Transferred melanoma-specific CD8 + T cells persist, mediate tumor regression, and acquire central memory phenotype
- 5 March 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (12), 4592-4597
- https://doi.org/10.1073/pnas.1113748109
Abstract
Adoptively transferred tumor-specific T cells offer the potential for non-cross-resistant therapy and long-term immunoprotection. Strategies to enhance in vivo persistence of transferred T cells can lead to improved antitumor efficacy. However, the extrinsic (patient conditioning) and intrinsic (effector cell) factors contributing to long-term in vivo persistence are not well-defined. As a means to enhance persistence of infused T cells in vivo and limit toxicity, 11 patients with refractory, progressive metastatic melanoma received cyclophosphamide alone as conditioning before the infusion of peripheral blood mononuclear cell-derived, antigen-specific, CD8(+) cytotoxic T-lymphocyte (CTL) clones followed by low-dose or high-dose IL-2. No life-threatening toxicities occurred with low-dose IL-2. Five of 10 evaluable patients had stable disease at 8 wk, and 1 of 11 had a complete remission that continued for longer than 3 y. On-target autoimmune events with the early appearance of skin rashes were observed in patients with stable disease or complete remission at 4 wk or longer. In vivo tracking revealed that the conditioning regimen provided a favorable milieu that enabled CTL proliferation early after transfer and localization to nonvascular compartments, such as skin and lymph nodes. CTL clones, on infusion, were characterized by an effector memory phenotype, and CTL that persisted long term acquired phenotypic and/or functional qualities of central memory type CTLs in vivo. The use of a T-cell product composed of a clonal population of antigen-specific CTLs afforded the opportunity to demonstrate phenotypic and/or functional conversion to a central memory type with the potential for sustained clinical benefit.Keywords
This publication has 26 references indexed in Scilit:
- Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer ImmunotherapyClinical Cancer Research, 2011
- Adoptive transfer of virus-specific and tumor-specific T cell immunityCurrent Opinion in Immunology, 2009
- Adoptive cell therapy for the treatment of patients with metastatic melanomaCurrent Opinion in Immunology, 2009
- Fludarabine Modulates Immune Response and Extends In Vivo Survival of Adoptively Transferred CD8 T Cells in Patients with Metastatic MelanomaPLOS ONE, 2009
- Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative RegimensJournal of Clinical Oncology, 2008
- Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysisJCI Insight, 2008
- Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1New England Journal of Medicine, 2008
- IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapyBlood, 2008
- Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primatesJCI Insight, 2008
- Lineage relationship and protective immunity of memory CD8 T cell subsetsNature Immunology, 2003