Next-generation leukemia immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 2951-2959 ◽  
Author(s):  
Krystel Vincent ◽  
Denis-Claude Roy ◽  
Claude Perreault
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Convincing Evidence ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cell Immunotherapy ◽  
Rudimentary Form ◽  
Preclinical And Clinical Studies ◽  
T Cell Immunotherapy

Abstract Allogeneic hematopoietic cell transplantation led to the discovery of the allogeneic GVL effect, which remains the most convincing evidence that immune cells can cure cancer in humans. However, despite its great paradigmatic and clinical relevance, induction of GVL by conventional allogeneic hematopoietic cell transplantation remains a quite rudimentary form of leukemia immunotherapy. It is toxic and its efficacy is far from optimal. It is therefore sobering that since the discovery of the GVL effect 3 decades ago, the way GVL is induced and manipulated has practically not changed. Preclinical and clinical studies suggest that injection of T cells primed against a single Ag present on neoplastic cells could enhance the GVL effect without causing any GVHD. We therefore contend that Ag-targeted adoptive T-cell immunotherapy represents the future of leukemia immunotherapy, and we discuss the specific strategies that ought to be evaluated to reach this goal. Differences between these strategies hinge on 2 key elements: the nature of the target Ag and the type of Ag receptor expressed on T cells.

scholarly journals Therapeutic Vaccination of Hematopoietic Cell Transplantation Recipients Improves Protective CD8 T-Cell Immunotherapy of Cytomegalovirus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Kerstin M. Gergely ◽  
Jürgen Podlech ◽  
Sara Becker ◽  
Kirsten Freitag ◽  
Steffi Krauter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Mhc Class I ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Class I ◽  
Therapeutic Vaccination ◽  
Cell Immunotherapy ◽  
T Cell Immunotherapy

Reactivation of latent cytomegalovirus (CMV) endangers the therapeutic success of hematopoietic cell transplantation (HCT) in tumor patients due to cytopathogenic virus spread that leads to organ manifestations of CMV disease, to interstitial pneumonia in particular. In cases of virus variants that are refractory to standard antiviral pharmacotherapy, immunotherapy by adoptive cell transfer (ACT) of virus-specific CD8+ T cells is the last resort to bridge the “protection gap” between hematoablative conditioning for HCT and endogenous reconstitution of antiviral immunity. We have used the well-established mouse model of CD8+ T-cell immunotherapy by ACT in a setting of experimental HCT and murine CMV (mCMV) infection to pursue the concept of improving the efficacy of ACT by therapeutic vaccination (TherVac) post-HCT. TherVac aims at restimulation and expansion of limited numbers of transferred antiviral CD8+ T cells within the recipient. Syngeneic HCT was performed with C57BL/6 mice as donors and recipients. Recipients were infected with recombinant mCMV (mCMV-SIINFEKL) that expresses antigenic peptide SIINFEKL presented to CD8+ T cells by the MHC class-I molecule Kb. ACT was performed with transgenic OT-I CD8+ T cells expressing a T-cell receptor specific for SIINFEKL-Kb. Recombinant human CMV dense bodies (DB-SIINFEKL), engineered to contain SIINFEKL within tegument protein pUL83/pp65, served for vaccination. DBs were chosen as they represent non-infectious, enveloped, and thus fusion-competent subviral particles capable of activating dendritic cells and delivering antigens directly into the cytosol for processing and presentation in the MHC class-I pathway. One set of our experiments documents the power of vaccination with DBs in protecting the immunocompetent host against a challenge infection. A further set of experiments revealed a significant improvement of antiviral control in HCT recipients by combining ACT with TherVac. In both settings, the benefit from vaccination with DBs proved to be strictly epitope-specific. The capacity to protect was lost when DBs included the peptide sequence SIINFEKA lacking immunogenicity and antigenicity due to C-terminal residue point mutation L8A, which prevents efficient proteasomal peptide processing and binding to Kb. Our preclinical research data thus provide an argument for using pre-emptive TherVac to enhance antiviral protection by ACT in HCT recipients with diagnosed CMV reactivation.

scholarly journals Donor-Derived CD4+ T Cells and Human Herpesvirus 6B Detection After Allogeneic Hematopoietic Cell Transplantation

2020 ◽  
Author(s):  
Derek J Hanson ◽  
Hu Xie ◽  
Danielle M Zerr ◽  
Wendy M Leisenring ◽  
Keith R Jerome ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Peripheral Blood Mononuclear

Abstract We sought to determine whether donor-derived human herpesvirus (HHV) 6B–specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell transplantation. We identified 33 patients who received HLA-matched, non–T-cell–depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B–specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B–specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation.

scholarly journals Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

2011 ◽  
Vol 208 (5) ◽  
pp. 1069-1082 ◽  
Author(s):  
Daigo Hashimoto ◽  
Andrew Chow ◽  
Melanie Greter ◽  
Yvonne Saenger ◽  
Wing-Hong Kwan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Expansion ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Host Macrophage

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

Characterization of NK1.1+ CD8 T Cells in Allogeneic Hematopoietic Cell Transplantation Recipients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4616-4616
Author(s):  
Yi Wang ◽  
Hui Wang ◽  
Shumei Wang ◽  
Megan Sykes ◽  
Yong-Guang Yang
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Flow Cytometric Analysis ◽  
Nkt Cells ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Memory Phenotype

Abstract NKT cells from naïve mice are mainly CD4+ or CD4−CD8−. However, it has been reported that CD8+ NKT cells can be expanded in vitro from splenocytes, bone marrow cells and thymocytes of C57BL/6 (B6) mice by stimulation with anti-CD3 mAb and cytokines, and that the expanded CD8+ NKT cells mediate strong graft-vs.-leukemic (GVL) effects without severe GVHD after adoptive transfer into allogeneic mice. We now describe the presence of CD8+NK1.1+ cells in recipient livers (approximately 2–6%), but not in other tissues (spleen, lung, bone marrow, thymus and PBMC), in various allogeneic hematopoietic cell transplantation (allo-HCT) models. The generation of CD8+NK1.1+ cells is likely a consequence of alloresponses, as these cells were not detected in the liver of syngeneic HCT controls. Flow cytometric analysis confirmed that these cells are CD1d-independent, TCRαβ+ T cells with a memory phenotype (CD44+ and CD62L−), and do not express CD49b, Ly-49C/I, Ly-49G2, or Ly-49D. In a sublethally (6 Gy)-irradiated B6-to-B6D2F1 allo-HCT model, NK1.1+ CD8 T cells became detectable by week 2, increased in number until approximately week 8, and gradually declined thereafter but were still detectable in the liver at day 100 after allo-HCT. By using CD45.1 and CD45.2 congeneic donors, we determined that the majority of NK1.1+ CD8 T cells were derived from the donor splenocytes. Furthermore, depletion of CD8+, but not NK1.1+, cells from the donor splenocytes prior to transplantation prevented the generation of NK1.1+ CD8 T cells, indicating that these cells were derived from donor NK1.1−CD8+ splenic T cells. Our data demonstrate that donor CD8 T cells can acquire NK1.1 expression upon activation in allo-HCT recipients, and that these NK1.1+ CD8 T cells maintain a memory phenotype and persist in the recipients with preferential accumulation in the liver. Studies are currently in progress to determine the role of activated donor NK1.1+ CD8 T cells in GVHD and GVL effects.

Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3832-3839 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Li-Hui Tseng ◽  
Haydar Frangoul ◽  
Ted Gooley ◽  
Ji Pei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Apoptosis ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cd4 T Cell ◽  
Spontaneous Apoptosis ◽  
T Cell Apoptosis

Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3+ T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3+ T cells taken from patients 19-23 days after transplantation (30.4% ± 12.5%,P < .05), and 1 year after transplantation (9.7% ± 2.8%, P < .05) compared with healthy controls (4.0% ± 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3+/CD4+ and CD3+/CD8+ T-cell subsets, while CD56+/CD3− natural killer cells were relatively resistant to apoptosis. The extent of CD4+T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33.9% ± 11.3%) compared with grade 0-I GVHD (14.6 ± 6.5%, P < .05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% ± 10.4%,P < .05) or HLA-matched unrelated donors (32.1% ± 11.4%, P < .05) compared with patients who received transplantations from HLA-identical siblings (19.6% ± 6.7%). The intensity of apoptosis among CD4+ T cells was significantly correlated with a lower CD4+ T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT.

scholarly journals Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation

Blood ◽  
2013 ◽  
Vol 122 (18) ◽  
pp. 3116-3121 ◽  
Author(s):  
Dominik Schneidawind ◽  
Antonio Pierini ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Regulatory Function ◽  
Animal Modeling ◽  
Early Results ◽  
Immune Mediated ◽  
Cell Subpopulations

Abstract Alloreactivity of donor lymphocytes leads to graft-versus-host disease (GVHD) contributing to significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Within the past decade, significant progress has been made in elucidating the mechanisms underlying the immunologic dysregulation characteristic of GVHD. The recent discoveries of different cell subpopulations with immune regulatory function has led to a number of studies aimed at understanding their role in allogeneic HCT and possible application for the prevention and treatment of GVHD and a host of other immune-mediated diseases. Preclinical animal modeling has helped define the potential roles of distinct populations of regulatory cells that have progressed to clinical translation with promising early results.

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