TY - JOUR
T1 - Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide
AU - Aversa, Franco
AU - Bachar-Lustig, Esther
AU - Or-Geva, Noga
AU - Prezioso, Lucia
AU - Bonomini, Sabrina
AU - Manfra, Ilenia
AU - Monti, Alessandro
AU - Schifano, Chiara
AU - Zlotnikov-Klionsky, Yael
AU - Martelli, Massimo F.
AU - Sammarelli, Gabriella
AU - Sassi, Maria
AU - Soli, Maurizio
AU - Giuliodori, Silvia
AU - Benecchi, Magda
AU - Giuliani, Nicola
AU - Lohr, Frank
AU - Pratissoli, Silvia
AU - Reisner, Yair
N1 - Funding Information:
This work was supported in part by Cell Source Ltd. and by a research grant from Roberto and Renata Ruhman. Y.R. holds the Henry Drake Professorial Chair in Transplantation Immunology.
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/11/14
Y1 - 2017/11/14
N2 - 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 highdose 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.
AB - 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 highdose 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.
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U2 - 10.1182/bloodadvances.2017009423
DO - 10.1182/bloodadvances.2017009423
M3 - Article
C2 - 29296864
AN - SCOPUS:85064206290
SN - 2473-9529
VL - 1
SP - 2166
EP - 2175
JO - Blood Advances
JF - Blood Advances
IS - 24
ER -