Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma.

Publication Type:

Journal Article

Source:

PloS one, Volume 4, Issue 3, p.e4749 (2009)

Keywords:

2009, Adult, Aged, Antineoplastic Agents, Biologics Production Core Facility, CD8-Positive T-Lymphocytes, Cell Processing Core Facility, Center-Authored Paper, Clinical Research Division, Cytokine Analysis Core Facility, Cytokines, DNA (Cytosine-5-)-Methyltransferase, Drug Resistance, Neoplasm, Flow Cytometry Core Facility, Forkhead Transcription Factors, Humans, Immune Monitoring Core Facility, Immunotherapy, Adoptive, MELANOMA, Middle Aged, Neoplasm Recurrence, Local, Shared Resources, Skin Neoplasms, Treatment Outcome, Vidarabine

Abstract:

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.