Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individual with neuroblastoma

Martin A P. et al. Nat. Med. 14, 1264 - 1270 (2008)

Speaker: Hong-Ming Liao (廖宏明)                              Time: 13:10~14:00, Mar. 18, 2009

Commentator: Dr. Ai-Li Shiau (蕭璦莉老師)         Place: Room 601

Abstract:

 To make a tumor-specific T lymphocyte, a novel strategy is established by introducing a chimeric antigen receptor (CAR) with an antigen-binding domain from an tumor-specific antibody coupled to a signal-transducing endodomain derived from the native T cell receptor into activated T cells (ATCs)¹. However, these engineered CAR-ATCs had only limited antitumor activity and poor survivability, even when IL-2 exists, and this problem is probably due to a lack of the appropriate costimulatory molecules². In this study, the authors introduced GD2-specific CARs recognizing neuroblastoma into EBV-specific cytotoxic T lymphocytes (CTLs) and ATCs. Showed the transduction efficiency for both ATCs and CTLs was above 35% by checking with qPCR and FACS. CAR-CTLs showed uniformly CD45RO⁺CD45RA^-CCR7^-CD62L^- effector memory phenotype, but only 60% of CAR-ATCs had effector memory phenotype. CAR-CTLs express CXCR4 higher than CAR-ATCs did. The expression of cytokine receptors and adhesion molecules in CAR-CTLs are similar to CAR-ATCs. In vitro CAR-CTLs recognized and killed EBV⁺ target cells and GD2⁺neuroblastoma, and CAR-ATCs killed only GD2⁺ neuroblastoma. These cells were infused into patients, and the PCR signals from the vector associated with CAR-CTLs were higher and persisted longer than that from the CAR-ATCs. Using EBV antigen to stimulate CTLs and ATCs from peripheral blood after infusion, GD2-receptor-transgene of CTLs but not ATCs consistently expanded, and accompanied by a corresponding enrichment of CAR expression on the cell surface. Two weeks after infusion, CTLs but not ATCs killed EBV⁺ B cells and GD2⁺ neuroblastoma. After infusion CAR-CTLs and CAR-ATCs, four of eight individuals with evaluable tumors had evidence of tumor necrosis or regressions, including a sustained complete remission. This results show viral specific CTLs expressing nonviral tumor-specific CAR can be modified to function as tumor-directed effector cells.

References:

1.      Sadelain, M. et al. Targeting tumours with genetically enhanced T lymphocytes. Nat. Rev. Cancer 3, 35–45 (2003).

2.      Park, J.R. et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol. Ther. 15, 825 – 833 (2007)