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.

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 Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1974 ◽  
Author(s):  
Linde Dekker ◽  
Coco de Koning ◽  
Caroline Lindemans ◽  
Stefan Nierkens
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
T Cell Subset

Allogeneic (allo) hematopoietic cell transplantation (HCT) is the only curative treatment option for patients suffering from chemotherapy-refractory or relapsed hematological malignancies. The occurrence of morbidity and mortality after allo-HCT is still high. This is partly correlated with the immunological recovery of the T cell subsets, of which the dynamics and relations to complications are still poorly understood. Detailed information on T cell subset recovery is crucial to provide tools for better prediction and modulation of adverse events. Here, we review the current knowledge regarding CD4+ and CD8+ T cells, γδ T cells, iNKT cells, Treg cells, MAIT cells and naive and memory T cell reconstitution, as well as their relations to outcome, considering different cell sources and immunosuppressive therapies. We conclude that the T cell subsets reconstitute in different ways and are associated with distinct adverse and beneficial events; however, adequate reconstitution of all the subsets is associated with better overall survival. Although the exact mechanisms involved in the reconstitution of each T cell subset and their associations with allo-HCT outcome need to be further elucidated, the data and suggestions presented here point towards the development of individualized approaches to improve their reconstitution. This includes the modulation of immunotherapeutic interventions based on more detailed immune monitoring, aiming to improve overall survival changes.

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.

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 Method of Mobilization: Implication on Cell Subsets in the Graft and Immune Reconstitution Post Autologous Hematopoietic Cell Transplantation (AHCT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1132-1132
Author(s):  
Melhem M. Solh ◽  
Rathmann Kristin ◽  
Sauvi chang-Fong ◽  
Jeremiah Oyer ◽  
Wesam B. Ahmed ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
P Value ◽  
Autologous Hematopoietic Cell Transplantation ◽  
Graft Composition

Abstract Method of Mobilization: Implication on Cell Subsets in The Graft and Immune Reconstitution post Autologous Hematopoietic Cell Transplantation (AHCT) The optimal mobilization method for either myeloma or lymphoma patients undergoing AHCT is still debatable and strategies for graft collection vary between different institutions. Plerixafor, a CXCR4 antagonist is used for peripheral blood stem cell mobilization in multiple myeloma and non-Hodgkins lymphoma patients requiring AHCT. The effect of plerixafor on graft composition has scarce data that are based mostly on cryopreserved samples. Moreover; the effect of plerixafor on immune reconstitution and hematologic recovery post AHCT has not been well evaluated. The goal of our study was to compare graft composition, hematologic and immune reconstitution recovery among patients mobilized with plerixafor plus G-CSF to those mobilized with G-CSF alone. Methods: 49 patients eligible for AHCT were enrolled on a single arm prospective trial at a single transplant center. All patients were mobilized with G-CSF 10µg/kg/day for 4 consecutive days. A peripheral blood CD34 level of <20/µl on day 4 was used as a cutoff to use plerixafor 0.24mg/kg in addition to G-CSf on 9pm of the fourth day. Peripheral blood collection was started on day 5 and was continued till the target dose is achieved or a minimum CD 34+ cell dose of >2x106 cells/Kg was obtained after 3 collection days. Samples from the freshly collected graft and patients' peripheral blood on days +30 and +60 were analyzed by flow cytometry (BD FACSCanto II) . A single platform assay was used (Beckman-Coulter Stem kit) via a ISHAGE protocol. The antibody cocktail contained the following pre-conjugated monoclonal antibodies: CD56-PE (Miltenyi Biotech, Auburn, CA), CD3-APC, CD16-FITC, (Beckman Coulter, Brea, CA), CD19-PE-CY7 (BD Biosciences, San Jose, CA). Data were acquired using BD FACSCanto II (BD Biosciences) and analyzed with the FACSDiva software (BD Biosciences) to quantify CD3+ T cells, CD3+ CD56+ NK-like T cells, CD56+ CD16+ and CD56+ CD16- NK cells as well as CD19+ B cells. Results: 49 patients with a median age of 58 years (range 21-75) were mobilized with either G-CSF alone (N=16) or plerixafor +G-CSF (G+P)(N=33).The median number of collection days was 1.42 and 1.81 (p=0.2) and the median collected CD34+ dose was 8.28x106/kg and 5.24x106 /kg (p=022) in the G+P and G-CSF alone groups respectively. Both groups had similar times to neutrophil and platelet engraftment. The graft analysis showed a white blood count of 309x109/l and 262x109/l (p=0.38), median percentage of CD34+ cells of 0.75% and 0.73% (p=0.81), percentage of CD3+ T cells of 25.6% and 22% (p=0.6) in the G+P and G-CSF alone groups resepectively. Both groups had similar proportions of CD3+, CD4+,CD8+, NK, NKT and iNKT cells in the mobilized grafts. Peripheral blood samples at day +30 and day +60 were analyzed for T cell markers and hematologic recovery (table 1). There was no significant difference between absolute lymphocyte counts, NK cell counts, T cells and absolute neutrophil count. Conclusion: Plerixafor when combined with G-CSF helps in achieving mobilization goals in patients predicted to be poor mobilizers based on peripheral CD34 levels. The addition of plerixafor doesn't not seem to affect T cell composition of the graft and yields similar hematologic and immune recovery when compared to mobilization with G-CSF alone. Table 1: Immune Reconstitution at Day 30 and Day 60 post Autologous Transplantation Treatment Group G-CSF (N=16) Plerixafor + G-CSF (N=33) P-value G-CSF (N=16) Plerixafor + G-CSF (N=33) P-value Day 30 Day 60 WBC 5.08 5.41 0.873 4.94 5.38 0.654 HGB 10.86 11.19 0.353 11.22 11.17 0.757 HCT 32.35 33.66 0.321 33.36 33.53 0.565 PLT 119.88 161.42 0.068 166.94 173.73 0.949 Abs Lymph 1.09 1.44 0.296 1.41 1.50 0.974 % NK 26.14 30.38 0.277 11.53 20.09 0.095 Abs NK 0.31 0.35 0.186 0.17 0.21 0.470 % T cell 67 60 0.183 76.15 67.39 0.340 Abs T cell 0.72 0.96 0.717 1.35 .82 0.095 NKT%* 5.28 3.33 8.25 3.38 B cell % 2.38 1.52 0.922 2.63 5.58 0.424 Abs. Neut count 2.99 2.64 0.488 2.85 3.01 0.848 Disclosures No relevant conflicts of interest to declare.

scholarly journals Expression of CD30 in patients with acute graft-versus-host disease

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 691-696 ◽  
Author(s):  
Yi-Bin Chen ◽  
Sean McDonough ◽  
Robert Hasserjian ◽  
Heidi Chen ◽  
Erin Coughlin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Plasma Levels ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
Activated T Cells ◽  
Potential Biomarker ◽  
Soluble Cd30

Abstract Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8+ T cells with the difference especially pronounced in the central memory subset (CD8+CD45RO+CD62L+): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4+ T cells, and regulatory (CD4+CD127lowCD25+) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30+ infiltrating lymphocytes present. These results suggest that CD30 expression on CD8+ T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.

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