stephan A Grupp, David M Barrett, Yangbing Zhao
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 11 Pg. 1059-70 (Nov 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 25104548 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Gangliosides
• Receptors, Antigen, T-Cell
• ganglioside, GD2

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Gangliosides (immunology)
• Humans
• Immunohistochemistry
• Immunotherapy (methods)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neuroblastoma (immunology)
• Protein Engineering (methods)
• Receptors, Antigen, T-Cell (genetics)
• T-Lymphocytes, Cytotoxic (immunology)
• Transduction, Genetic
• Xenograft Model Antitumor Assays