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The In vivo Expansion Rate of Properly Stimulated Transferred CD8⁺ T Cells Exceeds That of an Aggressively Growing Mouse Tumor

Clinical Research Center, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Zhiya Yu, Clinical Research Center, National Cancer Institute, NIH, Building CRC, Room 3W-5816, Bethesda, MD 20892. Phone: 301-451-6908; Fax: 301-451-6949; E-mail: zhiya_yu{at}nih.gov.

It has been hypothesized that rapidly dividing tumor cells can outpace adoptively transferred antitumor lymphocytes when tumors are large. However, this hypothesis is at odds with clinical observations indicating that bulky tumors can be destroyed by small numbers of adoptively transferred antitumor T cells. We sought to measure the relative growth rates of T cells and tumor cells in a model using transgenic CD8⁺ T cells specific for the gp100_25-33 H-2D^b epitope (called pmel-1) to treat large, well-established s.c. B16 melanoma. We tested the effect of the immunization using an altered peptide ligand vaccine alone or in combination with interleukin-2 (IL-2) by analyzing the kinetics of T-cell expansion using direct enumeration. We found that pmel-1 T cells proliferated explosively during a 5-day period following transfer. Calculations from net changes in population suggest that, at the peak of cell division, pmel-1 T cells divide at a rate of 5.3 hours per cell division, which was much faster than B16 tumor cells during optimal growth (24.9 hours per cell division). These results clearly indicate that the notion of a kinetic "race" between the tumor and the lymphocyte is no contest when adoptively transferred cells are stimulated with immunization and IL-2. When appropriately stimulated, tumor-reactive T-cell expansion can far exceed the growth of even an aggressively growing mouse tumor. (Cancer Res 2006; 66(2): 1132-8)

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