Transferred WT1-Reactive CD8 + T Cells Can Mediate Antileukemic Activity and Persist in Post-Transplant Patients
- 27 February 2013
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 5 (174), 174ra27
- https://doi.org/10.1126/scitranslmed.3004916
Abstract
Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T cell–mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft-versus-host disease (GVHD). Providing T cells that can selectively target Wilms tumor antigen 1 (WT1), a transcription factor overexpressed in leukemias that contributes to the malignant phenotype, represents an opportunity to promote antileukemic activity without inducing GVHD. HLA-A*0201–restricted WT1-specific donor-derived CD8+ cytotoxic T cell (CTL) clones were administered after HCT to 11 relapsed or high-risk leukemia patients without evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to interleukin-21 (IL-21) to prolong in vivo CTL survival, because IL-21 can limit terminal differentiation of antigen-specific T cells generated in vitro. Transferred cells exhibited direct evidence of antileukemic activity in two patients: a transient response in one patient with advanced progressive disease and the induction of a prolonged remission in a patient with minimal residual disease (MRD). Additionally, three treated patients at high risk for relapse after HCT survive without leukemia relapse, GVHD, or additional antileukemic treatment. CTLs generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long term and maintained or acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8+ T cells. This study supports expanding efforts to immunologically target WT1 and provides insights into the requirements necessary to establish potent persistent T cell responses.Keywords
This publication has 59 references indexed in Scilit:
- Transferred melanoma-specific CD8 + T cells persist, mediate tumor regression, and acquire central memory phenotypeProceedings of the National Academy of Sciences of the United States of America, 2012
- Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapiesClinical and Experimental Immunology, 2012
- An Interleukin-21- Interleukin-10-STAT3 Pathway Is Critical for Functional Maturation of Memory CD8+ T CellsImmunity, 2011
- Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid LeukemiaJournal of Clinical Oncology, 2010
- Adoptive cell therapy for the treatment of patients with metastatic melanomaCurrent Opinion in Immunology, 2009
- Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1The New 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
- Cancer Regression in Patients After Transfer of Genetically Engineered LymphocytesScience, 2006
- Lineage relationship and protective immunity of memory CD8 T cell subsetsNature Immunology, 2003