Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 1125–1136

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy

  • Katayoun Rezvani
  • Agnes S. M. Yong
  • Stephan Mielke
  • Bipin N. Savani
  • Behnam Jafarpour
  • Rhoda Eniafe
  • Robert Quan Le
  • Laura Musse
  • Carole Boss
  • Richard Childs
  • A. John Barrett
Original article

DOI: 10.1007/s00262-011-1187-z

Cite this article as:
Rezvani, K., Yong, A.S.M., Mielke, S. et al. Cancer Immunol Immunother (2012) 61: 1125. doi:10.1007/s00262-011-1187-z

Abstract

PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30–120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.

Keywords

PR1WT1VaccineLymphopenia-driven homeostasisLeukemiaImmunotherapy

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Katayoun Rezvani
    • 1
    • 2
  • Agnes S. M. Yong
    • 1
  • Stephan Mielke
    • 1
    • 3
  • Bipin N. Savani
    • 1
    • 4
  • Behnam Jafarpour
    • 1
  • Rhoda Eniafe
    • 1
  • Robert Quan Le
    • 1
  • Laura Musse
    • 1
  • Carole Boss
    • 1
  • Richard Childs
    • 1
  • A. John Barrett
    • 1
  1. 1.Hematology Branch, National Heart, Lung and Blood InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Department of HematologyImperial CollegeLondonUK
  3. 3.Wuerzburg UniversityWuerzburgGermany
  4. 4.Vanderbilt University Medical CenterNashvilleUSA