Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide.

The establishment of safe approaches to attain durable donor-type chimerism and immune tolerance toward donor antigens represents a major challenge in transplantation biology. Haploidentical hematopoietic stem cell transplantation (HSCT) is currently used for cancer therapy either as a T-cell-depleted megadose HSCT following myeloablative conditioning or with T-cell-replete HSCT following nonmyeloablative conditioning (NMAC) and high-dose posttransplant cyclophosphamide (PTCY). The latter approach suffers from a significant rate of chronic graft-versus-host disease (GVHD), despite prolonged immunosuppression. The use of T-depleted grafts, although free of GVHD risk, is not effective after NMAC because of graft rejection. We now demonstrate in mice conditioned with NMAC that combining the power of high-dose PTCY with T-cell-depleted megadose HSCT can overcome this barrier. This approach was evaluated in 2 patients with multiple myeloma and 1 patient with Hodgkin lymphoma. The first myeloma patient now followed for 25 months, exhibited full donor-type chimerism in the myeloid and B-cell lineages and mixed chimerism in the T-cell compartment. The second myeloma patient failed to attain chimerism. Notably, the low toxicity of this protocol enabled a subsequent successful fully myeloablative haploidentical HSCT in this patient. The third patients was conditioned with slightly higher total body irradiation and engrafted promptly. All patients remain in remission without GVHD. Both engrafted patients were able to control cytomegalovirus reactivation. Enzyme-linked immunospot analysis revealed immune tolerance toward donor cells. Our results demonstrate a novel and safer nonmyeloablative haplo-HSCT offering a platform for immune tolerance induction as a prelude to cell therapy and organ transplantation.

[1]  K. Raj,et al.  Haploidentical Stem Cell Transplantation in Adult Haematological Malignancies , 2016, Advances in hematology.

[2]  A. Bacigalupo,et al.  HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide , 2016, Advances in hematology.

[3]  E. Peres,et al.  Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow—Review of Published Literature , 2016, Advances in hematology.

[4]  Y. Reisner,et al.  The evolution of T‐cell depletion in haploidentical stem‐cell transplantation , 2016, British journal of haematology.

[5]  M. Ramanathan,et al.  Review on Haploidentical Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies , 2016, Advances in hematology.

[6]  D. Rizzieri,et al.  Haploidentical Hematopoietic Stem Cell Transplantation: Expanding the Horizon for Hematologic Disorders , 2016, Advances in hematology.

[7]  L. Luznik,et al.  Modern approaches to HLA-haploidentical blood or marrow transplantation. , 2016, Nature Reviews Clinical Oncology.

[8]  Shannon R. McCurdy,et al.  Comparable Outcomes for Hematologic Malignancies after HLA-Haploidentical Transplantation with Posttransplantation Cyclophosphamide and HLA-Matched Transplantation , 2015, Advances in hematology.

[9]  E. Fuchs HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide , 2015, Bone Marrow Transplantation.

[10]  S. Bicciato,et al.  Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. , 2015, Blood.

[11]  A. Santoro,et al.  Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. , 2015, Blood.

[12]  Marianna Zahurak,et al.  Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide , 2013, Science Translational Medicine.

[13]  S. Reich-Zeliger,et al.  Murine anti-third-party central-memory CD8(+) T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells. , 2013, Blood.

[14]  M. Abecassis,et al.  Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation , 2012, Science Translational Medicine.

[15]  E. Engleman,et al.  Induced immune tolerance for kidney transplantation. , 2011, The New England journal of medicine.

[16]  A. Berrebi,et al.  Immune regulatory activity of CD34+ progenitor cells: evidence for a deletion-based mechanism mediated by TNF-alpha. , 2005, Blood.

[17]  James Hope,et al.  Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. , 2003, Transplantation.

[18]  O Ouchterlony,et al.  Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. , 1988, Journal of immunological methods.

[19]  C. Taswell,et al.  Quantitation and Cloning of Cytolytic T Lymphocytes and their Precursors , 1980, Immunological reviews.