scholarly journals Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

Safely Improving the in Vivo Survival of Tumor Specific Cytotoxic T Lymphocytes by Co-Transfer of IL7 Receptor Alpha Chain and icaspase9

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3534-3534
Author(s):  
Juan F Vera ◽  
Valentina Hoyos ◽  
Barbara Savoldo ◽  
Concetta Quintarelli ◽  
Greta A Giordano ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Adoptive Transfer ◽  
Fold Increase ◽  
Suicide Gene ◽  
Antigen Specificity ◽  
Anti Tumor Activity

Abstract Providing a proliferative and survival advantage to tumor-specific cytotoxic T lymphocytes (CTLs) remains a challenge in the adoptive therapy of cancer patients. It is now evident that the in vivo expansion of T cells after adoptive transfer is best accomplished in the lymphodepleted host due to the increased production of endogenous IL15 and IL7, which help restore lymphopoiesis. We have found that antigen activated cytotoxic T lymphocytes (CTLs) directed to tumor associated epitopes (for example derived from EBV, or from cancer testis antigens such as PRAME) down regulate a chain of IL7R, a common γ chain cytokine receptor, impairing their capacity to respond to IL7. We hypothesized that despite receptor downregulation, the signal transduction pathway for IL7R would remain intact in the CTLs so that forced expression of IL7Rα would restore IL7 responsiveness and improve in vivo expansion and survival of CTLs. We used EBV-specific CTLs as our model, and showed in vitro that a functional IL-7Ra molecule can be expressed in CTLs using retroviral gene transfer so that the percentage of receptor + cells increased from 2.4%±0.5% to 50%±20. This modification restored the in vitro proliferation of genetically modified CTLs in response to IL7 so that cell numbers increased from 1×106 cells to 0.1×109 (range, 0.6×108 to 0.3×109)] comparable with the effects of IL2 [from 1×106 cells to 0.7×109 (range, 0.7×107 to 1.6×109)] In contrast, control EBV-CTL with IL7 progressively declined in number (p<0.001) These effects were accomplished without alteration of antigen specificity or responsiveness to other common γ chain cytokines, and cell survival remained antigen dependent. In a xenogeneic mouse model, CTLs expressing IL7Ra significantly expanded in vivo in response to EBV-tumor antigen and the administration of IL7. By day 15, both control CTLs and IL7Ra+ CTLs had modestly proliferated in response to IL-2 (2.3 fold, range 1.1–5.1 for control CTLs, and 2.67 fold, range 0.6 to 8.15 for IL7Ra+ CTLs). In contrast, only IL7Ra+ CTLs significantly expanded in the presence of IL7, showing a 6.09 fold increase (range 0.7 to 25.2) compared to mice that received control CTLs and IL7 (0.9 fold, range 0.5–1.7) (p<0.0001). Modified CTLs also provided enhanced anti-tumor activity. SCID mice engrafted i.p with 3×106 tumor cells marked with Firefly luciferase, showed a rapid increase in signal in the absence of CTLs (Fold increase in luminance = 29.8 median, range 4.4 to 103) by day 14 after tumor engraftment. Similar tumor growth was observed in mice receiving IL7Ra+ CTLs without cytokines (luminance increase14.4 fold, range 1 to 90). In contrast, mice receiving IL7Ra+ CTLs and either IL2 or IL7, had a decline in tumor luminance (fold expansion 0.7, range 0.08 to 2.9, and 0.8, range 0.004 to 3.5, respectively p<0.0001). Although growth of the transgenic T cells remained antigen dependent, as a further safety measure, we incorporated an inducible suicide gene based on icaspase9 that can be activated by exposure to a small chemical inducer of dimerization (CID) (AP20187). Incorporation of this suicide gene did not affect the in vitro or in vivo anti-tumor activity of the CTL’s but allowed them to be rapidly eliminated. So that after a single dose of CID (50 nM) the transgenic population were decreased by >98.5% We conclude that forced expression of the IL-7Ra by CTLs can be used to recapitulate the response of these cells to this cytokine and thereby promote their in vivo anti-tumor activity after adoptive transfer either in a lymphodepleted host or after the administration of the recombinant protein.

scholarly journals Cd8 Expression up to the Double-Positive CD3Low/Intermediate Stage of Thymic Differentiation Is Sufficient for Development of Peripheral Functional Cytotoxic T Lymphocytes

2001 ◽  
Vol 194 (5) ◽  
pp. 685-694 ◽  
Author(s):  
X.-L. Zhang ◽  
S. Zhao ◽  
S.H. Borenstein ◽  
Y. Liu ◽  
B. Jayabalasingham ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Intermediate Stage ◽  
Cell Receptor ◽  
Double Positive ◽  
Cis Acting ◽  
Functional Studies ◽  
Peripheral T Cells

Control of CD8α transcription during development of α/β T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8α−/−knockout (KO) background, cis-mechanism I and cis-mechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8α expression and “rescue” development of peripheral CD8+ single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8+/+ or CD8α−/−KO backgrounds, a CD8α Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3low/intermediate DP stage but not in more mature DP or SP thymocytes or peripheral T cells. As loss of cis mechanism I activity occurs around the onset of positive selection, it is possible that events associated with TCR/major histocompatibility complex (MHC) interactions and selection are involved in initiating these changes in CD8α transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8α−/−KO mice that expressed a CD8α Tg under control of cis-mechanism I only. Despite loss of CD8α expression at the DP CD3low/intermediate stage, increased populations of mature CD3hiCD4−CD8− thymocytes and CD3+CD4−CD8− peripheral T cells were detected. By several criteria, including MHC class I–restricted antigen recognition, these cells have at least partially undergone positive and negative selection. Therefore, initiation of selection and sublineage commitment are determined before loss of cis-mechanism I–mediated control of CD8α transcription. Further, CD8 expression beyond the CD3low/intermediate DP thymic stage is not essential for CTL development in vivo or function.

scholarly journals Subsets of Memory Cytotoxic T Lymphocytes Elicited by Vaccination Influence the Efficiency of Secondary Expansion In Vivo

2004 ◽  
Vol 78 (1) ◽  
pp. 206-215 ◽  
Author(s):  
Michael S. Seaman ◽  
Fred W. Peyerl ◽  
Shawn S. Jackson ◽  
Michelle A. Lifton ◽  
Darci A. Gorgone ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Memory T Cells ◽  
Central Memory ◽  
Effector Memory ◽  
Interleukin 12 ◽  
Effector Cells ◽  
Memory Cytotoxic T Lymphocytes

ABSTRACT Vaccine-elicited cytotoxic T lymphocytes (CTL) should be long-lived memory cells that can rapidly expand in number following re-exposure to antigen. The present studies were initiated to analyze the ability of plasmid interleukin-12 (IL-12) to augment CTL responses in mice when delivered during the peak phase of an immune response elicited by a plasmid human immunodeficiency virus type 1 gp120 DNA vaccine. Delivery of plasmid IL-12 on day 10 postimmunization resulted in a robust expansion of gp120-specific CD8+ T cells, as measured by tetramer, gamma interferon ELISPOT, and functional-killing assays. Interestingly, this delayed administration of plasmid IL-12 had no significant effect on antigen-specific CD4+-T-cell and antibody responses. Phenotypic analyses suggested that administration of plasmid IL-12 near the time of the peak CTL response activated and expanded antigen-specific effector cells, preventing their loss through apoptosis. However, this IL-12-augmented population of gp120-specific CD8+ T cells did not efficiently expand following gp120 boost immunization, suggesting that these effector cells would be of little utility in expanding to contain a viral infection. Analyses of the phenotypic profile and anatomic distribution of the plasmid IL-12-augmented CTL population indicated that these lymphocytes were primarily effector memory rather than central memory T cells. These observations suggest that CTL-based vaccines should elicit central memory rather than effector memory T cells and illustrate the importance of monitoring the phenotype and functionality of vaccine-induced, antigen-specific CTL.

Fucosylated Antigen-Specific Cytotoxic T Lymphocytes Demonstrate Enhanced Killing of Leukemia Targets

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1888-1888
Author(s):  
Gheath Alatrash ◽  
Mao Zhang ◽  
Na Qiao ◽  
Pariya Sukhumalchandra ◽  
Madhushree Zope ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Adhesion Molecules ◽  
Cytotoxic T Lymphocytes ◽  
Cell Surface Expression ◽  
Target Cells

Abstract Introduction Immunotherapy using cytotoxic T lymphocytes (CTL) has shown efficacy in the management of leukemia. However the efficacy of CTL, whether they are engineered and adoptively transferred or administered as part of allogeneic stem cell transplantation, must be balanced by their off-target toxicities, which at times can be lethal. Fucosylation, which is mediated by fucosyl transferases, is a process by which fucose sugar groups are added to cell surface receptors. Fucosylated T cells have been shown to preferentially home to inflamed tissues, including bone marrow. In view of recent data showing that fucosylation with fucosyltransferase (FT)-VI facilitates homing of regulatory T cells (T-regs) to inflamed tissues and cord blood engraftment into the bone marrow, we hypothesized that fucosylation could enhance the efficacy of CTL that target leukemia antigens. In this study, we tested whether ex vivo fucosylation of CTL that target the HLA-A2 restricted leukemia peptides, CG1 (derived from cathepsin G) and PR1 (derived from neutrophil elastase and proteinase 3), with the novel enzyme FT-VII enhances their migration and anti-leukemia functions. Experimental design CG1- and PR1-CTL were generated using standard methodologies. Fucosylation was achieved by incubating T cells with FTVII enzyme and GDP fucose (Targazyme). To study migration, fucosylated and non-fucosylated CTL were passed through chambers coated with a HUVEC barrier and migrated CTL were detected using cell fluorescence. To examine CTL surface markers, cells were stained for standard co-stimulatory and adhesion molecules and were analyzed using flow cytometry. Calcein AM cytotoxicity assays were used to determine the effects of fucosylation on CTL killing of target cells. In vitro effects of fucosylation on leukemia-CTL specificity was accomplished using standard CFU assays. For in vivo assessment of fucosylation on activity of CTL, NSG mice were engrafted with U937-A2 human acute myeloid leukemia (AML) cells or primary AML and were treated with intravenous injections of 5.0 x 105 fucosylated or non-fucosylated CTL. Mice were followed twice weekly and were sacrificed for bone marrow and tissue analysis at prespecified time points or when they became moribund. Results Fucosylated CG1-CTL and PR1-CTL showed approximately 2-fold higher migration through the HUVEC cell barrier compared to non-fucosylated CTL. Analysis of T cell surface expression of chemokine/adhesion molecules showed an approximately a 5-fold increase in CD49d and CD195, and a 50% increase in CXCR1 and CXCR3 following fucosylation. Fucosylation enhanced the cytotoxicity of leukemia specific-CTL against primary HLA-A2+ leukemia and HLA-A2+ U937 cells at increasing effector to target ratios. For primary patient AML, we show enhanced leukemia killing by fucosylated-PR1-CTL in comparison with non-fucosylated-PR1-CTL at the 20:1 effector to target (E:T) ratio (25-fold higher killing ) and the 10:1 E:T ratio (4-fold higher killing). Similar results were seen using the U937-A2 AML cell line favoring fucosylated-CG1-CTL: 20-fold higher killing at 20:1 E:T ratio and a 9-fold higher killing at the 10:1 E:T ratio. In vitro CFU assays using HLA-A2+ healthy donor bone marrow showed no change in the specificity of the antigen specific CTL following fucosylation. Specifically we show 283 and 295 colonies in the fucosylated and non-fucosylated CG1-CTL groups, respectively (P >0.05). These were also compared to irrelevant peptide HIV-CTL, which demonstrated 286 and 269 CFUs in the fucosylated and non-fucosylated HIV-CTL groups, respectively (P >0.05). In vivo experiments using CG1-CTL against primary AML showed 5-fold higher killing of AML by fucosylated CTL vs. non-fucosylated CTL. Similar results were also seen using U937-A2 AML targets. Conclusion Fucosylation with FT-VII enhances the efficacy of leukemia-targeting CTL against primary human AML and AML cell lines. These data demonstrate a novel approach to enhance the efficacy of antigen specific CTL that could be used in adoptive cellular immunotherapy approaches for leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Epstein Barr virus–specific cytotoxic T lymphocytes expressing the anti-CD30ζ artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2620-2630 ◽  
Author(s):  
Barbara Savoldo ◽  
Cliona M. Rooney ◽  
Antonio Di Stasi ◽  
Hinrich Abken ◽  
Andreas Hombach ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Chimeric Antigen Receptor ◽  
Epstein Barr Virus ◽  
Antigen Receptor ◽  
Xenograft Model ◽  
Antitumor Effects ◽  
Barr Virus ◽  
Epstein Barr

Adoptive transfer of Epstein Barr virus (EBV)–specific cytotoxic T-lymphocytes (EBV-CTLs) has shown that these cells persist in patients with EBV+ Hodgkin lymphoma (HD) to produce complete tumor responses. Treatment failure, however, occurs if a subpopulation of malignant cells in the tumor lacks or loses expression of EBV antigens. We have therefore determined whether we could prepare EBV-CTLs that retained the antitumor activity conferred by their native receptor while expressing a chimeric antigen receptor (CAR) specific for CD30, a molecule highly and consistently expressed on malignant Hodgkin Reed-Sternberg cells. We made a CD30CAR and were able to express it on 26% (± 11%) and 22% (± 5%) of EBV-CTLs generated from healthy donors and HD patients, respectively. These CD30CAR+ CTLs killed both autologous EBV+ cells through their native receptor and EBV−/CD30+ targets through their major histocompatibility complex (MHC)–unrestricted CAR. A subpopulation of activated T cells also express CD30, but the CD30CAR+ CTLs did not impair cellular immune responses, probably because normal T cells express lower levels of the target antigen. In a xenograft model, CD30CAR+ EBV-CTLs could be costimulated by EBV-infected cells and produce antitumor effects even against EBV−/CD30+ tumors. EBV-CTLs expressing both a native and a chimeric antigen receptor may therefore have added value for treatment of HD.

Engineering CD19-Redirected T Lymphocytes to Enhance Their Safety and Efficacy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 824-824
Author(s):  
Valentina Hoyos ◽  
Barbara Savoldo ◽  
Juan F Vera ◽  
Concetta Quintarelli ◽  
Cliona M Rooney ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Suicide Gene ◽  
Firefly Luciferase ◽  
Transduction Efficiency ◽  
Phenotypic Analysis ◽  
Antitumor Effects ◽  
Transgenic Expression

Abstract Modification of primary T cells to express chimeric antigen receptors (CARs) is an attractive strategy for the generation of tumor-specific T cells for adoptive therapies. However, their efficacy is limited by poor expansion within the tumor microenvironment. The addition of co-stimulatory endodomains, such as CD28, to the CAR may enhance cell expansion in response to the antigen, but cell growth and survival remain suboptimal since the co-stimulation provided through these endodomains cannot recapitulate the spatiotemporal sequence of signals T cells receive during physiologic activation. To further potentiate the expansion and survival of CAR-modified T lymphocytes, we generated a new vector encoding 3 molecules: CAR.19 incorporating the CD28 endodomain, codon optimized hIL15 to enhance cell survival and growth, and an inducible suicide gene based on the expression of Caspase9 (iCasp9) to increase the margin of safety associated with transgenic expression of an autocrine growth factor. These three sequences were linked using 2A-like peptide sequences. We compared the proliferative capacity, cytotoxic activity and in vivo anti-tumor effects of T lymphocytes expressing either CAR.19-28z alone or CAR.19-28z, IL15 and the suicide gene. T lymphocytes were activated with OKT3/CD28 antibodies and then transduced with retroviral supernatants. Phenotypic analysis showed 70±10% and 75±5% transduction efficiency for iCasp9/CAR19-28z/IL15 and CAR19-28z T cells, respectively. Only the iCasp9/CAR19-28z/IL15 T cells produced IL15 (>100pg/mL) after stimulation with CD19+ tumor cells. In co-culture experiments, T cells expressing CAR.19-28z alone or iCasp9/CAR19-28z/IL15 both completely eliminated CD19+ tumor cells within 72 hours. However, labeling with carboxyfluorescein diacetate succinimidyl ester (CFSE) showed that the proliferation of the iCasp9/CAR19-28z/IL15+ T cells in response to CD19+ tumor cells was greater than that of CAR.19-28z control+ T cells. Finally, the activation of the suicide gene iCasp9 with a small-molecule dimerizer (CID 50ng/mL) rapidly induced >90% apoptosis of T cells expressing iCasp9/CAR19-28z/IL15. Hence all three transgenes were functional. To assess the antitumor effects of the modified cells in vivo, we used a xenograft SCID mouse model and an in vivo bioluminescence system. CD19+ Daudi cells (1×106) expressing firefly Luciferase (FL) were injected i.p., and on day 4, mice received i.p iCasp9/CAR19-28z/IL15+ or CAR19-28z+ or control T cells (10×106). By day 30 the tumor signal was significantly reduced in mice receiving iCasp9/CAR19-28z/IL15+ T cells (ROI<7×107) compared to mice receiving CAR19-28z or control T cells (ROI>2.0×109). In conclusion, our data indicate that a tricistronic vector can effectively be expressed in tumor-redirected human T cells, improving their survival and allowing their destruction should unwanted effects occur.

Genetically Modified EBV-Specific Cytotoxic T Lymphocytes Induce Regression Of EBV Lymphoproliferation Despite Immunosuppression In Xenografted Mice: A Novel Strategy For EBV-Associated Post-Transplant Lymphoproliferative Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3264-3264
Author(s):  
Ida Ricciardelli ◽  
Jenny Brewin ◽  
Mike Blundell ◽  
Martin Pule ◽  
Persis Amrolia
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Cytotoxic T Lymphocytes ◽  
Adoptive Transfer ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disease ◽  
Genetically Engineered ◽  
Solid Organ

Abstract Background EBV associated lymphoproliferative disease (PTLD) remains a major cause of morbidity and mortality after stem cell (SCT) or solid organ (SOT) transplant. Adoptive transfer of ex vivo-derived EBV-specific cytotoxic T lymphocytes (EBV-CTL) to reconstitute immunity to the oncogenic virus EBV has been highly effective for both the prophylaxis and treatment of PTLD after SCT, where immunosuppression could be withdrawn before transfer of EBV-CTLs. In contrast, the application of this approach for the treatment of PTLD in SOT patients, although feasible, has been challenging with restricted expansion, persistence and efficacy of the adoptive transferred T cells. This difference is likely to reflect the need for the on-going immunosuppression to prevent graft-rejection post SOT which inhibits the virus-specific T cell responses. Our group has previously genetically engineered EBV-CTL to enable them to function in vitro in the presence of the calcineurin inhibitor Tacrolimus (FK506) through retroviral transfer of a calcineurin mutant (CNA12). Aim To examine the ability of genetically engineered EBV-CTLs resistant to FK506 to control EBV+ B cell lymphoma progression in vivoin a xenogeneic mouse model in the presence of FK506. Methods NOD/SCID/IL2rgnull (NSG) mice were inoculated subcutaneously with 5×106 EBV-transformed lymphoblastoid B cell lines (LCL) labelled with F-Luc to develop human EBV+ lymphoma. To evaluate in vivo antitumor activity, 5×106 CTLs retrovirally transduced with CNA12 or eGFP control CTLs were injected intravenously after 7 days in the presence or absence of FK506 (10mg/kg/day). Tumour growth was analysed using the Xenogen-IVIS system. Results Adoptive transfer of autologous CNA12 transduced CTLs induced EBV+ lymphoma regression in the presence of FK506, as assessed both by IVIS and tumour size, whereas FK506 treated mice receiving eGFP control CTLs had tumour progression (P<0.05). This resulted in significantly improved survival of mice treated with CNA12-CTL in the presence of FK506 than eGFP-CTLs treated animals (P<0.0001). CNA12 transduced EBV CTLs persisted longer and expanded more (P<0.0001) than eGFP-CTLs in peripheral blood of mice treated with FK506 demonstrating a selective growth advantage and enrichment of CTLs resistant to immunosuppression. Immunohistochemical staining showed that adoptively transferred CTLs home to the tumour and an increase of tumour infiltrating T cells in CNA12-CTL compared with eGFP-CTLs treated mice in the presence of FK506 was observed. Conclusions Our results demonstrate that CNA12 modified EBV-CTL can induce regression of EBV-associated tumours in vivo in the face of on-going immunosuppression with FK506. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy. Disclosures: No relevant conflicts of interest to declare.

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