Abstract
Generation of cellular immune responses against acute myelogenous leukemia (AML) blasts is a possible therapeutic approach in leukemia therapy. However, when using native AML blasts as stimulator cells during ex vivo generation of leukemia-reactive T cells, one has to ensure that the T population is not contaminated with proliferating AML blasts. Our results demonstrate that gamma could be used to stop AML blast proliferation for all patients investigated. However, irradiation also caused a dose-dependent reduction in the constitutive AML blast secretion of potentially T cell stimulatory cytokines IL-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha ). At the same time, gamma-irradiation resulted in a dose-dependent decrease in anti-CD3-stimulated proliferative responses of T cell clones in the presence of AML blast accessory cells. When using 50 Gy irradiation, however, AML blast expansion was avoided, and anti-CD3 and PHA-stimulated T cell proliferation was detected in the presence of accessory AML blasts for most AML/T cell combinations investigated. When AML blasts were cultured with GM-CSF + IL-4 to develop a dendritic cell enhanced T cell proliferation in the presence of in vitro precultured AML blasts was observed for most patients even after 50 Gy irradiation. We conclude that when using native AML blasts as accessory cells during in vitro generation of leukemia-reactive T cells, an irradiation of 50 Gy can be used for a majority of AML patients to avoid the risk of leukemia cell expansion during culture and with the maintenance of AML blast accessory cell function. However, when in vitro expanded cells are used in clinical trials, this antiproliferative effect should be documented with appropriate in vitro testing for every patient so that the possibility of decreased sensitivity gamma-irradiation in exceptional patients is excluded.
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