Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.

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.

• Authors: Aude G Chapuis, Gunnar B Ragnarsson, Hieu N Nguyen, Colette N Chaney, Jeffrey S Pufnock, Thomas M Schmitt, Natalie Duerkopp, Ilana M Roberts, Galina L Pogosov, William Y Ho, Sebastian Ochsenreither, Matthias Wölfl, Merav Bar, Jerald P Radich, Cassian Yee, Philip D Greenberg
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 174 Pg. 174ra27 (Feb 27 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 23447018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Interleukins
• WT1 Proteins
• interleukin-21

Topics

• Adoptive Transfer
• Adult
• Aged
• Antigens, CD (metabolism)
• Bone Marrow (drug effects, pathology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Clone Cells
• Dose-Response Relationship, Immunologic
• Female
• Hematopoietic Stem Cell Transplantation
• Humans
• Immunologic Memory (drug effects)
• Interleukins (pharmacology)
• Leukemia (immunology, therapy)
• Male
• Middle Aged
• Neoplasm, Residual (immunology)
• Phenotype
• T-Lymphocytes, Cytotoxic (drug effects, immunology)
• Transplantation, Homologous
• Treatment Outcome
• Tumor Burden (drug effects, immunology)
• WT1 Proteins (metabolism)