Comparison of common gamma-chain cytokines, interleukin-2, interleukin-7, and interleukin-15 for the in vitro generation of human tumor-reactive T lymphocytes for adoptive cell transfer therapy.
The adoptive transfer of human tumor-reactive T lymphocytes into autologous patients can mediate the regression of metastatic melanoma. Here, the in vitro generation of melanoma-reactive T lymphocytes was compared using 3 common gamma-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, alone or in combination. The proliferation, function, and phenotype were evaluated for tumor-reactive T cells derived from peripheral blood mononuclear cells (PBMCs) from patients previously immunized with the melanoma-associated peptide gp100:209-217(210M) and PBMCs transduced with a retrovirus encoding the alpha and beta chains of a gp100-reactive T-cell receptor (TCR). IL-7 alone did not induce significant proliferation of any tumor-reactive T-cell population, whereas IL-2 and IL-15 induced significant proliferation of tumor-reactive T lymphocytes from both sources. Cells cultured in the presence of IL-2 or IL-15 secreted comparable amounts of interferon-gamma and IL-2 in response to melanoma cells in vitro and were phenotypically similar in terms of costimulatory molecules (CD27 and CD28), cytokine receptors (CD25, CD122, and CD127), and a lymphoid homing molecule (CD62L). In addition, the proliferation, function, and phenotype of T cells cultured with combinations of IL-2, IL-7, and IL-15 were similar to those grown with IL-2 alone. The effects of these cytokines on TCR stimulation of CD45RA+ naive cells derived from adult patients and from human umbilical cord blood were also compared. Similar to the data with activated tumor-reactive T lymphocytes, IL-7 alone did not support significant proliferation of naive T cells after TCR stimulation with anti-CD3, although IL-2 and IL-15 induced comparable proliferation of T lymphocytes with similar phenotypic attributes.
Liu
Shujuan
S
Surgery Branch, National Cancer Institute (NCI), Bethesda, Maryland 20892-1502, USA.
Riley
John
J
Rosenberg
Steven
S
Parkhurst
Maria
M
D019264:Adoptive Transfer; D017252:CD3 Complex / Q000096:biosynthesis; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010641:Phenotype; D012190:Retroviridae / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*
D017252:CD3 Complex; D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D017493:Leukocyte Common Antigens