Haploidentical Allogeneic Peripheral Blood Transplantation: Examining Checkpoint Immune Regulators' Expression

Summary

The standard Johns Hopkins' regimen will be used in study subjects, with the use of donor peripheral blood stem cells, rather than marrow. Clinical outcomes will be defined while focusing efforts on immune reconstitution focusing on immune checkpoint regulators after a related haploidentical stem cell transplant.

Timeline

Start

2018-03-28

Primary completion

2025-02-14

Completion

2025-10-17

Publications

• Background Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, Morris LE, Solomon SR. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013 Apr 1;31(10):1310-6. doi: 10.1200/JCO.2012.44.3523. Epub 2013 Feb 19.
• Background Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012 Dec;18(12):1859-66. doi: 10.1016/j.bbmt.2012.06.019. Epub 2012 Aug 1.
• Background Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, Armand P, Antin JH, Chen J, Devine SM, Fowler DH, Luznik L, Nakamura R, O'Donnell PV, Perales MA, Pingali SR, Porter DL, Riches MR, Ringden OT, Rocha V, Vij R, Weisdorf DJ, Champlin RE, Horowitz MM, Fuchs EJ, Eapen M. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015 Aug 20;126(8):1033-40. doi: 10.1182/blood-2015-04-639831. Epub 2015 Jun 30.
• Background Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.
• Background Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM, Maris MB, Storb R. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003 Jul 15;102(2):756-62. doi: 10.1182/blood-2002-08-2628. Epub 2003 Mar 27.
• Background Giralt S, Logan B, Rizzo D, Zhang MJ, Ballen K, Emmanouilides C, Nath R, Parker P, Porter D, Sandmaier B, Waller EK, Barker J, Pavletic S, Weisdorf D. Reduced-intensity conditioning for unrelated donor progenitor cell transplantation: long-term follow-up of the first 285 reported to the national marrow donor program. Biol Blood Marrow Transplant. 2007 Jul;13(7):844-52. doi: 10.1016/j.bbmt.2007.03.011. Epub 2007 May 24.
• Background Kekre N, Antin JH. Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist. Blood. 2014 Jul 17;124(3):334-43. doi: 10.1182/blood-2014-02-514760. Epub 2014 Jun 9.
• Background Bayraktar UD, Champlin RE, Ciurea SO. Progress in haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2012 Mar;18(3):372-80. doi: 10.1016/j.bbmt.2011.08.001. Epub 2011 Aug 9.
• Background Parmesar K, Raj K. Haploidentical Stem Cell Transplantation in Adult Haematological Malignancies. Adv Hematol. 2016;2016:3905907. doi: 10.1155/2016/3905907. Epub 2016 May 30.
• Background Luznik L, Engstrom LW, Iannone R, Fuchs EJ. Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation. Biol Blood Marrow Transplant. 2002;8(3):131-8. doi: 10.1053/bbmt.2002.v8.pm11939602.
• Background Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, Bosque D, Chen J, Rondon G, Alatrash G, Alousi A, Bashir Q, Korbling M, Qazilbash M, Parmar S, Shpall E, Nieto Y, Hosing C, Kebriaei P, Khouri I, Popat U, de Lima M, Champlin RE. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44. doi: 10.1016/j.bbmt.2012.07.003. Epub 2012 Jul 11.
• Background Chang YJ, Zhao XY, Huang XJ. Immune reconstitution after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014 Apr;20(4):440-9. doi: 10.1016/j.bbmt.2013.11.028. Epub 2013 Dec 4.
• Background Habicht A, Kewalaramani R, Vu MD, Demirci G, Blazar BR, Sayegh MH, Li XC. Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+) and CD8(+) T cells in vivo. Am J Transplant. 2007 Dec;7(12):2683-92. doi: 10.1111/j.1600-6143.2007.01999.x. Epub 2007 Oct 9.
• Background Schilbach K, Schick J, Wehrmann M, Wollny G, Simon P, Schlegel PG, Eyrich M. PD-1-PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating t cells during murine gvhd across minor histocompatibility antigen barriers. Transplantation. 2007 Jul 27;84(2):214-22. doi: 10.1097/01.tp.0000268074.77929.54.
• Background Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Sharpe AH, Vallera DA. Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J Immunol. 1999 Jun 1;162(11):6368-77.
• Background Wallace PM, Johnson JS, MacMaster JF, Kennedy KA, Gladstone P, Linsley PS. CTLA4Ig treatment ameliorates the lethality of murine graft-versus-host disease across major histocompatibility complex barriers. Transplantation. 1994 Sep 15;58(5):602-10. doi: 10.1097/00007890-199409150-00013.
• Background Al-Chaqmaqchi H, Sadeghi B, Abedi-Valugerdi M, Al-Hashmi S, Fares M, Kuiper R, Lundahl J, Hassan M, Moshfegh A. The role of programmed cell death ligand-1 (PD-L1/CD274) in the development of graft versus host disease. PLoS One. 2013 Apr 4;8(4):e60367. doi: 10.1371/journal.pone.0060367. Print 2013.
• Background Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, Noelle RJ, Wang L. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res. 2014 Apr 1;74(7):1933-44. doi: 10.1158/0008-5472.CAN-13-1506.
• Background Lines JL, Sempere LF, Broughton T, Wang L, Noelle R. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res. 2014 Jun;2(6):510-7. doi: 10.1158/2326-6066.CIR-14-0072.
• Background Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, Miller HE, Guleria I, Barth RJ, Huang YH, Wang L. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A. 2015 May 26;112(21):6682-7. doi: 10.1073/pnas.1420370112. Epub 2015 May 11.
• Background Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R, Taylor PA, Panoskaltsis-Mortari A, Serody JS, Munn DH, Tolar J, Ochoa AC, Blazar BR. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood. 2010 Dec 16;116(25):5738-47. doi: 10.1182/blood-2010-06-287839. Epub 2010 Aug 31.
• Background Messmann JJ, Reisser T, Leithauser F, Lutz MB, Debatin KM, Strauss G. In vitro-generated MDSCs prevent murine GVHD by inducing type 2 T cells without disabling antitumor cytotoxicity. Blood. 2015 Aug 27;126(9):1138-48. doi: 10.1182/blood-2015-01-624163. Epub 2015 Jul 16.
• Background Rieber N, Wecker I, Neri D, Fuchs K, Schafer I, Brand A, Pfeiffer M, Lang P, Bethge W, Amon O, Handgretinger R, Hartl D. Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD. Bone Marrow Transplant. 2014 Apr;49(4):545-52. doi: 10.1038/bmt.2013.236. Epub 2014 Jan 27.

Drugs

Indications