Clinical-scale single-step CD4+ and CD8+ cell depletion for donor innate lymphocyte infusion (DILI)

Smetak, Manfred; Kimmel, Brigitte; Birkmann, Josef; Schaefer‐Eckart, Kerstin; Einsele, Hermann; Wilhelm, Martin; Kunzmann, Volker

doi:10.1038/sj.bmt.1705942

Cited by 11 publications

(10 citation statements)

References 57 publications

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“…Preservation of the function of γδ T cells was tested after separation by proliferation and cytotoxicity assays against different targets (data not shown) [13]. The product contained 2.17 × 10 6 /kg (range 0.9-3.48) γδ T cells and 8.87 × 10 6 /kg (range 1.54-18.82) NK cells (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells

et al. 2014

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BackgroundThe primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical γδ T lymphocytes.MethodsPatients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS® device according to the manufacturer’s instructions. On average, patients received 2.17 × 106/kg (range 0.9-3.48) γδ T cells with <1% CD4- or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m2 day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x106 IU/m2 IL-2 on day +1 until day +6 for the induction of γδ T cell proliferation in vivo.ResultsThis resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment.ConclusionThis pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.

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Section: Resultsmentioning

confidence: 99%

“…The collection of PBMCs and depletion of CD4 + and CD8 + cells were performed as previously described [13]. In brief, a single unstimulated leukapheresis was performed from family donors using a Cobe Spectra (Gambro BCT, Planegg-Martinsried, Germany).…”

Section: Methodsmentioning

confidence: 99%

Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells

et al. 2014

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“…In contrast to αβ T cells, no CAR + γδ T cells expressed CD4, some were CD8 + , but most were CD4 neg CD8 neg , which is consistent with what is known for γδ T cells. 31 The relative frequencies for each donor are shown in Figure 2b. Markers associated with memory, e.g., CD27, CD28, CD62L, and CCR7, were expressed by CAR + γδ T cells (Figure 2a, bottom).…”

Section: Immunophenotype Of Numerically Expanded Car + γδ T Cellsmentioning

confidence: 99%

Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor

et al. 2013

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Even though other γδ T-cell subsets exhibit antitumor activity, adoptive transfer of γδ Tcells is currently limited to one subset (expressing Vγ9Vδ2 T-cell receptor (TCR)) due to dependence on aminobisphosphonates as the only clinically appealing reagent for propagating γδ T cells. Therefore, we developed an approach to propagate polyclonal γδ T cells and rendered them bispecific through expression of a CD19-specific chimeric antigen receptor (CAR). Peripheral blood mononuclear cells (PBMC) were electroporated with Sleeping Beauty (SB) transposon and transposase to enforce expression of CAR in multiple γδ T-cell subsets. CAR(+)γδ T cells were expanded on CD19(+) artificial antigen-presenting cells (aAPC), which resulted in >10(9) CAR(+)γδ T cells from <10(6) total cells. Digital multiplex assay detected TCR mRNA coding for Vδ1, Vδ2, and Vδ3 with Vγ2, Vγ7, Vγ8, Vγ9, and Vγ10 alleles. Polyclonal CAR(+)γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19(+) tumor cell lines compared with CAR(neg)γδ T cells. CD19(+) leukemia xenografts in mice were reduced with CAR(+)γδ T cells compared with control mice. Since CAR, SB, and aAPC have been adapted for human application, clinical trials can now focus on the therapeutic potential of polyclonal γδ T cells.

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“…[13][14][15] Data from our group have also demonstrated that isolated gamma-delta T cells can mediate anti-aspergillus activity. 11 Gamma-delta T lymphocytes can be highly enriched for under good manufacturing practice conditions using the Clinimacs device 16,17 and also easily be activated and expanded in vivo by stimulation with aminobisphosphonates. 18 Thus, this cell population that also mediates antiviral and antitumor activity, 19,20 but does not mediate alloreactivity will be a very attractive option to be used for adoptive immunotherapy for infection and tumor control post transplant.…”

Section: Immunotherapy For Fungal Infectionsmentioning

confidence: 99%

Immunotherapy for viral and fungal infections

Einsele

Löffler

Kapp

et al. 2015

Bone Marrow Transplant

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Allogenic stem cell transplantation (allo-SCT) represents the only curative option for several hematological malignancies. Due to a delayed and dysfunctional immunological recovery infectious complications and residual tumor cells following allo-SCT are still major causes of failure of this procedure. Here we discuss the most common infectious complications of allo-SCT and describe current and future strategies to prophylaxe or treat these complications using novel immunotherapeutic strategies.

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Clinical-scale single-step CD4+ and CD8+ cell depletion for donor innate lymphocyte infusion (DILI)

Cited by 11 publications

References 57 publications

Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells

Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells

Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor

Immunotherapy for viral and fungal infections

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