Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy.

Abstract

Advances in the design of chimeric antigen receptors (CARs) have improved the antitumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. We proposed that CAR expression in Vα24-invariant natural killer T (NKT) cells can build on the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKT cells were engineered to express a CAR against the GD2 ganglioside (CAR.GD2), which is highly expressed by neuroblastoma (NB). We compared CAR.GD2 constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB costimulatory endodomains. CAR.GD2 expression rendered NKT cells highly cytotoxic against NB cells without affecting their CD1d-dependent reactivity. We observed a striking T helper 1-like polarization of NKT cells by 4-1BB-containing CARs. Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKT cells. These CAR.GD2 NKT cells effectively localized to the tumor site had potent antitumor activity, and repeat injections significantly improved the long-term survival of mice with metastatic NB. Unlike T cells, CAR.GD2 NKT cells did not induce graft-versus-host disease. These results establish the potential of NKT cells to serve as a safe and effective platform for CAR-directed cancer immunotherapy.

• Authors: Andras Heczey, Daofeng Liu, Gengwen Tian, Amy N Courtney, Jie Wei, Ekaterina Marinova, Xiuhua Gao, Linjie Guo, Eric Yvon, John Hicks, Hao Liu, Gianpietro Dotti, Leonid S Metelitsa
• Journal: Blood (Blood) Vol. 124 Issue 18 Pg. 2824-33 (Oct 30 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25049283 (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: © 2014 by The American Society of Hematology.

Chemical References

• 4-1BB Ligand
• Antigens, CD1d
• CD28 Antigens
• Cancer Vaccines
• Cytokines
• Gangliosides
• Receptors, Antigen
• ganglioside, GD2

Topics

• 4-1BB Ligand (chemistry, metabolism)
• Animals
• Antigens, CD1d (metabolism)
• CD28 Antigens (metabolism)
• Cancer Vaccines (immunology)
• Cell Line
• Cell Proliferation
• Cytokines (metabolism)
• Cytotoxicity, Immunologic
• Gangliosides
• Graft vs Host Disease (immunology)
• Humans
• Immunotherapy
• Lymphocyte Activation (immunology)
• Macrophages (metabolism)
• Mice
• Natural Killer T-Cells (immunology)
• Neoplasm Metastasis
• Neuroblastoma (immunology, pathology, therapy)
• Protein Structure, Tertiary
• Receptors, Antigen (immunology)
• Retroviridae (genetics)
• Transduction, Genetic
• Treatment Outcome