Journal
BLOOD
Volume 115, Issue 17, Pages 3508-3519Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-09-241398
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Funding
- National Institutes of Health (NIH) [CA59350]
- MSKCC, NIH MSTP [GM07739]
- Cancer Research Institute
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The gamma(c)-cytokines are critical regulators of immunity and possess both overlapping and distinctive functions. However, comparative studies of their pleiotropic effects on human T cell-mediated tumor rejection are lacking. In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21. We demonstrate that each cytokine enhanced the eradication of systemic CD19(+) B-cell malignancies in non-obese diabetic/severe combined immunodeficient (NOD/SCID)/gamma(c) null mice with markedly different efficacies and through singularly distinct mechanisms. IL-7-and IL-21-transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2-and IL-15-transduced T cells. IL-7 best sustained in vitro T-cell accumulation in response to repeated antigenic stimulation, but did not promote long-term T-cell persistence in vivo. Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice; however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively. These results support the use of gamma(c)-cytokines in cancer immunotherapy, and establish that there exists more than 1 human T-cell memory phenotype associated with long-term tumor immunity. (Blood. 2010; 115(17): 3508-3519)
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