Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15.
The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.
Brentjens
Renier J
RJ
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Latouche
Jean-Baptiste
JB
Santos
Elmer
E
Marti
Francesc
F
Gong
Michael C
MC
Lyddane
Clay
C
King
Philip D
PD
Larson
Steven
S
Weiss
Mark
M
Rivière
Isabelle
I
Sadelain
Michel
M
D019264:Adoptive Transfer; D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes; D018122:B7-1 Antigen / Q000276:immunology*; D014408:Biomarkers, Tumor; D001853:Bone Marrow / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology*; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
D018941:Antigens, CD19; D018122:B7-1 Antigen; D014408:Biomarkers, Tumor; D019409:Interleukin-15; D011993:Recombinant Fusion Proteins