Graft engineering for allogeneic haploidentical stem cell transplantation

Tabilio, Antonio; Falzetti, Franca; Zei, Tiziana; Ioanni, Maria De; Bonifacio, Elisabetta; Battelli, Feliciana; Ostini, Roberta Iacucci; Ballanti, Stelvio; Cimminiello, Michele; Capponi, Monia; Silvani, Carlo; Minelli, Olivia; Fettucciari, Katia; Marconi, Pierfrancesco; Rosati, Emanuela; Santucci, A; Ianni, Mauro Di; Aversa, Franco; Martelli, Massimo F.

doi:10.1016/j.bcmd.2004.08.016

Cited by 18 publications

(10 citation statements)

References 26 publications

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“…Tabilio et al 13 and Dey and Spitzer 12 suggested a megadose of hematopoietic progenitor cells, very few T lymphocytes, or selective depletion of alloreactive T cells in preparing a graft for haploidentical transplants. However, in our study, with a relatively small dose of stem cells and more T cells, the patients underwent HLA-mismatched/haploidentical transplant with potentially acceptable outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 These mixture grafts (G-BM and G-PB) offer different results than the usual myeloablative transplantation strategies using 'megadose' stem cells vigorously depleted of T cells for patients without an HLA-matched donor. 12,13 The mixture grafts (G-BM and G-PB), without in vitro T-cell depletion, lead to rapid and stable engraftment and strong GVL, without significantly increasing the incidence of aGVHD and cGVHD. 10,11 In vitro tests have shown that mixture grafts are specifically associated with T-cell hyporesponsiveness and polarization.…”

Section: Introductionmentioning

confidence: 99%

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The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic SCT

et al. 2008

Bone Marrow Transplant

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This study examines the absolute numbers and relative proportions of CD4 þ , CD8 þ , CD14 þ and CD34 þ cells contained in allografts and their impact on early engraftment and later clinical outcomes in 141 patients with hematological malignancies who underwent unmanipulated HLA-mismatched/haploidentical hematopoietic SCT without in vitro T-cell depletion. These patients received G-CSF-primed BM grafts (G-BM) and peripheral blood grafts (G-PB) following a modified regimen of BU/CY 2 plus antithymocyte globulin. Multivariate analysis showed that high CD34 þ cell numbers were associated with accelerated plt engraftment (P ¼ 0.001). Meanwhile, patients with a higher CD4/CD8 ratio in G-BM (X1.16) had a survival disadvantage (Po0.01) and a trend towards relapse (P ¼ 0.086) after controlling for disease status. A higher CD4/CD8 was also associated with a significantly increased risk of acute GVHD grades II-IV (P ¼ 0.013), even after adjusting for an ABO major mismatch. No aspect of graft composition affected neutrophil engraftment or chronic GVHD. In conclusion, the differences in CD34 þ cell dose and the CD4/CD8 ratio in grafts seem to affect engraftment and clinical outcomes; in particular, a lower CD4/CD8 ratio in primed BM graft is associated with a survival benefit.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic SCT

et al. 2008

Bone Marrow Transplant

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“…[8][9][10][11][12][13] But only about 80% of all grafts can reach the level of cell doses required. 14,15 Additionally, the relatively high cost of ex vivo CD34 ϩ cell selection makes it difficult to use this approach widely.…”

Section: Introductionmentioning

confidence: 99%

Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation

Dong

et al. 2006

Blood

465

417

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The outcomes of 293 patients with leukemia undergoing HLA-identical sibling (n ‫؍‬ 158) or related HLA-mismatched (n ‫؍‬ 135) hematopoietic cell transplantation (HCT) performed during the same time period were compared. Patients received BUCY2 in HLA-identical sibling HCT or BUCY2 ؉ ATG in mismatched HCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the matched and mismatched cohorts were 32% (CI, 25%-39%) versus 40% (CI, 32%-48%, P ‫؍‬ .13), respectively, with the relative risk (RR) ‫؍‬ 0.64 (95% CI, 0.43-0.94), P ‫؍‬ .02. The incidence of chronic GVHD did not differ significantly between the cohorts (P ‫؍‬ .97). Two-year incidences of treatment-related mortality and relapse for matched versus mismatched were 14% (range, 9%-20%) versus 22% (range, 15%-29%) with P ‫؍‬ .10 and 13% (range, 8%-19%) versus 18% (range, 10%-27%) with P ‫؍‬ .40, respectively. Two-year adjusted leukemia-free survival (LFS) and overall survival were 71% (range, 63%-78%) versus 64% (range, 54%-73%) with P ‫؍‬ .27 and 72% (range, 64%-79%) versus 71% (range, 62%-77%) with P ‫؍‬ .72, respectively. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia had increased risk of relapse, treatment failure, and overall mortality. In summary, HCT performed with related HLA-mismatched donors is a feasible approach with acceptable outcomes. (Blood. 2006;107:3065-3073)

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“…3 Although variable success in the reduction of aGVHD incidence and/or severity without alteration of GVL responses could be obtained with the use of manipulated grafts either ex vivo [7][8][9][10][11][12][13] or in vivo by using, as part of conditioning regimens, polyclonal Abs such as antithymocyte globulin 14 or MoAb against CD52, 15 separation of GVHD from GVL responses and anti-infective effect is still an elusive goal. Although panlymphocyte depletion resulted in significantly less GVHD, there was increased incidence of viral and opportunistic infections and relapse, leading to an absence of significant improvement on overall survival.…”

Section: Introductionmentioning

confidence: 99%

Donor-derived CD4+/CCR7+ T-cell partial selective depletion does not alter acquired anti-infective immunity

Choufi

Trauet

Thiant

et al. 2014

Bone Marrow Transplant

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In previous studies, we observed that a high proportion of donor-derived CD4 þ T cells expressing the chemokine receptor 7 (CCR7) was a major determinant of acute GVHD, without interfering with the incidence of other post-transplant outcomes, especially relapse and nonrelapse mortality rates. Here, we investigated in vitro the impact of partially selective CD4 þ /CCR7 þ T lymphocytes on acquired anti-infective immune response in 10 donors who underwent G-CSF-primed PBSC collection. Similar quantitative and functional proliferative reactions were observed in lymphocyte cultures in the presence of adenovirus and pp65 Ags with unmanipulated and partially depleted donor samples. No responses were observed in the presence of human T-cell lymphotropic virus type 1 used as a negative control. These results complete the proof of concept needed to build a clinical trial investigating partially selective CD4 þ /CCR7 þ T cell-depleted allo-SCT.

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Graft engineering for allogeneic haploidentical stem cell transplantation

Cited by 18 publications

References 26 publications

The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic SCT

The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched/haploidentical hematopoietic SCT

Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation

Donor-derived CD4+/CCR7+ T-cell partial selective depletion does not alter acquired anti-infective immunity

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