fludarabine modulates immune response and extends in vivo survival of adoptively transferred cd8 t cells in patients with metastatic melanoma氟达拉滨调节免疫反应和延长体内生存过继转移cd8 t细胞在转移性黑色素瘤患者.pdfVIP

Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic Melanoma Herschel Wallen*, John A. Thompson, J. Zachary Reilly, Rebecca M. Rodmyre, Jianhong Cao, Cassian Yee Department of Clinical Research, Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America Abstract Background: Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence. Methods/Findings: We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 1010 2 /m ; the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m2/day 65 days). This design permi