Streptamer Technology for the Assessment of CMVpp65 Specific CD8+ T Cell Frequencies and for the Adoptive T Cell Transfer to Post-Transplant Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1964-1964
Author(s):  
Anita Schmitt ◽  
Junxia Yao ◽  
Hermann Einsele ◽  
Ulrich Grigoleit ◽  
Dirk Busch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer ◽  
Cmv Antigenemia

Abstract Cytomegalovirus (CMV) reactivation constitutes a serious complication after allogeneic peripheral blood stem cell transplantation (PBSCT). The frequency of CMVpp65 specific CD8+ T cells is pivotal for the clearance of CMV. CMVpp65 specific CD8+ T cell frequencies can be measured using tetra-, penta- and streptamer technologies, streptamers can also be applied therapeutically. In donors, these frequencies might allow us to define the best available donor in addition to the mere serostatus. In the present study we investigated the specificity and sensitivity of all three methods and compared the results to the serostatus. A therapeutical application, i.e. an adoptive transfer of CMV specific CD8+ T cells selected by streptamer technology to a patient with acute lymphatic leukemia suffering from life-threatening CMV antigenemia after allogeneic PBSCT was performed. 23 samples from CMV seropositive healthy volunteers (HV) and 10 samples from CMV seropositive patients before and after allogeneic stem cell transplantation (all HLA-A2 or -B7 positive) were analyzed with tetra-, penta- or streptamer conjugated to PE by flow cytometry. Our lab took part in an inter-lab CMV multimer assay including 20 European countries in the framework of www.kimt.de. For the adoptive T cell transfer a donor leukapheresis was performed followed by an HLA-B7 CMVpp65 streptamer positive selection. The patient received 2×10E5 CMV specific CD8+ T cells per kg body weight as a single transfusion. Optimal amounts of HLA-A2 multimers to stain a pellet of 10E6 cells were 0.44 mcg tetramer, 0.15 mcg pentamer and 0.2 mcg MHC/0.3 mcg streptactin complex. Surprisingly, only in 48% (11/23) seropositive HV CD8+ multimer+ T cells could be detected. The ALL patient developed a foscarvir resistant CMV antigenemia with a maximum of 959/500,000 CMVpp65 positive cells. After a switch to ganciclovir/valganciclovir and an adoptive transfer of CMV specific T cells, the antigenemia was cleared. Valganciclovir was discontinued, but CMV antigenemia remained controlled. The frequency of CMVpp65 specific CD8+ T cells increased dramatically from 0.0% till 19.8%. All of these T cells were donor derived as demonstrated by small tandem repeat (STR) analysis. The patient did not develop signs of CMV disease at any time point. This study demonstrates the power of multimer staining to define appropriate donors for transplantation. Donors should be screened for their CMVpp65 specific CD8+ T cell frequency. All three multimer technologies can be used yielding similar results. The streptamer technology additionally offers the advantage to select CMVpp65 specific CD8+ T cells at the GMP level for adoptive T cell transfer and can induce long-lasting CD8+ T cell responses effectively clearing even a high virus load.

Adoptive Transfer and Consequential Selective Reconstitution of Streptamer-Selected Cytomegalovirus-Specific CD8+ T Cells Leads to Enduring Virus Clearance in Patients after Allogeneic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1181-1181 ◽  
Author(s):  
Anita Schmitt ◽  
Torsten Tonn ◽  
Dirk Busch ◽  
Götz Grigoleit ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cd8 T Cell ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer ◽  
Cmv Reactivation ◽  
Cmv Antigenemia

Abstract Background: Cytomegalovirus (CMV) disease constitutes a serious complication after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). For the clearance of CMV, CD8+ T cells are pivotal. Patients after allo-PBSCT with recurrent CMV reactivation usually lack such CMV specific T cells. Conventional antiviral therapy of CMV reactivation characteristically results in myelosuppression and further suppression of CMV specific T cells. Adoptive transfer of CMV specific T cells may help to overcome this problem. A novel technology designated “streptamers” allows the selection of CMVpp65 specific CD8+ T cell up to 98% purity without altering the functional properties of the selected T cells and without requiring cumbersome and time consuming T cell cultures. Materials and Methods: Here, the novel streptamer technology was used for adoptive transfer of CMV specific T cells into two acute leukemia patients with recurrent high CMV antigenemia after allo-PBSCT. Standard peripheral blood mononuclear cell apheresis was performed on the former stem cell donors of two patients with acute leukemia. Isolation of CMV specific donor lymphocytes was performed using a Good Manufacturing Product (GMP)-grade Streptamer selection kit on a CliniMacs™ device. Briefly, MHC-Streptamers (CMVpp65/HLA-B7 for patient 1; CMVpp65/HLA-A2 for patient 2) were labeled with beads overnight to obtain MHC-streptamer-bead complexes. Subsequently CMV specific T-lymphocytes were immunomagnetically labeled by incubating mononuclear cells with MHC-Streptamer-bead complexes. Cells were run on a CliniMacs™ device. The positive fraction was then incubated with biotin to detach the steptamers from the T cells. Results: A single specific donor lymphocyte infusion (sDLI) of 0.4 or 2.2 ×105 CMVpp65 specific T cells per kg body weight was performed in an AML or ALL patient respectively, after allogeneic PBSCT developing a CMVpp65 antigenemia with a maximum of 959 or 716 CMVpp65 positive/500,000 cells and treatment with foscarnet, ganciclovir and valganciclovir. After sDLI, the CMV antigenemia was cleared and remained persistently controlled even after discontinuation of valganciclovir therapy in both patients. No acute or chronic toxic side effect, particularly no aggravation of graft-versus-host disease (GvHD) was observed. A strong and sustained increase of the absolute count of CMV-specific CD8+ T cells in concordance with the increase of CD3+CD8+ T cells up to 440/μl was detected. CMV-specific CD8+ T cells showed no significant expression of CCR7, CD62L or CD107, but stained increasingly positive for CD45RA, indicating a preferential effector T cell phenotype. Results from stimulation experiments of CD3+ T cells with HLA-B7 versus HLA-A2 restricted CMVpp65 derived peptides demonstrate late reconstitution of HLA-A2-restricted CMV-specific T cells, whereas the adoptively transferred HLA-B7-restricted CMV-specific T-cell response augmented very early und was maintained over time. The chimerism analysis of the in vivo expanded CMV-specific CD8+ T cells demonstrated a 100% donor chimerism. T cell receptor excision circle (sjTRECs) analysis revealed a frequency of sjTRECs two logs lower than expected, indicating peripheral expansion rather than thymic proliferation of CMV specific CD8+ T cells. cDNA generated from FACS-purified donor-derived CMV B7 pp65-specific CD8+ T cells was probed with the indicated 5′ Vß14-specific and 3′ CDR3-specific primers for the presence of clonotypic T cells. The respective CDR3 region sequence was identical for both donor T cells and CMVpp65 specific T cells in the patients at different time points after the adoptive T cell transfer, thus clearly indicating that the expanded CMV specific T cell were of clonogenic donor origin. Conclusion: Streptamer technology offers the advantage of selecting CMV specific CD8+ T cells at GMP level for adoptive T cell transfer. Two CMVpp65 specific T cell transfers resulted in a marked increase of CMV-specific CD8+ T cells and induced long-lasting CD8+ T cell responses, which allowed the patients to discontinue toxic antiviral drug therapy without further high level reactivation of CMV.

Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 80-80
Author(s):  
Tobias F. Feuchtinger ◽  
Susanne Matthes-Martin ◽  
Celine Richard ◽  
Thomas Lion ◽  
Klaus Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Cell Transfer ◽  
New Treatment ◽  
T Cell Transfer

Abstract Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.

scholarly journals Donor T Cells Maintain Myeloma-Immune Equilibrium after Autologous Stem Cell Transplantation and Concurrent Immunotherapy Promotes Cure

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2031-2031
Author(s):  
Simone A Minnie ◽  
David Smith ◽  
Kate H Gartlan ◽  
Thomas S Watkins ◽  
Kate A Markey ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Median Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Post Transplant

Abstract Autologous stem cell transplantation (ASCT) remains an important consolidation treatment for multiple myeloma (MM) patients, even in the era of novel agents. The prolongation of plateau-phase induced by ASCT is generally attributed to intensive cytoreduction. However, ASCT generates inflammation and profound lymphodepletion, which may result in hitherto unexpected immunological effects. To investigate potential immunological contributions to myeloma control after ASCT, we developed preclinical models of transplantation for MM using Vk*MYC myeloma that generates bony lytic lesions, a serum M band and marrow plasmacytosis that are hallmarks of clinical disease. Myeloma-bearing B6 recipients underwent myeloablative conditioning and were transplanted with naïve B6 bone marrow (BM) grafts with or without T cells from donors that were myeloma-naïve (SCT) or had low M bands at the time of harvest to mimic ASCT. Surprisingly, we demonstrate the broad induction of T cell-dependent myeloma control with enhanced median survival in recipients of grafts containing T cells compared to T cell depleted (TCD) BM alone (SCT= 91 days and ASCT > 100 days post-transplant vs TCD BM alone= 44 days; p<0.0001). Myeloma was most efficiently controlled when recipients were transplanted with memory T cells (CD44+) from autologous grafts (median survival: ASCT-CD44+ T cells >90 days post-transplant vs. CD44─ T cells = 50 days; p = 0.0006). Importantly, T cells adoptively transferred from recipients surviving > 120 days (MM-primed) protected secondary recipients compared to T cells from naïve donors (median survival: MM-primed > 120 days post-transplant vs 65 days naïve T cells; p = 0.0003). Furthermore, MM-primed CD8 T cells were restricted in TCR repertoire and provided protection in a myeloma clone-specific fashion, indicative of a tumor-specific T cell response. Despite this immune-mediated control of myeloma after SCT, progression still occurred in the majority of recipients. We phenotyped CD8+ T cells from the BM of MM-relapsed, MM-controlled and MM-free (that had never seen myeloma) mice 8 weeks after SCT. Expression of the inhibitory receptors, programmed cell death protein 1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) on BM CD8+ T-cells strongly correlated with myeloma cell number (r = 0.729, p<0.0001 and r = 0.796, p<0.0001 respectively). Additionally, the co-stimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated as myeloma progressed (r = - 0.865, p<0.0001), as was interferon-γ secretion (r = - 0.76, p = 0.0022). t-SNE analysis confirmed an irreversible exhaustion signature at myeloma progression, characterized by the absence of DNAM-1 and co-expression of PD-1, TIM-3, TIGIT together with CD101 and CD38. Immune-checkpoint inhibition (CPI) early post-SCT, using antibodies against PD-1 or TIGIT facilitated long-term myeloma control (median survival in both treatment arms > 120 days post-SCT vs. 60 and 68 days respectively; p <0.05). Furthermore, TIGIT blockade limited CD8+ T cell exhaustion, increased CD107a and IFNγ secretion and expanded a memory CD8+ T cell population in the BM. Genetic deletion of either IFNγ or the IFNγ receptor from the donor graft resulted in dramatic myeloma progression after SCT. Consequently, treatment with a CD137 (4-IBB) agonist early after SCT profoundly augmented CD8+IFNγ+GranzymeB+ T-cell expansion in the BM, such that majority of treated animals eliminated myeloma and survived long-term. These data provide insights into an unappreciated mechanism of action of ASCT whereby myeloma immune-equilibrium is established and suggest that combination with immunotherapeutic strategies is a rational approach to generate long term disease control. Disclosures Smyth: Bristol Myers Squibb: Other: Research agreement; Tizona Therapeutics: Research Funding.

Immune Reconstitution Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation: The Impact of Expanding CD28negCD8+ T-Cells on Relapse.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1146-1146
Author(s):  
Ibrahim Yakoub-Agha ◽  
Pasquine Saule ◽  
Julia Salleron ◽  
Pascale Cracco ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Immune Recovery ◽  
Clinical Complication ◽  
The Impact

Abstract Allogeneic stem cell transplantation has become standard therapy for haematological malignancies through the positive immunologic graft-versus-leukaemia effect. Initial immune recovery relies on peripheral expansion of infused T-cells which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes late complications after myeloablative HLA-matched transplantation. Of 80 recipients, 51 experienced neither early infection nor acute graft-versus-host disease (GVHD), of whom 18 were still free of clinical complication throughout 395 – 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic GVHD as the only event recovered similar numbers of circulating T-cells with predominance of CD8+ T-cells lacking CC-chemokine receptor-7 and CD28 expression. Conversely, poor CD8+ T-cell recovery with diminished numbers of CD28neg CD8+ T-cells (~1/4th of that of relapse-free patients) preceded occurrence of relapse. In multivariate analysis, lower CD28neg CD8+ T-cell counts by day 60 were associated with greater risk of subsequent relapse (HR 0.33; 95% CI 0.14 - 0.76; P = 0.01). Enumeration of CD28neg CD8+ T-cells in patients without early clinical complication could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive regimen and considering the introduction of prophylactic donor lymphocyte infusions.

Simultaneous Isolation and Enrichment of Multi Specific and Multi Functional T-Cells Populations for Treatment of Patients Undergoing Allogeneic Hematopoetic Stem Cell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4056-4056
Author(s):  
Meike Kruse ◽  
Halvard Bonig ◽  
Markus Kapp ◽  
Lothar Germeroth ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Transfer ◽  
Hematopoetic Stem Cell ◽  
Healthy Donors ◽  
T Cell Transfer ◽  
Hematopoetic Stem Cell Transplantation

Abstract Abstract 4056 Allogeneic hematopoetic stem cell transplantation (aHSCT) is a treatment option for a variety of diseases in particular heamatological malignancies. Due to an ongoing immunosuppression to prevent graft versus host reaction (GvHD), disease relapses as well as viral infections are major causes of morbidity and mortality after aHSCT. T cell responses against different tumor-associated and tumor-specific antigens could be detected not only in patients with malignant diseases but also in healthy donors. We investigated the selection of MART-1 (Melanoma Antigen Recognized by T-cells), Proteinase 3 and WT-1 (Wilms Tumor- Antigen) specific T cells from the blood of healthy donors as basis for a tumor-specific T cell transfer in the context of aHSCT. With a newly established protocol, based on streptamer selection, we isolated simultaneously multi-functional and multi-specific T-cell populations. We selected tumor-antigen-specific CTL′s (Cytotoxic T- Lymphocytes) mentioned above and also antiviral T-cells namely against CMV, EBV and AdV from a single blood donation. In this simultaneous selection with up to 7 different epitopes in one step, even the tumor specific T cells, which are known to be rarely detected among healthy donors, could be enriched to an amount sufficient for a direct T cell transfer. Purity achieved after selection was at least 82% and up to 98,87%, which minimizes the risk for GvHD after clinical application. The possibility to transfer these selected CTL`s to patients after stem cell transplantation improves the graft versus tumor effect as well as the anti infective T cell immunity without a relevant risk for GvHD. Furthermore, the selected multi specific T cell populations could be expanded in vitro without loss of specificity and include different phenotypes such as central memory and memory effector cells, which may provide long lasting immunity. Moreover, starting with a leukapheresis, we successfully transferred our selection protocol in a closed system according to current good manufacturing practice (cGMP) requirements, which allows clinical application in the future. With that, it opens new perspectives in cellular immunotherapy against malignancies and viral infection for patients after aHSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract A14: Neoepitope-specific CD8+ T cells in adoptive T-cell transfer

2020 ◽  
Author(s):  
Nikolaj Pagh Kristensen ◽  
Christina Heeke ◽  
Siri A. Tvingsholm ◽  
Anne-Mette Bjerregaard ◽  
Arianna Draghi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer

Late diversification in the clonal composition of human cytomegalovirus-specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3427-3438 ◽  
Author(s):  
Maher K. Gandhi ◽  
Mark R. Wills ◽  
Georgina Okecha ◽  
Elizabeth K. Day ◽  
Ray Hicks ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hemopoietic Stem Cell ◽  
Transplant Recipients ◽  
Hemopoietic Stem Cell Transplantation ◽  
Clonal Composition

Abstract To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent diversification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation; this diversification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late diversification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.

Transfer of Specific T Cell Clones with Graft-Versus-Leukemia (GVL) Activity from Donor to Recipient in Stem Cell Transplantation: Identification, Quantification and Characterization.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2958-2958 ◽  
Author(s):  
Katayoun Rezvani ◽  
David A. Price ◽  
Jason Brenchley ◽  
Yasemin Kilical ◽  
Emma Gostick ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Clones ◽  
Memory Phenotype ◽  
Cell Clones ◽  
Healthy Donors

Abstract The self-antigens PR1 and WT1 that are aberrantly expressed on malignant cells may be important target antigens for GVL effects from donor-derived anti-leukemia T cells. It is now clear that T cells recognizing these antigens circulate in transplant recipients and can be detected in small numbers in healthy individuals. To determine whether the same T cell clones in the donor are transferred to the recipient and induce GVL effects we sought for presence of leukemia-reactive T cell clones in healthy donors and their transfer into the patient after transplant and following DLI. We identified CD8+ T cell clones specific for PR1 and WT1 from 2 healthy donors. The HLA-A2/PR1-binding and HLA-A2/WT1-binding CD8+ T cells were purified by flow cytometric cell sorting and analyzed for their T cell receptor (TCR) usage by template switch anchored RT-PCR. This showed an oligoclonal population of WT1-specific CD8+ T cells and a polyclonal population of PR1-specific CD8+ T cells. In addition, using a fluorescent peptide/MHC class I multimeric complex incorporating mutations in the a3 domain that abrogate binding to the CD8 coreceptor, we selectively isolated WT1-specific CD8+ T cells of high functional avidity and demonstrated that high avidity T cells comprise a single clonotype. One patient with CML received an alloSCT from the donor in whom PR1-specific CD8+ T cell clones were detected. Using quantitative real-time PCR for IFN-g production and HLA-A2/PR1 tetrameric complexes, we showed the emergence of PR1-specific CD8+ T cells in the blood of the recipient 10 weeks after SCT and again 8 weeks post-DLI given to treat a molecular relapse of CML. HLA-A2/PR1 tetramer-positive CD8+ T cells were sorted by flow cytometry post-alloSCT and again following DLI. By comparing TCRb CDR3 sequences, we confirmed direct transfer and expansion of PR1-specific CD8+ T cell clones from the donor into the recipient and the reemergence of the same PR1-specific clones following DLI. The appearance of these HLA-A2/PR1 tetramer-positive CD8+ T cells was followed by complete molecular remission of CML by sensitive PCR for BCR/ABL The PR1-specific CD8+ T cells in the donor were of memory phenotype and expanded in the recipient after both alloSCT and DLI. During the early phase post-transfer in the recipient, the majority of PR1-specific CD8+ T cells had an effector memory phenotype (CD45RO+ CD57+). There was a shift towards a central memory phenotype (CD45 RO+ CD57−) during the course of the GVL effect. This is the first direct demonstration of the transfer of leukaemia-reactive specific T cell clones from a healthy donor to a patient with leukemia. Further, the identification and monitoring of T cell clones that mediate the GVL effect as described here can be undertaken before stem cell transplantation and could aid donor selection.

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