scholarly journals Tumor-specific donor lymphocyte infusion therapy with allogeneic T cells utilizing novel retrovirus vector silencing endogenous TCR expression

2014 ◽  
Vol 2 (S3) ◽  
Author(s):  
Hiroaki Ikeda ◽  
Hiroaki Ueno ◽  
Ayumi Kawamura ◽  
Naoko Imai ◽  
Sachiko Okamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Donor Lymphocyte Infusion ◽  
Infusion Therapy ◽  
Retrovirus Vector

Tumor-Specific TCR-Engineered Donor Lymphocyte Infusion Therapy with Reduced GvHD Induction Utilizing Novel Retrovirus Vector Silencing Endogenous TCR Expression

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 656-656
Author(s):  
Hiroaki Ikeda ◽  
Hiroaki Ueno ◽  
Isao Tawara ◽  
Ayumi Kawamura ◽  
Naoko Imai ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Human Tumor ◽  
Donor Lymphocyte Infusion ◽  
Infusion Therapy ◽  
Advisory Committees ◽  
High Affinity ◽  
Retrovirus Vector ◽  
Engineered T Cells

Abstract Background The patients with relapsed hematological malignancy after allogeneic hematopoetic stem cell transplantation (HSCT) can be treated by donor lymphocyte infusion (DLI). However, the efficacy is often limited in association with the development of Graft-versus-Host Disease (GVHD) as a serious adverse event. By the use of the novel retrovirus vector that specifically silences endogenous T cell receptor (TCR) in gene-engineered T cells, here we demonstrate the development of DLI with lymphocytes engineered to express tumor-specific TCR that exhibit increased tumor-specificity in combination with decreased GVHD-inducing potential (Summarized in the figure). Methods Human PBMC were transduced with a high affinity TCR specific to a cancer/testis antigen, NY-ESO-1, by the retrovirus vector with siRNA specific to the endogenous TCR (siTCR vector). Resulting TCR gene-transduced T cells were examined for the expression of their endogenous TCR by flow cytometry and for their reactivity to allogeneic LCL by 3H uptake proliferation assay. Immunodeficient NOG mice were innoculated with a NY-ESO-1 expressing human tumor cell line NW-MEL-38, received TCR gene-transduced T cells, and monitored for the tumor growth and the development of GVHD. Results Human lymphocytes that were genetically engineered to express a high affinity NY-ESO-1-specific TCR with siTCR vector showed significantly reduced expression of endogenous TCR associated with dramatically diminished reactivity to allogeneic LCL. When adoptively transferred into NOG mice, control non-engineered T cells failed to control the growth of human tumor cells despite the fact that the lymphocytes were allogeneic to the tumor cells and developed lethal GVHD including severe bone-marrow destruction. The development of GVHD was dependent on both the CD4+ and CD8+ T cells suggesting that the simple purification of CD8+ T cells was not a sufficient enough strategy to prevent GVHD. In contrast, adoptive transfer of NY-ESO-1-specific TCR gene-transduced T cells induced complete tumor regression without the development of GVHD. Conclusions The results here suggest that the allogeneic T cells transduced with a tumor-specific TCR by siTCR vector showed increased tumor-reactivity with diminished GVHD potential. These T cells will be applicable to the donor lymphocytes infusion therapy after allogeneic stem cell transplantation for the treatment of hematological malignacy. Currently we plan a clinical trial of DLI with siTCR technology for the patients with relapsed NY-ESO-1 positive adult T cell leukemia/lymphoma after HSCT. Figure 1 Figure 1. Disclosures Ikeda: Takara Bio Inc.: Research Funding. Kawamura:Takara Bio Inc.: Employment. Imai:Takara Bio Inc.: Research Funding. Okamoto:CDM Center, Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Membership on an entity's Board of Directors or advisory committees. Takesako:Takara Bio Inc.: Membership on an entity's Board of Directors or advisory committees. Shiku:Takara Bio Inc.: Research Funding.

Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4089-4096 ◽  
Author(s):  
Cornelis A. M. van Bergen ◽  
Michel G. D. Kester ◽  
Inge Jedema ◽  
Mirjam H. M. Heemskerk ◽  
Simone A. P. van Luxemburg-Heijs ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Cell Types ◽  
Donor Lymphocyte Infusion ◽  
Cellular Immunotherapy ◽  
Cell Reactivity ◽  
Cellular Activation ◽  
Minor Histocompatibility Antigens ◽  
Suitable Target ◽  
T Cell Reactivity

Abstract Minor histocompatibility antigens (mHags) play an important role in both graft-versus-tumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infusion. A frequently occurring single nucleotide polymorphism in the human ATP-dependent interferon-responsive (ADIR) gene was found to encode the epitope we designated LB-ADIR-1F. Although gene expression could be found in cells from hematopoietic as well as nonhematopoietic tissues, the patient suffered from only mild acute GVHD despite high percentages of circulating LB-ADIR-1F–specific T cells. Differential recognition of nonhematopoietic cell types and resting hematopoietic cells as compared with activated B cells, T cells, and tumor cells was demonstrated, illustrating variable LB-ADIR-1F expression depending on the cellular activation state. In conclusion, the novel mHag LB-ADIR-1F may be a suitable target for cellular immunotherapy when applied under controlled circumstances.

Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3408-3414 ◽  
Author(s):  
Kevin J. Young ◽  
Liming Yang ◽  
M. James Phillips ◽  
Li Zhang
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nonhuman Primates ◽  
Cell Receptor ◽  
Donor Lymphocyte Infusion ◽  
Transplantation Tolerance ◽  
Double Negative ◽  
Skin Grafts ◽  
Skin Allografts ◽  
Specific Tolerance

Abstract Donor-lymphocyte infusion (DLI) before transplantation can lead to specific tolerance to allografts in mice, nonhuman primates, and humans. We and others have demonstrated a role for regulatory T cells in DLI-induced, donor-specific transplantation tolerance, but it is not known how regulatory T cells are activated and where they execute their function. In this study, we observed, in both transgenic and normal mice, that DLI before transplantation is required for activation of αβ-T-cell-receptor–positive, CD3+CD4−CD8− double-negative (DN) regulatory T cells in the periphery of recipient mice. More interestingly, DLI induced DN regulatory T cells to migrate preferentially to donor-specific allogeneic skin grafts and to form a majority of graft-infiltrating T cells in accepted skin allografts. Furthermore, both recipient-derived peripheral and graft-infiltrating DN T cells were able to suppress and kill antidonor CD8+ T cells in an antigen-specific manner. These data indicate that DLI may induce donor-specific transplantation tolerance by activating recipient DN regulatory T cells in the periphery and by promoting migration of regulatory T cells to donor-specific allogeneic skin grafts. Our results also show that DN regulatory T cells can eliminate antidonor T cells both systemically and locally, a finding suggesting that graft-infiltrating T cells can be beneficial to graft survival.

scholarly journals Treg Downregulation Was Associated with Augmentation of T Cell Responses Against Immunogenic Antigens and Clinical Responses in Patients with Hematological Malignancies after Donor Lymphocyte Infusion (DLI)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3423-3423
Author(s):  
Jochen Greiner ◽  
Marlies Götz ◽  
Michael Schmitt ◽  
Hartmut Döhner ◽  
Markus Wiesneth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Research Funding ◽  
T Cell Responses ◽  
Donor Lymphocyte Infusion ◽  
Cytotoxic T Cell ◽  
Epitope Recognition ◽  
Cell Responses ◽  
Before And After

Abstract In order to maintain remission and to prolong overall-survival after allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI), cytotoxic T-cell responses against malignant cells play a pivotal role, however they are not well characterized so far. In this study, we focused on the detection of immune responses in patients before and after DLI. A broader epitope-specific T cell activity is associated with clinical response of patients treated with DLI and a concurrent reduction of regulatory T cell frequency may contribute to clinical response in patients after DLI. For a better characterization of the T cell responses, frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells was assessed using ELISpot and pMHC multimer assays. Furthermore, the frequency of regulatory T cells (Treg) before and after DLI was analyzed. Results were correlated to the clinical course of the patients. Independently of their clinical response, 7/11 patients (63.6%) showed an immunological response through an increase in the number of recognized epitopes over the course of DLI. There was a significant increase (p=0.02) in epitope recognition comparing early screening and maximum response after DLI and a significant increase in the mean augmentation from 1 to 4 of the spotted epitopes in the course of DLI was detected in the cohort of clinical responders (R) compared to non-responders (NR) who did not show any dynamics in epitope recognition with a median of 3 to 4 recognized LAA. The proportion of the CD4+CD25highFoxP3+ Treg within the CD4+CD25high T cell fraction decreased significantly in R from a median of 72.9% to 54.6% when comparing the variation at the time points before and after DLI (p=0.04). In NR there was no significant change in the Treg fraction in the course of DLI. In general, significantly more LAA-derived T cell epitopes (p=0.02) were recognized in R when compared to NR. Moreover, the frequency of Treg in R decreased significantly (p=0.008) while remaining stable in NR. Taken together, an increase of specific CTL responses against several LAA after DLI was detected. This study suggests that decreasing numbers of Treg as well as enhanced LAA diversity in T cell responses contribute to clinical outcome of patients treated with DLI. Disclosures Döhner: AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding.

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