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Detection and Long-Term In Vivo Monitoring of Individual Tumor-Specific T Cell Clones in Patients with Metastatic Melanoma¹

Jaroslav Michalek^2,*,, Ivo Kocak, Vuk Fait, Jan Zaloudik and Roman Hajek^*,

^* Cell Immunotherapy Center, Masaryk University, Brno, Czech Republic; Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; Masaryk Memorial Oncology Institute, Brno, Czech Republic; and Department of Hematooncology, University Hospital, Brno, Czech Republic

We investigated the presence of individual melanoma-specific T cell clones in patients with metastatic melanoma. Ten patients were examined for the presence of melanoma-reactive T cells using dendritic cells loaded with autologous tumor cells. Their specificity was tested using nonradioactive cytotoxicity test. Individual immunodominant T cell clones were identified by the clonotypic assay that combines in vitro cell culture, immunomagnetic sorting of activated IFN-⁺ T cells, TCR locus-anchored RT-PCR, and clonotypic quantitative PCR. All patients had detectable melanoma-reactive T cells in vitro. Expanded melanoma-reactive T cells demonstrated specific cytotoxic effect against autologous tumor cells in vitro. Three patients experienced objective responses, and their clinical responses were closely associated with the in vivo expansion and long-term persistence of individual CD8⁺ T cell clones with frequencies of 10^–6 to 10^–3 of all circulating CD8⁺ T cells. Five patients with progressive disease experienced no or temporary presence of circulating melanoma-reactive T cell clones. Thus, circulating immunodominant CD8⁺ T cell clones closely correlate with clinical outcome in patients with metastatic melanoma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Grant Agency of the Czech Republic (no. 301/04/1387).

² Address correspondence and reprint requests to Dr. Jaroslav Michalek, Cell Immunotherapy Center, Masaryk University, Kamenice 5, Brno 61300, Czech Republic. E-mail address: jmichalek{at}fnbrno.cz

³ Abbreviations used in this paper: DC, dendritic cell; MM, metastatic melanoma; GVHD, graft-vs-host disease; GVL, graft-vs-leukemia; qPCR, quantitative PCR.

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