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Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia.

Nishida, Tetsuya and Hudecek, Michael and Kostic, Ana and Bleakley, Marie and Warren, Edus H and Maloney, David and Storb, Rainer and Riddell, Stanley R (2009) Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research, 15 (14). pp. 4759-4768. ISSN 1078-0432

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Abstract

PURPOSE: Allogeneic nonmyeloablative hematopoietic stem cell transplant (NM-HSCT) can result in durable remission of chronic lymphocytic leukemia (CLL). It is thought that the efficacy of NM-HSCT is mediated by recognition of tumor cells by T cells in the donor stem cell graft. We evaluated the development of CTLs specific for CLL after NM-HSCT to determine if their presence correlated with antitumor efficacy. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells obtained from 12 transplant recipients at intervals after NM-HSCT were stimulated in vitro with CLL cells. Polyclonal T-cell lines and CD8(+) T-cell clones were derived from these cultures and evaluated for lysis of donor and recipient target cells including CLL. The presence and specificity of responses was correlated with clinical outcomes. RESULTS: Eight of the 12 patients achieved remission or a major antitumor response and all 8 developed CD8(+) and CD4(+) T cells specific for antigens expressed by CLL. A clonal analysis of the CD8(+) T-cell response identified T cells specific for multiple minor histocompatibility (H) antigens expressed on CLL in six of the responding patients. A significant fraction of the CD8(+) T-cell response in some patients was also directed against nonshared tumor-specific antigens. By contrast, CLL-reactive T cells were not detected in the four patients who had persistent CLL after NM-HSCT, despite the development of graft-versus-host disease. CONCLUSIONS: The development of a diverse T-cell response specific for minor H and tumor-associated antigens expressed by CLL predicts an effective graft-versus-leukemia response after NM-HSCT.

Item Type: Article
DOI: 10.1158/1078-0432.CCR-09-0199
PubMed ID: 19567591
NIHMSID: NIHMS146416
PMCID: PMC2785487
Keywords or MeSH Headings: * Animals * Antigens, CD40/immunology * CD4-Positive T-Lymphocytes/cytology * CD4-Positive T-Lymphocytes/immunology * CD8-Positive T-Lymphocytes/cytology * CD8-Positive T-Lymphocytes/immunology * Clone Cells/cytology * Clone Cells/immunology * Cytotoxicity, Immunologic/immunology * Female * Flow Cytometry * Graft vs Host Disease/immunology * Hematopoietic Stem Cell Transplantation/methods* * Hematopoietic Stem Cells/cytology * Hematopoietic Stem Cells/drug effects * Hematopoietic Stem Cells/immunology * Humans * Leukemia, Lymphocytic, Chronic, B-Cell/blood * Leukemia, Lymphocytic, Chronic, B-Cell/immunology* * Leukemia, Lymphocytic, Chronic, B-Cell/surgery* * Leukocytes, Mononuclear/cytology * Leukocytes, Mononuclear/immunology * Male * Mice * Middle Aged * Minor Histocompatibility Antigens/immunology * Myeloablative Agonists/pharmacology * NIH 3T3 Cells * T-Lymphocytes/cytology * T-Lymphocytes/immunology* * Transplantation, Homologous * Treatment Outcome * Vidarabine/analogs & derivatives * Vidarabine/pharmacology
Subjects: Diseases > Hematologic and lymphatic diseases > Leukemia
Therapeutics > Transplantation > Stem Cell transplantation
Cellular and Organismal Processes > Immune Response
Depositing User: Library Staff
Date Deposited: 30 Sep 2009 20:54
Last Modified: 14 Feb 2012 14:43
URI: http://authors.fhcrc.org/id/eprint/334

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