Clinical-Scale Rapid Autologous BK Virus-Specific T Cell Line Generation From Kidney Transplant Recipients With Active Viremia for Adoptive Immunotherapy

Lamarche, Caroline; Orio, Julie; Georges-Tobar, Victoria; Pincez, Thomas; Goupil, Mathieu; Dahmani, Amina; Carli, Cédric; Brasey, Ann; Busque, Lambert; Delisle, Jean-Sébastien

doi:10.1097/tp.0000000000001698

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…The findings of our work on immune modes of action are especially relevant for future immunotherapeutic approaches against BKVN, since they suggest that the immune response against regulatory sLT antigens is central for BKV clearance. The use of T cells specific for BKV regulatory antigens is an interesting clinical approach, which has recently been shown to be technically possible [ 35 ]. In this study, the authors established a protocol for the ex-vivo generation of T cells specific for the antigens VP1 and LT, offering evidence of the specificity and safety of these cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The use of T cells specific for BKV regulatory antigens is an interesting clinical approach, which has recently been shown to be technically possible [ 35 ]. In this study, the authors established a protocol for the ex-vivo generation of T cells specific for the antigens VP1 and LT, offering evidence of the specificity and safety of these cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach

et al. 2018

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BK virus (BKV) associated nephropathy affects 1–10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach

et al. 2018

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“…Suppression of MLRs. Adherent cells from PBMCs from HLA-A2 + healthy donors were differentiated into monocyte-derived dendritic cells as described previously (62). For MLRs, HLA-A2 -PBMC responder cells were labeled with cell proliferation dye eF450 (Thermo Fisher Scientific, 65-0842-85), then plated with 5 × 10 4 HLA-A2 + monocyte-derived dendritic cells and increasing ratios of expanded ΔNGFR-or hA2-CAR-expressing Tregs labeled with cell proliferation dye e670 (Thermo Fisher Scientific, 65-0840-90).…”

Section: Methodsmentioning

confidence: 99%

Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

Dawson¹,

et al. 2019

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“…Based on our methods, monocytes from PBMCs were isolated by plastic adherence and cultured in DC medium (X‐vivo 15 ‐ Lonza, 5% human AB serum, 100 U/mL penicillin, 100 μg/mL streptomycin, 2 mM l ‐Glutamine, and 1 mM sodium pyruvate) supplemented with 800 IU/mL granulocyte‐macrophage colony‐stimulating factor and 1000 IU/mL IL‐4; both cytokines from Feldan). After 7 days, moDCs were matured for 48 hours with granulocyte‐macrophage colony‐stimulating factor (800 IU/mL), IL‐4 (1000 IU/mL), 10 ng/mL tumor necrosis factor‐α (TNF‐α), 10 ng/mL IL‐1β, 100 ng/mL IL‐6 (Feldan) and 1 μg/mL prostaglandin E2 (Sigma‐Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

et al. 2018

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BACKGROUND Following solid organ or hematopoietic cell transplantation, refractory opportunistic viral reactivations are a significant cause of morbidity and mortality but can effectively be controlled by virus‐specific T‐cell transfer. Among effective and safe strategies is the use of “third‐party” (neither from the transplant donor nor recipient) virus‐specific T cells that can be manufactured from healthy donors and used as “off‐the‐shelf” therapies. Leukoreduction system chambers (LRSCs), recovered after routine plateletpheresis, were evaluated as a potential source of peripheral blood mononuclear cells (PBMCs) for the manufacturing of clinical‐scale virus‐specific T cell. STUDY DESIGN AND METHODS PBMCs from the same donors obtained either from LRSCs or peripheral blood were compared, focusing on T‐cell function and phenotype as well as the potential to generate cytomegalovirus (CMV)‐specific T‐cell lines from both CMV seropositive and seronegative donors. RESULTS PBMCs from both sources were comparable except for a transient downregulation of CD62L expression on freshly extracted PBMCs from LRSCs. Both nonspecific stimulation using anti‐CD3/CD28 antibodies and CMV peptides revealed that LRSCs or blood T cells were equivalent in terms of expansion, differentiation, and function. Moreover, PBMCs from LRSCs can be used to generate autologous monocyte‐derived dendritic cells to prime and expand CMV‐specific T cells from seronegative donors. CONCLUSION LRSCs are a reliable source of PBMCs for the generation of virus‐specific T cells for immunotherapy. These findings have implications for the development of third‐party therapeutic T‐cell products from well‐characterized blood product donors.

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Clinical-Scale Rapid Autologous BK Virus-Specific T Cell Line Generation From Kidney Transplant Recipients With Active Viremia for Adoptive Immunotherapy

Abstract: Using a rapid, clinically compliant culture system, we show that autologous BK virus-specific T cell lines can be reliably generated from viremic KTR. Our results pave the way for the treatment or prevention of PVAN with adoptive immunotherapy.

Cited by 18 publications

References 38 publications

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach

Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in T regulatory cells

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

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