Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells.
Adoptive immunotherapy with tumour-specific T cells is an emerging technology that may be applicable to a broad range of cancers. However, tumours can avoid T cell-mediated attack through multiple mechanisms including downregulation of major histocompatability complex (MHC). Consequently, engineering T cells to target intact protein antigen directly, thus bypassing the need for MHC presentation, can facilitate T cell targeting of tumour cells. Peripheral blood lymphocytes from nine of nine patients with non-Hodgkin lymphoma (NHL) were successfully gene-modified to express a receptor consisting of a CD19 single chain variable fragment (scFv) fused to the T cell CD3zeta signalling molecule. These T cells were functionally active against the CD19(+) Raji Burkitt's lymphoma cell line. Importantly, engineered T cells from seven of nine NHL patients efficiently lysed autologous lymph node tumour biopsy cells. There was a clear correlation between levels of CD19 expression on the tumour and effective killing by the engineered T cells. For two patients with a low or absent CD19(+) cells within the biopsy, no significant killing was observed. These results demonstrate that patients with CD19(+) NHL would be suitable candidates for this form of therapy in the setting of a phase I clinical trial.
Cheadle
Eleanor J
EJ
Cancer Research UK Department of Medical Oncology, University of Manchester and Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
Gilham
David E
DE
Thistlethwaite
Fiona C
FC
Radford
John A
JA
Hawkins
Robert E
RE
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000032:analysis*; D001706:Biopsy; D017252:CD3 Complex / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion / Q000379:methods*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D018941:Antigens, CD19; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D007371:Interferon-gamma