Ex vivo expansion of tumor specific lymphocytes with IL-15 and IL-21 for adoptive immunotherapy in melanoma.
Although T central memory cells have been described as the most effective T-cell subtype against tumor growth, little is known about the requirements needed for their optimal ex vivo generation. Hence, our goal is to establish a protocol that will lead to consistent ex vivo generation of lymphocytes skewed toward a central memory phenotype. Antigen-specific T-cell lines were generated by ex vivo stimulation with Class-I and Class-II melanoma peptide pulsed dendritic cells in the presence of either IL-2 or IL-15 plus IL-21. Tumor specific lymphocytes of both central memory and effector characteristics were consistently generated from healthy donors and melanoma patients. IL15/IL21 cultures result in a cell population with a lower proportion of CD4(+)CD25(high)FoxP3(+) regulatory cells and higher number of CD8(+) and CD56(+) cells, and consequently render a higher yield of cells with a greater cytolytic activity and IFN-gamma production against melanoma cell lines.
Huarte
Eduardo
E
Department of Medicine, Lebanon, NH 03756, USA.
Fisher
Jan
J
Turk
Mary Jo
MJ
Mellinger
Diane
D
Foster
Cathy
C
Wolf
Benita
B
Meehan
Kenneth R
KR
Fadul
Camilo E
CE
Ernstoff
Marc S
MS
D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019002:CD56 Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005240:Feasibility Studies; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007378:Interleukins / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation; D000098546:Interleukin-21
D000951:Antigens, Neoplasm; D019002:CD56 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D007371:Interferon-gamma; D000098546:Interleukin-21