Transplantation of hematopoietic stem cells from an allogeneic donor can be followed by serious graft-versus-host disease (GVHD) despite the best available regimen for immune suppression. Experimental animal data and results of clinical trials have demonstrated that T cells play a central role in GVHD. Recent advances in understanding the mechanisms of peripheral T cell tolerance have made it feasible to test the hypothesis that GVHD can be prevented in man by T cell receptor (TCR) partial agonist ligands through the selective depletion of alloreactive T cells. Transplantation tolerance is facilitated by activation-induced cell death (AICD) of peripheral T cells triggered by the specific alloantigens, and TCR signals are indispensable for induction of antigen-specific tolerance. TCR engagement can induce either T cell proliferation and differentiation or AICD. Monoclonal antibodies (mAb) to CD3, a monomorphic chain associated to the TCR complex, mimic antigen and induce TCR signaling and T cell activation. Fc receptor (FcR)-binding anti-CD3 mAbs recruit antigen-presenting cells (APC) and deliver full agonist signals that promote T cell proliferation and effector functions, independent of antigen. In contrast, non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern causing anergy in naive T cells and AICD in antigen-activated, cycling T cells. In mice, we found that non-FcR-binding anti-CD3 mAbs induce selective depletion of donor T cells that recognize recipient alloantigens thereby preventing GVHD across MHC disparities, and spare T cell specific to third party antigens. In collaboration with J. Tso, we designed a `humanized'non-FcR-binding anti-CD3 mAb, visilizumab, which delivers a partial agonist signal to the TCR. Visilizumab is more effective than other anti-CD3 mAbs in inducing AICD of activated, cycling human T cells. Our preliminary results in human trials show that visilizumab can induce complete clinical responses in some patients with severe acute GVHD, refractory to conventional immune suppressive agents. We propose here to study efficacy of visilizumab in the prevention of GVHD after hematopoietic cell transplantation (HCT) from HLA incompatible donors, and assess whether its immune suppressive effects are selective for alloantigens. We will pursue the following specific aims:
Aim 1 : Determine the safety and efficacy of humanized non-FcR-binding anti-CD3 mAb visilizumab in preventing severe GVHD after transplantation of T-replete hematopoietic cell grafts from HLA-incompatible donors.
Aim 2 : Investigate whether visilizumab therapy depletes the alloreactive T cell pool, while sparing immunity to third party alloantigens, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), and tumor- associated antigen WT1.

Public Health Relevance

The development of effective regimens for the prevention of GVHD will improve patient safety and survival after transplantation, and extend the use of this procedure to a larger number of patients. Progress in the prevention of GVHD has the potential for advancing the fields of organ transplantation and therapy for autoimmune disorders. Anti-CD3 mAbs represent the prototype of a new class of therapeutic agents that suppress the immune system by inducing an abortive activation and T cell death. What makes anti-CD3 mAbs unique and more attractive than other agents is the potential for achieving immunological tolerance rapidly and irreversibly. Showing that non-FcR-binding anti-CD3 mAbs spare T cells specific for viral and tumor-associated antigens is key to predict patient safety.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132197-07
Application #
7679536
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2008-08-25
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
7
Fiscal Year
2009
Total Cost
$374,107
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Perez, L E; Fernandez, H; Ayala, E et al. (2017) Visilizumab with tacrolimus and methotrexate for GvHD prevention after allogeneic hematopoietic cell transplantation from mismatched unrelated donors. Bone Marrow Transplant 52:627-629
Li, Jun; Heinrichs, Jessica; Haarberg, Kelley et al. (2015) HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease. J Immunol 195:717-25
Pidala, Joseph; Kim, Jongphil; Alsina, Melissa et al. (2015) Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease. Haematologica 100:970-7
Betts, Brian C; Sagatys, Elizabeth M; Veerapathran, Anandharaman et al. (2015) CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response. J Leukoc Biol 97:807-19
Betts, Brian C; Veerapathran, Anandharaman; Pidala, Joseph et al. (2014) STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity. J Leukoc Biol 95:205-13
Veerapathran, Anandharaman; Pidala, Joseph; Beato, Francisca et al. (2013) Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease. Blood 122:2251-61
Kumar, A; Mhaskar, A R; Reljic, T et al. (2012) Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review. Leukemia 26:582-8
Pidala, J; Perez, L; Beato, F et al. (2012) Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transplant 47:747-8
Pidala, Joseph; Kim, Jongphil; Jim, Heather et al. (2012) A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 97:1882-9
Pidala, Joseph; Tomblyn, Marcie; Nishihori, Taiga et al. (2011) ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant 17:1237-44

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