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A Novel System for Simultaneous in Vivo Tracking and Biological Assessment of Leukemia Cells and ex Vivo Generated Leukemia-Reactive Cytotoxic T Cells

¹ University of Minnesota Cancer Center and Department of Pediatrics, Division of Pediatric Hematology/Oncology and Blood and Marrow Transplant, Minneapolis, Minnesota; Departments of ² Dermatology and ³ Medicine, University of Minnesota, Minneapolis, Minnesota; ⁴ Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania; and ⁵ University of North Carolina, Chapel Hill, North Carolina

To determine the mechanisms by which adoptive immunotherapy could reduce lethality to acute myelogenous leukemia (AML), a novel technique was developed to track both leukemic blasts and adoptively transferred cytotoxic T cells (CTLs) independently and simultaneously in mice. To follow the fate of ex vivo generated anti-AML-reactive CTLs, splenocytes obtained from enhanced green fluorescent protein transgenic mice were cocultured with AML lysate-pulsed dendritic cells, which subsequently were expanded by exposure to anti-CD3/CD28 monoclonal antibody-coated magnetic microspheres. To track AML cells, stable transfectants of C1498 expressing DsRed2, a red fluorescent protein, were generated. Three factors related to CTLs correlated with disease-free survival: (a) CTL L-selectin expression. L-Selectin high fractions resulted in 70% disease-free survival, whereas L-selectin low-expressing CTLs resulted in only 30% disease-free survival. (b) Duration of ex vivo expansion (9 versus 16 days). Short-term expanded CTLs could be found at high frequency in lymphoid organs for longer than 4 weeks after transfer, whereas long-term expanded CTLs were cleared from the system after 2 weeks. Duration of expansion correlated inversely with L-selectin expression. (c) CTL dose. A higher dose (40 versus 5 x 10⁶) resulted in superior disease-free survival. This survival advantage was achieved with short-term expanded CTLs only. The site of treatment failure was mainly the central nervous system where no CTLs could be identified at AML sites.

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