Abstract
Haploidentical hematopoietic cell transplantation (haplo-HCT) offers a curative procedure for patients with malignant and nonmalignant hematological diseases, as well as an expanding number of inherited disorders. Haplo-HCT is likely the best HLA-related unmatched source of hematopoietic cell transplantation (HCT). Over the past decade, haplo-HCT has emerged as an important clinical option in the treatment of neoplastic hematologic diseases, especially for patients who lack a HLA-matched sibling donor (MSD). The risk of graft-versus-host disease (GvHD) and graft rejection associated with such transplants has been markedly reduced by extensive T-cell depletion (TCD) for GvHD prevention and escalated doses of CD34+ progenitors (i.e., megadose) to overcome graft rejection. Haplo-HCT in the context of TCD and nonmyeloablative (NMA) conditioning is associated with minimal risk for GvHD but with risk of higher rates of graft rejection. Thus new approaches to address this challenge are being developed. If successful, non-myeloablative haplo-HCT potentially could offer a highly attractive and safer treatment modality for patients with different hematological diseases or a platform for organ transplantation and cell therapy by addition of CD34+ cell megadose. In this chapter, we describe novel approaches for chimerism induction with CD34+ megadose in settings of TCD and NMA conditioning regimens, based on insights regarding the mechanism by which CD34+ megadose transplants overcome graft rejection.
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References
Kanda Y, Oshima K, Asano-Mori Y, et al. In vivo alemtuzumab enables haploidentical human leukocyte antigen-mismatched hematopoietic stem-cell transplantation without ex vivo graft manipulation. Transplantation. 2005;79(10):1351–7.
Kasamon YL, Bolanos-Meade J, Prince GT, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol. 2015;33(28):3152–61.
Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.
McCurdy SR, Kanakry JA, Showel MM, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125(19):3024–31.
Bachar-Lustig E, Li HW, Gur H, et al. Induction of donor-type chimerism and transplantation tolerance across major histocompatibility barriers in sublethally irradiated mice by Sca-1(+)Lin(−) bone marrow progenitor cells: synergism with non-alloreactive (host x donor)F(1) T cells. Blood. 1999;94(9):3212–21.
Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood. 1983;61(2):341–8.
Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for acute leukaemia with HLA-A and B nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet. 1981;2(8242):327–31.
Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49(1-3):25–43.
Hagin D, Reisner Y. Haploidentical bone marrow transplantation in primary immune deficiency: stem cell selection and manipulation. Hematol Oncol Clin North Am. 2011;25(1):45–62.
Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014;371(5):434–46.
Ash RC, Horowitz MM, Gale RP, et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Transplant. 1991;7(6):443–52.
Mehta J, Singhal S, Gee AP, et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004;33(4):389–96.
Kernan NA, Flomenberg N, Dupont B, et al. Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation. 1987;43(6):842–7.
Reisner Y, Ben-Bassat I, Douer D, et al. Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation. Proc Natl Acad Sci U S A. 1986;83(11):4012.
Bachar-Lustig E, Rachamim N, Li HW, et al. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med. 1995;1(12):1268–73.
Lapidot T, Terenzi A, Singer TS, et al. Enhancement by dimethyl myleran of donor type chimerism in murine recipients of bone marrow allografts. Blood. 1989;73(7):2025–32.
Reisner Y. Engraftment of T-cell-depleted bone marrow in murine models for allogeneic bone marrow transplantation. Cancer Treat Res. 1990;50:9–25.
Uharek L, Gassmann W, Glass B, et al. Influence of cell dose and graft-versus-host reactivity on rejection rates after allogeneic bone marrow transplantation. Blood. 1992;79(6):1612–21.
Bensinger W, Singer J, Appelbaum F, et al. Autologous transplantation with peripheral blood mononuclear cells collected after administration of recombinant granulocyte stimulating factor. Blood. 1993;81(11):3158–63.
Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23(15):3447–54.
Redei I, Langston A, Cherry J, et al. Haploidentical transplantation for adults with poor prognostic hematologic malignancies using the Perugia approach. Leukemia. 2002;16:414.
Zuckerman T, Haddad N, Elhasis R, et al. Haploidentical transplantation: a single center experience. Leukemia. 2002;16:417.
Handgretinger R, Klingebiel T, Lang P, et al. Haploidentical transplantation in children with hematological malignancies and non-malignant disorders. A single center 5-year experience. Leukemia. 2002;16(3):410.
Marks DI, Khattry N, Cummins M, et al. Haploidentical stem cell transplantation for children with acute leukaemia. Br J Haematol. 2006;134(2):196–201.
Gur H, Krauthgamer R, Berrebi A, et al. Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34(+) cells. Blood. 2002;99(11):4174–81.
Rachamim N, Gan J, Segall H, et al. Tolerance induction by “megadose” hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation. 1998;65(10):1386–93.
Miller RG. An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recognizing it. Nature. 1980;287(5782):544–6.
Claesson MH, Miller RG. Functional heterogeneity in allospecific cytotoxic T lymphocyte clones. I. CTL clones express strong anti-self suppressive activity. J Exp Med. 1984;160(6):1702–16.
Lask A, Goichberg P, Cohen A, et al. TCR-Independent killing of B cell malignancies by anti–third-party CTLs: The critical role of MHC–CD8 engagement. J Immunol. 2011;187(4):2006–14.
Gur H, Krauthgamer R, Bachar-Lustig E, et al. Immune regulatory activity of CD34+ progenitor cells: evidence for a deletion-based mechanism mediated by TNF-alpha. Blood. 2005;105(6):2585–93.
Milstein O, Hagin D, Lask A, et al. CTLs respond with activation and granule secretion when serving target for T cell recognition. Blood. 2010;117(3):1042–52.
Reich-Zeliger S, Gan J, Bachar-Lustig E, et al. Tolerance induction by veto CTLs in the TCR transgenic 2C mouse model. II. Deletion of effector cells by Fas-Fas ligand apoptosis. J Immunol. 2004;173(11):6660–6.
Reich-Zeliger S, Eidelstein Y, Hagin D, et al. Deletion of alloreactive T cells by veto cytotoxic T lymphocytes is mediated through extracellular signal-regulated kinase phosphorylation. Transplantation. 2010;90(4):380–6.
Ophir E, Or-Geva N, Gurevich I, 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. Blood. 2013;121(7):1220–8.
Zangi L, Edelshtein Y, Klionsky Y, et al. Tolerance induction by immature dendritic cells is mediated by distinct MHC dependent and independent mechanisms: a novel role for perforin, granzyme A and toll like receptor 7. 51st ASH meeting, New Orleans. Blood. 2009;114:a65.
Zangi L, Klionsky YZ, Yarimi L, et al. Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7. Blood. 2012;120(8):1647–57.
Hiruma K, Nakamura H, Henkart PA, et al. Clonal deletion of postthymic T cells: veto cells kill precursor cytotoxic T lymphocytes. J Exp Med. 1992;175(3):863–8.
Azuma E, Kaplan J. Role of lymphokine-activated killer cells as mediators of veto and natural suppression. J Immunol. 1988;141(8):2601–6.
Asiedu C, Meng Y, Wang W, et al. Immunoregulatory role of CD8alpha in the veto effect. Transplantation. 1999;67(3):372–80.
Chrobak P, Gress RE. Veto activity of activated bone marrow does not require perforin and Fas ligand. Cell Immunol. 2001;208(2):80–7.
Antin JH, Childs R, Filipovich AH, et al. Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2001;7(9):473–85. https://doi.org/10.1053/bbmt.2001.v7.pm11669214.
Ildstad ST, Wren SM, Bluestone JA, et al. Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance. J Exp Med. 1985;162(1):231–44.
Ruedi E, Sykes M, Ildstad ST, et al. Antiviral T cell competence and restriction specificity of mixed allogeneic (P1 + P2----P1) irradiation chimeras. Cell Immunol. 1989;121(1):185–95.
Sachs DH, Kawai T, Sykes M. Induction of tolerance through mixed chimerism. Cold Spring Harb Perspect Med. 2014;4(1):a015529. https://doi.org/10.1101/cshperspect.a015529.
Sykes M. Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med. 2007;262(3):288–310.
Or-Geva N, Reisner Y. Megadose stem cell administration as a route to mixed chimerism. Curr Opin Organ Transplant. 2014;19(4):334–41.
Claesson MH, Miller RG. Functional heterogeneity in allospecific cytotoxic T lymphocyte clones. III. Direct correlation between development of syngeneic cytotoxicity and loss of veto activity; implications for the mechanism of veto action. Scand J Immunol. 1989;29(4):493–7.
Claesson MH, Ropke C. Antiself suppressive (veto) activity of responder cells in mixed lymphocyte cultures. Curr Top Microbiol Immunol. 1986;126:213–23.
Fink PJ, Rammensee HG, Benedetto JD, et al. Studies on the mechanism of suppression of primary cytotoxic responses by cloned cytotoxic T lymphocytes. J Immunol. 1984;133(4):1769–74.
Fink PJ, Shimonkevitz RP, Bevan MJ. Veto cells. Annu Rev Immunol. 1988;6:115–37.
Ophir E, Eidelstein Y, Afik R, et al. Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo-induced central memory CD8 T cells. Blood. 2010;115(10):2095–104.
Slatter MA, Gennery AR. Advances in hematopoietic stem cell transplantation for primary immunodeficiency. Expert Rev Clin Immunol. 2013;9(10):991–9.
Worth AJ, Booth C, Veys P. Stem cell transplantation for primary immune deficiency. Curr Opin Hematol. 2013;20(6):501–8.
Griffith LM, Pavletic SZ, Tyndall A, et al. Feasibility of allogeneic hematopoietic stem cell transplantation for autoimmune disease: position statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute-Sponsored International Workshop, Bethesda, MD, March 12 and 13, 2005. Biol Blood Marrow Transplant. 2005;11(11):862–70.
Karussis D, Petrou P, Vourka-Karussis U, et al. Hematopoietic stem cell transplantation in multiple sclerosis. Expert Rev Neurother. 2013;13(5):567–78.
Wynn R. Stem cell transplantation in inherited metabolic disorders. Hematology Am Soc Hematol Educ Program. 2011;2011:285–91.
Fuchs EJ. Transplantation tolerance: from theory to clinic. Immunol Rev. 2014;258(1):64–79.
Lucarelli G, Isgro A, Sodani P, et al. Hematopoietic stem cell transplantation in thalassemia and sickle cell anemia. Cold Spring Harb Perspect Med. 2012;2(5):a011825.
Anasetti C, Beatty PG, Storb R, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990;29(2):79–91.
Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med. 1990;322(7):417–21.
Storb R, Champlin RE. Bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant. 1991;8(2):69–72.
Storb R, Weiden PL, Graham TC, et al. Hemopoietic grafts between DLA-identical canine littermates following dimethyl myleran. Evidence for resistance to grafts not associated with DLA and abrogated by antithymocyte serum. Transplantation. 1977;24(5):349–57.
Lucarelli G, Clift RA, Galimberti M, et al. Bone marrow transplantation in adult thalassemic patients. Blood. 1999;93(4):1164–7.
Sodani P, Isgrò A, Gaziev J, et al. T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients. Pediatric Rep. 2011;3(Suppl 2):e13.
Sodani P, Isgro A, Gaziev J, et al. Purified T-depleted, CD34+ peripheral blood and bone marrow cell transplantation from haploidentical mother to child with thalassemia. Blood. 2010;115(6):1296–302.
Andreani M, Nesci S, Lucarelli G, et al. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant. 2000;25(4):401–4. https://doi.org/10.1038/sj.bmt.1702151.
Andreani M, Testi M, Battarra M, et al. Split chimerism between nucleated and red blood cells after bone marrow transplantation for haemoglobinopathies. Chimerism. 2011a;2(1):21–2. https://doi.org/10.4161/chim.2.1.15057.
Andreani M, Testi M, Gaziev J, et al. Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica. 2011b;96(1):128–33. https://doi.org/10.3324/haematol.2010.031013.
Walters MC, Patience M, Leisenring W, et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 2001;7(12):665–73.
Hsieh MM, Fitzhugh CD, Tisdale JF. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood. 2011;118(5):1197–207.
Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med. 2009;361(24):2309–17.
Krishnamurti L, Kharbanda S, Biernacki MA, et al. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2008;14(11):1270–8.
Iannone R, Casella JF, Fuchs EJ, et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant. 2003;9(8):519–28.
van Besien K, Bartholomew A, Stock W, et al. Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease. Bone Marrow Transplant. 2000;26(4):445–9.
Bolanos-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120(22):4285–91.
Liu B, Shu S, Kenny TP, et al. Stem cell therapy in autoimmune rheumatic diseases: a comprehensive review. Clin Rev Allergy Immunol. 2014;47(2):244–57.
Openshaw H, Nash RA, McSweeney PA. High-dose immunosuppression and hematopoietic stem cell transplantation in autoimmune disease: clinical review. Biol Blood Marrow Transplant. 2002;8(5):233–48.
Good RA. Progress toward production of immunologic tolerance with no or minimal toxic immunosuppression for prevention of immunodeficiency and autoimmune diseases. World J Surg. 2000;24(7):797–810.
Daikeler T, Hugle T, Farge D, et al. Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant. 2009;44(1):27–33.
Strober S, Spitzer TR, Lowsky R, et al. Translational studies in hematopoietic cell transplantation: treatment of hematologic malignancies as a stepping stone to tolerance induction. Semin Immunol. 2011;23(4):273–81.
Scandling JD, Busque S, Dejbakhsh-Jones S, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008;358(4):362–8.
Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008;358(4):353–61.
Leventhal J, Abecassis M, Miller J, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med. 2012;4(124):124ra28.
Acknowledgments
Y.R. holds the Henry Drake professorial chair in immunology.
Conflicts of Interest Y.R. serves as a consultant and shareholder of Cell Source Ltd which supported part this work.
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Or-Geva, N., Reisner, Y. (2018). Toward Safer CD34+ Megadose T-Cell-Depleted Transplants Following Reduced Intensity and Nonmyeloablative Conditioning Regimens. In: Ciurea, S., Handgretinger, R. (eds) Haploidentical Transplantation. Advances and Controversies in Hematopoietic Transplantation and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-54310-9_2
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