Page 1875 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 108 Graft-Versus-Host Disease and Graft-Versus-Leukemia Responses 1667

It is characterized by an acute (days, depending on the inducing Blazar BR, Murphy WJ, Abedi M: Advances in graft-versus-host disease
agent) and intense inflammatory response wherein the majority of biology and therapy. Nat Rev Immunol 12(6):443, 2012.
the infused CAR T cells along with other immune cells such as NK Choi SW, Braun T, Chang L, et al: Vorinostat plus tacrolimus and mycophe-
cells, monocyte-macrophages, and dendritic cells become activated nolate to prevent graft-versus-host disease after related-donor reduced-
and release inflammatory cytokines. 449,450 Much remains to be intensity conditioning allogeneic haemopoietic stem-cell transplantation:
understood about the biology of CRS following CAR T-cell therapy. a phase 1/2 trial. Lancet Oncol 15(1):87, 2014.
However, it appears that the incidence and severity of the syndrome Den Haan JM, Sherman NE, Blokland E, et al: Identification of a graft
is greater in patients with large tumor burdens, presumably because versus host disease-associated human minor histocompatibility antigen.
414
of higher levels of T-cell expansion and activation. However, as Science 268:1476, 1995.
yet, no clear relationship between the cell infusion dose and the Dickinson AM, Middleton PG, Rocha V, et al: Genetic polymorphisms
incidence/severity of CRS has been observed. It is associated with a predicting the outcome of bone marrow transplants. Br J Haematol
massive proinflammatory cytokine storm with elevated IFN-γ, IL-6, 127:479, 2004.
+
+
TNF-α, IL-2, granulocyte-macrophage colony-stimulating factor Edinger M, Hoffmann P, Ermann J, et al: CD4 CD25 regulatory T
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and IL-5. Amongst these cytokines, it appears that in many cells preserve graft-versus-tumor activity while inhibiting graft-versus-
instances IL-6 may be the most critical cytokine and its effects are host disease after bone marrow transplantation. Nat Med 9:1144,
likely from trans-signaling. The source of IL-6 and mechanisms 2003.
remain unknown. The biology behind the incidence of neurotoxici- Glucksberg H, Storb R, Fefer A, et al: Clinical manifestations of graft-versus-
ties remains unclear. It is also unknown whether CRS is required host disease in human recipients of marrow from HL-A-matched sibling
for eventual clinical response and/or if mitigating it blunts response donors. Transplantation 18:295, 1974.
rates. Furthermore, whether CRS is reduced when selected T cells Goulmy E, Schipper R, Pool J, et al: Mismatches of minor histocompatibility
(central memory subset) are engineered with CARs instead of using antigens between HLA-identical donors and recipients and the develop-
bulk T cells remains an open question. The relationship of CRS ment of graft-versus-host disease after bone marrow transplantation. N
with the type of vectors or other methodologic aspects also remains Engl J Med 334:281, 1996.
unknown. Henden AS, Hill GR: Cytokines in Graft-versus-Host Disease. J Immunol
Several other critical mechanisms for enhancing the efficacy of 194:4604, 2015.
CAR T cells or for mitigating their toxicities remain to be understood. Kolb H, Mittermuller J, Clemm C, et al: Donor leukocyte transfusions
The data on whether other targets (instead of CD19) can be as for treatment of recurrent chronic myelogenous leukemia in marrow
effective remain to be explored. The role of costimulatory domains transplant patients. Blood 76:2462, 1990.
in promoting efficacy, toxicity or exhaustion remains largely unknown. Korngold R, Sprent J: Negative selection of T cells causing lethal graft-versus-
Recent experimental observations suggest that CARs against non- host disease across minor histocompatibility barriers. Role of the H-2
CD19 targets may be more susceptible to exhaustion and in these complex. J Exp Med 151:1114, 1980.
cells CD28 costimulation augments, whereas 4-1BB costimulation Levine JE, Braun TM, Harris AC, et al: A prognostic score for acute graft-
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reduces, exhaustion induced by persistent CAR signaling. Thus versus-host disease based on biomarkers: a multicentre study. Lancet
much remains to be understood with regards to the immunobiology Haematol 2:e21–e29, 2015.
of CRS, and CAR T-cell therapy. Lindemans CA, Calafiore M, Mertelsmann AM, et al: Interleukin-22
promotes intestinal-stem-cell-mediated epithelial regeneration. Nature
528(7583):560–564, 2015.
FUTURE DIRECTIONS Lowsky R, Takahashi T, Liu YP, et al: Protective conditioning for acute graft-
versus-host disease. N Engl J Med 353:1321, 2005.
Complications of HCT, particularly GVHD, remain major barriers Martin PJ, Weisdorf D, Przepiorka D, et al: National Institutes of Health
to the wider application of allogeneic HCT for a variety of diseases. Consensus Development Project on Criteria for Clinical Trials in Chronic
Recent advances in the biology of genetic polymorphisms, the che- Graft-versus-Host Disease: VI. Design of Clinical Trials Working Group
mocytokine networks, several novel cellular subsets including regula- report. Biol Blood Marrow Transplant 12:491, 2006.
tory T cells, and the direct mediators of cellular cytotoxicity have led Mathewson ND, Jenq R, Mathew AV, et al: Gut microbiome-derived
to improved understanding of this complex disease process. Animal metabolites modulate intestinal epithelial cell damage and mitigate graft-
studies show that modulation of several mediators of the complex versus-host disease. Nat Immunol 17(5):505–513, 2016.
GVHD cascade may be able to reduce the undesirable inflammatory Petersdorf EW, Hansen JA, Martin PJ, et al: Major-histocompatibility-
aspects of GVHD while preserving the benefits of GVL. However, complex class I alleles and antigens in hematopoietic-cell transplantation.
most of the laboratory observations remain to be studied in well- N Engl J Med 345:1794, 2001.
controlled clinical trials. Multiple cellular effectors may be involved Ratanatharathorn V, Nash RA, Przepiorka D, et al: Phase III study compar-
in GVL, although donor T-cell recognition of host antigens is an ing methotrexate and tacrolimus (prograf, FK506) with methotrexate
important element of this process. Cellular immunotherapy such as and cyclosporine for graft-versus-host disease prophylaxis after
DLI offers a strategy for separating GVHD and the GVL effect. Both HLA-identical sibling bone marrow transplantation. Blood 92:2303,
experimental and clinical data suggest that posttransplantation cel- 1998.
lular immunotherapy can be performed relatively safely and effectively, Reddy P, Maeda Y, Liu C, et al: A crucial role for antigen-presenting cells
and optimization of patient selection, cell dose, and timing of admin- and alloantigen expression in graft-versus-leukemia responses. Nat Med
istration may all serve to limit toxicity and enhance the potential 11:1244, 2005.
GVL effects. Shlomchik WD, Couzens MS, Tang CB, et al: Prevention of graft versus host
disease by inactivation of host antigen-presenting cells. Science 285:412,
1999.
SUGGESTED READINGS Shulman HM, Sharma P, Amos D, et al: A coded histologic study of hepatic
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leukin or pentostatin plus corticosteroids for acute graft vs. host disease: Storb R, Deeg HJ, Whitehead J, et al: Methotrexate and cyclosporine
a randomized phase II trial from the BMT CTN. Blood 114:511, 2009. compared with cyclosporine alone for prophylaxis of acute graft versus
Anasetti C, Beatty PG, Storb R, et al: Effect of HLA incompatibility on graft- host disease after marrow transplantation for leukemia. N Engl J Med
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patients with leukemia or lymphoma. Hum Immunol 29:79, 1990. van Bekkum DW, Roodenburg J, Heidt PJ, et al: Mitigation of secondary
Billingham RE: The biology of graft-versus-host reactions. Harvey Lect 62:21, disease of allogeneic mouse radiation chimeras by modification of the
1966-67. intestinal microflora. J Natl Cancer Inst 52:401, 1974.