Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions

Matthias Piesche, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Vincent T. Ho, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Haesook Kim, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
Yukoh Nakazaki, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Michael Nehil, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Nasser K. Yaghi, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Dmitriy Kolodin, Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
Jeremy Weiser, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Peter Altevogt, Translational Immunology, German Cancer Research Center, Heidelberg, Germany.
Helena Kiefel, Translational Immunology, German Cancer Research Center, Heidelberg, Germany.
Edwin P. Alyea, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Joseph H. Antin, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Corey Cutler, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
John Koreth, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Christine Canning, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Jerome Ritz, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Robert J. Soiffer, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Glenn Dranoff, Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. glenn_dranoff@dfci.harvard.edu.

Document Type

Article

Abstract

PURPOSE: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed patients with advanced myelodysplasia (MDS) and acute myelogenous leukemia (AML) who received an autologous, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were used to characterize sera obtained longitudinally from 15 patients with AML/MDS who were vaccinated early after allogeneic HSCT. RESULTS: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. CONCLUSIONS: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with natural killer cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias.

Medical Subject Headings

Angiogenesis Inducing Agents (immunology); Antibodies (immunology); Cancer Vaccines (immunology); Cytokines (immunology); Gene Library; Graft vs Leukemia Effect (immunology); Granulocyte-Macrophage Colony-Stimulating Factor (immunology, metabolism); Hematopoietic Stem Cell Transplantation (adverse effects); Humans; Leukemia (genetics, immunology, therapy); Longitudinal Studies; Patient Outcome Assessment; Reproducibility of Results; Time Factors; Transplantation, Homologous (mortality)

Publication Date

3-1-2015

Publication Title

Clinical cancer research : an official journal of the American Association for Cancer Research

E-ISSN

1557-3265

Volume

21

Issue

5

First Page

1010

Last Page

8

PubMed ID

25538258

Digital Object Identifier (DOI)

10.1158/1078-0432.CCR-14-1956

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