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Photodepletion to Promote Immune Reconstitution Without Graft-Versus-Host Disease After HLA-Haploidentical Transplantation

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Haploidentical Transplantation

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Abstract

Haploidentical hematopoietic cell transplantation (haplo-HCT) offers an immense challenge in terms of immunologic difference between donor and recipient cells. However, this major histocompatibility complex (MHC) disparity also represents a powerful tool for the ex vivo removal of alloreactive cells. Indeed, we found that it promotes donor T-cell activation upon exposure to host T-cells and leads to their selective elimination after exposure to a rhodamine-derived photosensitizer (TH9402) and visible light. In this chapter, we highlight the road to development of selectively depleted good manufacturing practice (GMP)-grade T-lymphocyte products (ATIR™, Kiadis Pharma, NL), from mechanistic determinants to bedside. This strategy enables haplo-HCT without the use of immune suppressors. A phase I clinical trial was able to identify a therapeutic ATIR cell dose associated with a decrease in infectious complications and treatment-related mortality (TRM). Long-term follow-up of these patients shows sustained remission in high-risk patients, suggesting preservation of graft-versus-leukemia activity in ATIR cells. Results from an ongoing phase II clinical trial in 23 acute leukemia patients using a single dose of ATIR at 2 million CD3+ cells/kg are in line with phase I outcomes. ATIR infusion also harbors the potential to promote immune reconstitution in different types of haplo-HCT.

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References

  1. Mielke S, Solomon SR, Barrett AJ. Selective depletion strategies in allogeneic stem cell transplantation. Cytotherapy. 2005;7:109–15.

    Article  CAS  Google Scholar 

  2. Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, Yvon E, Weiss H, Cobbold M, Gaspar HB, Rooney C, Kuehnle I, Ghetie V, Schindler J, Krance R, Heslop HE, Veys P, Vitetta E, Brenner MK. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood. 2006;108(6):1797–808.

    Article  CAS  Google Scholar 

  3. André-Schmutz I, Le Deist F, Hacein-Bey-Abina S, Vitetta E, Schindler J, Chedeville G, Vilmer E, Fischer A, Cavazzana-Calvo M. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet. 2002;360(9327):130–7.

    Article  Google Scholar 

  4. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco E, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Stampino CG, Bruzzi P, Bordignon C. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol. 2009;10(5):489–500.

    Article  Google Scholar 

  5. Datta AR, Barrett AJ, Jiang YZ, Guimarães A, Mavroudis DA, van Rhee F, Gordon AA, Madrigal A, Distinct T. cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions. Bone Marrow Transplant. 1994;14(4):517–24.

    CAS  PubMed  Google Scholar 

  6. Garderet L, Snell V, Przepiorka D, Schenk T, JG L, Marini F, Gluckman E, Andreeff M, Champlin RE. Effective depletion of allo-reactive lymphocytes from peripheral blood mononuclear cell preparations. Transplantation. 1999;67(1):124–30.

    Article  CAS  Google Scholar 

  7. Guimond M, Balassy A, Barrette M, Brochu S, Perreault C, Roy DC. P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells. Blood. 2002;100:375–82.

    Article  CAS  Google Scholar 

  8. Hartwig UF, Nonn M, Khan S, Meyer RG, Huber C, Herr W. Depletion of allo-reactive T cells via CD69: implications on antiviral, antileukemic and immunoregulatory T lymphocytes. Bone Marrow Transplant. 2006;37(3):297–305.

    Article  CAS  Google Scholar 

  9. Michalek J, Collins RH, Durrani HP, Vaclavkova P, Ruff LE, Douek DC, Vitetta ES. Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4+ T cells by virtue of their receptor beta loci sequences. Proc Natl Acad Sci U S A. 2003;100(3):1180–4.

    Article  CAS  Google Scholar 

  10. Samarasinghe S, Mancao C, Pule M, Nawroly N, Karlsson H, Brewin J, Openshaw P, Gaspar HB, Veys P, Amrolia PJ. Functional characterization of allo-reactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allo-depletion strategy. Blood. 2010;115(2):396–407.

    Article  CAS  Google Scholar 

  11. Solomon SR, Mielke S, Savani BN, Montero A, Wisch L, Childs R, Hensel N, Schindler J, Ghetie V, Leitman SF, Mai T, Carter CS, Kurlander R, Read EJ, Vitetta ES, Barrett AJ. Selective depletion of allo-reactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation. Blood. 2005;106(3):1123–9.

    Article  CAS  Google Scholar 

  12. Wehler TC, Nonn M, Brandt B, Britten CM, Gröne M, Todorova M, Link I, Khan SA, Meyer RG, Huber C, Hartwig UF, Herr W. Targeting the activation-induced antigen CD137 can selectively deplete allo-reactive T cells from antileukemic and antitumor donor T-cell lines. Blood. 2007;109(1):365–73.

    Article  CAS  Google Scholar 

  13. Boumédine RS, Roy DC. Elimination of allo-reactive T cells using photodynamic therapy. Cytotherapy. 2005;7(2):134–43.

    Article  Google Scholar 

  14. Chen BJ, Cui X, Liu C, Chao NJ. Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process. Blood. 2002;99:3083–8.

    Article  CAS  Google Scholar 

  15. Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, Nagler A, Di Bartolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V, Acute Leukemia Working Party (ALWP) of European Blood and Marrow Transplant (EBMT) Group. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112(9):3574–81.

    Article  CAS  Google Scholar 

  16. Roy DC, Lachance S, Kiss T, Cohen S, Busque L, Fish D, Sauvageau G, Egeler M, Roy J. Haploidentical stem cell transplantation: high doses of allo-reactive-T cell depleted donor lymphocytes administered post-transplant decrease infections and improve survival without causing severe GVHD. Blood. 2009;114(22):512.

    Google Scholar 

  17. Bastien JP, Roy J, Roy DC. Selective T-cell depletion for haplotype-mismatched allogeneic stem cell transplantation. Semin Oncol. 2012;39(6):674–82.

    Article  CAS  Google Scholar 

  18. Roy DC, Guerin M, Sidi Boumedine R, Lachance S, Cohen S, Sauvageau G, Kiss T, Busque L, Morin J, Guertin MC, Velardi A, Rezvani K, Mielke S, Egeler RM, Barrett AJ, Perreault C, Roy J. Reduction in incidence of severe infections by transplantation of high doses of haploidentical t cells selectively depleted of alloreactive units. Blood. 2011;118(21):3020.

    Google Scholar 

  19. Mielke S, Nunes R, Rezvani K, Fellowes VS, Venne A, Solomon SR, Fan Y, Gostick E, Price DA, Scotto C, Read EJ, Barrett AJ. A clinical-scale selective allo-depletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique. Blood. 2008;111(8):4392–402.

    Article  CAS  Google Scholar 

  20. Mielke S, McIver ZA, Shenoy A, Fellowes V, Khuu H, Stroncek DF, Leitman SF, Childs R, Battiwalla M, Koklanaris E, Haggerty J, Savani BN, Rezvani K, Barrett AJ. Selectively T cell-depleted allografts from HLA-matched sibling donors followed by low-dose posttransplantation immunosuppression to improve transplantation outcome in patients with hematologic malignancies. Biol Blood Marrow Transplant. 2011;17(12):1855–61.

    Article  CAS  Google Scholar 

  21. Roy DC, Lachance S, Roy J, Walker I, Maertens J, Delisle JS, Foley SR, Lewalle P, Olavarria E, Selleslag D, Rüdiger M, Velthuis J, Gerez L, Rovers J, Bönig H, Mielke S. Donor lymphocytes depleted of allo-reactive T-cells (ATIR101) improve event-free survival (GRFS) and overall survival in a T-cell depleted haploidentical HSCT: phase 2 trial in patients with AML and ALL. Blood. 2016;128(22):1226.

    Google Scholar 

  22. Mielke S, Maertens J, Selleslag D, Lewalle P, Walker I, Roy DC, Bos G, Devine S, Milojkovic D, Gerez L, Meewisse K, Reitsma K, Rüdiger M, Rovers J. Effect of graft source on safety and efficacy in patients undergoing hematopoietic stem cell transplantation. 2016;51:S348- S349. Abstract P442.

    Google Scholar 

  23. Krakow EF, Bergeron J, Lachance S, Roy DC, Delisle JS. Harnessing the power of alloreactivity without triggering graft-versus-host disease: how non-engrafting allo-reactive cellular therapy might change the landscape of acute myeloid leukemia treatment. Blood Rev. 2014;28(6):249–61.

    Article  Google Scholar 

  24. Panagiotis T, Or R, Resnick IB, Shapira MY. Immunotherapeutic approaches to improve graft-versus-tumor effect and reduce graft-versus-host disease. Immunotherapy. 2012;4:407–24.

    Article  Google Scholar 

  25. Rezvani K, Yong AS, Mielke S, Savani BN, Jafarpour B, Eniafe R, Le RQ, Musse L, Boss C, Childs R, John Barrett A. 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. Cancer Immunol Immunother. 2012;61(7):1125–36.

    Article  CAS  Google Scholar 

  26. Bastien JP, Krosl G, Therien C, Rashkovan M, Scotto C, Cohen S, Allan DS, Hogge D, Egeler RM, Perreault C, Roy DC. Photodepletion differentially affects CD4+ Tregs versus CD4+ effector T cells from patients with chronic graft-versus-host disease. Blood. 2010;116(23):4859–69.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. CellCAN: Canadian Regenerative Medicine and Cell Therapy Network, Universite de Montreal, Montreal, QC, Canada

    Denis Claude Roy M.D., F.R.C.P.C.

  2. TheCell-FRQS: Quebec Cell, Tissue and Gene Therapy Network, Quebec, QC, Canada

    Denis Claude Roy M.D., F.R.C.P.C.

  3. Centre of Excellence for Cell Therapy, Hopital Maisonneuve-Rosemont, Montreal, QC, Canada

    Denis Claude Roy M.D., F.R.C.P.C.

  4. Karolinska Institute and University Hospital, Stockholm, Sweden

    Stephan Mielke M.D.

Authors
  1. Denis Claude Roy M.D., F.R.C.P.C.
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  2. Stephan Mielke M.D.
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Correspondence to Denis Claude Roy M.D., F.R.C.P.C. .

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Editors and Affiliations

  1. Department of Stem Cell Transplantation, MD Anderson Cancer Center, Houston, Texas, USA

    Stefan O. Ciurea

  2. Department of General Pediatrics and Hematology/Oncology, University Children’s Hospital, Tübingen, Baden-Württemberg, Germany

    Rupert Handgretinger

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Roy, D.C., Mielke, S. (2018). Photodepletion to Promote Immune Reconstitution Without Graft-Versus-Host Disease After HLA-Haploidentical Transplantation. 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_6

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  • DOI: https://doi.org/10.1007/978-3-319-54310-9_6

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-54309-3

  • Online ISBN: 978-3-319-54310-9

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