scholarly journals Unmanipulated Haploidentical Transplant Followed By Post-Transplant Cyclophosphamide and Selective Ex Vivo T-Cell Depleted Haploidentical Transplant Results in Comparable Outcome As Unrelated Cord Blood Transplant for Adults with Haematological Malignancies- a Multicenter Study in Singapore

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4588-4588
Author(s):  
Cheryl XQ Lim ◽  
Yeh Ching Linn ◽  
Yin Jie Koh ◽  
Michelle Poon ◽  
Aloysius YL Ho ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cord Blood ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Haematological Malignancies ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Background: Outcomes after haploidentical (Haplo) haematopoietic cell transplantation (HCT) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk haematological malignancies without human leukocyte antigen (HLA) matched related or unrelated donor. There is paucity of data comparing the outcome of UCBT and haplo HCT. We retrospectively analyse and compare the outcome of adult patients with haematological malignancies receiving UCBT and haplo HCT using two different platform for graft-versus-host disease (GVHD) prophylaxis: selective ex-vivo T cell (TCRαβ and CD45RA+) depleted haplo HCT (Koh LP et al. Blood 2018; 132: 2093a) vs unmanipulated T cell replete haplo HCT with high dose posttransplant cyclophosphamide (PTCy). Methods: We studied 169 adults patients receiving allogeneic HCT using 4-6/6 HLA matched UCB (n=100) graft or Haplo (n=69) for various haematologic malignancies between Aug 2006 and July 2019, following myeloablative (MAC, n=76) or reduced intensity conditioning (RIC, N=93) regimen. 37 Haplo patients received unmanipulated non ex-vivo, T cell depleted graft followed by PT Cy for graft-versus-host disease (GVHD) prophylaxis (Haplo PTCy), whereas 32 patients received haplo-HCT with selective ex vivo T cell (TCRαβ and CD45RA+) depleted grafts for GVHD prophylaxis (Haplo-TCD). Results: Two year overall survival (OS) for patients undergoing UCB, Haplo PTCy and Haplo-TCD transplant were 46%, 54% and 55% (p=0.379), and event free survival (EFS) were 41%, 50% and 45% (p=0.573), respectively; these were not significantly different among the 3 groups. Two year cumulative incidence (C.I.) of non-relapse mortality (UCB 32% vs Haplo PT Cy 20% vs 31%; p=0.514), relapse-related mortality (RRM) (UCB 24% vs Haplo PT Cy 21% vs 16%; p=0.596) and grades 3 - 4 acute GVHD at 6 months (UCB 9% vs Haplo PT Cy 6% vs 10%; p=0.758) were not significantly different among the 3 groups. However, C.I. of chronic GVHD at 2 years was higher in PTCy as compared with others (Haplo PT Cy 28% vs UCB 4% and Haplo TCD 5%, respectively, P<0.001). Multivariable analysis showed a significant association with OS and EFS for disease risk index (DRI) (p<0.001) and HCT comorbidity index (p<0.001), with no statistically significant impact from the type of stem cell graft used. In patients with low/intermediate risk DRI, the 2 year OS for TCD, PTCy and UCB were 71%, 55% and 56%, respectively (p=0.729), and the corresponding 2 year LFS were 59%, 54% and 48%, respectively (p=0.994). In patients with high/very high risk DRI, the 2 year OS for TCD, PTCy and UCB were 19 %, 51% and 18%, respectively (p=0.177), and the corresponding 2 year LFS were 0 %, 18% and 18%, respectively (p=0.774). Conclusions: Haploidentical HCT using either unmanipulated graft and PTCy or selective Ex Vivo TCRαβ and CD45RA+ depleted graft results in equivalent outcome to those HCT performed using UCB. It provides additional alternative for patients lacking HLA matched donors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antilymphocytic antibodies and marrow transplantation. XII. Suppression of graft-versus-host disease by T-cell-modulating and depleting antimouse CD3 antibody is most effective when preinjected in the marrow recipient

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2661-2667
Author(s):  
J Mysliwietz ◽  
S Thierfelder
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Prolonged Treatment ◽  
Antibody Activity ◽  
Spleen Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract A hamster antimouse CD3 monoclonal antibody (MoAb) opened the way to experimental studies on the suppression of allograft rejection and cytokine-related morbidity after treatment with antibodies modulating the CD3/T-cell receptor complex (CD3/TCR). Because earlier attempts to suppress graft-versus-host disease (GVHD) in patients by in vitro treatment of donor marrow with anti-CD3 MoAb had remained inconclusive, we used a rat IgG2b antimouse CD3 MoAb (17A2) with fewer side effects to analyze suppression of GVHD in the mouse model. Detailed phenotyping of blood, spleen, and lymphnode T cells after the injection of 400 micrograms 17A2 in C57BL/6 mice showed 60% CD3 downmodulation and 50% T- cell depletion for spleen cells. Injection of these spleen cells, together with bone marrow cells, in fully mismatched preirradiated CBA mice delayed GVHD by only 6 days. Ex vivo treatment of donor cells with 17A2 was not effective. In contrast, conditioning of marrow recipients with a single injection of 17A2 delayed 50% GVHD mortality by 100 days and prevented GVHD altogether after prolonged treatment, with survivors showing complete chimerism and specific transplantation tolerance. This difference in antibody effect contrasts with earlier experiences with nonmodulating but more strongly T-cell-depleting MoAbs of the same isotype, which prevent GVHD no matter whether applied in vitro or injected into donor or recipient mice. Our data indicate that CD3/TCR reexpression in marrow recipients with no circulating 17A2 is the reason why ex vivo donor cell treatment with anti-CD3 MoAb is comparatively ineffective. Our data, which allow separate evaluation of cell-depleting and cell-modulating antibody activity, help to explain previous clinical failure to suppress GVHD and provide evidence in favor of conditioning the marrow recipient with anti-CD3 MoAb as a therapeutic alternative.

CD6+ Donor Marrow T-Cell Depletion as the Sole Form of Graft-Versus-Host Disease Prophylaxis in Patients Undergoing Allogeneic Bone Marrow Transplant From Unrelated Donors

2001 ◽  
Vol 19 (4) ◽  
pp. 1152-1159 ◽  
Author(s):  
Robert J. Soiffer ◽  
Edie Weller ◽  
Edwin P. Alyea ◽  
Peter Mauch ◽  
Iain L. Webb ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Bone Marrow Transplant ◽  
Graft Versus Host Disease ◽  
Marrow Transplant ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis. PATIENTS AND METHODS: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5 Gy (26 points) of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment. RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 × 106/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P = .002), cytomegalovirus seronegative status (P = .04), and early disease status at bone marrow transplant (P = .05) were associated with superior survival. CONCLUSION: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.

Adoptive Transfer Of Ex Vivo “Educated” CD4+CD25+FoxP3+ Regulatory T Cells Effectively Treats Acute Graft Versus Host Disease Preserving Graft Versus Tumor Effect

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4485-4485
Author(s):  
Antonio Pierini ◽  
Dominik Schneidawind ◽  
Mareike Florek ◽  
Maite Alvarez ◽  
Yuqiong Pan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Tumor Cells ◽  
Graft Versus Host Disease ◽  
Adoptive Transfer ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Host Disease ◽  
Graft Versus Host

Donor derived regulatory T cells (Tregs) effectively prevent graft versus host disease (GVHD) in mouse models and in early phase clinical trials. Interleukin 2 (IL-2) therapy in patients with chronic GVHD (cGVHD) can increase Treg number and the Treg/CD4+ T cell ratio resulting in organ damage reduction and symptom relief. Less is known regarding Treg-based treatment for acute GVHD (aGVHD). In this study we evaluated the role of donor Treg cellular therapy for aGVHD treatment in well established murine models. T cell depleted bone marrow (TCD BM) from C57BL/6 mice was transplanted into lethally irradiated (8 Gy) BALB/C recipients together with 7.5x105 to 1x106/animal donor derived luc+ Tcons. Naturally occurring CD4+CD25+FoxP3+ donor type Tregs (nTregs) were purified from C57BL/6 donor mice. 2.5x105/mouse nTregs were injected at day 6 or 7 after transplant in mice that showed clear clinical signs of aGVHD and Tcon proliferation assessed by bioluminescence imaging (BLI). Survival analysis showed a favorable trend for nTreg treated mice, but the impact of this treatment was modest and not statistically significant (p 0.08). aGVHD is a disease characterized by the activation and rapid proliferation of alloreactive donor conventional T cells (Tcons) directed against host antigens, so one of the major obstacles of this approach is to overcome the large number and effector function of activated Tcons. Several studies have utilized ex vivo expansion of Tregs to increase their number with the goal of maintaining suppressive function. We developed a different strategy with the intent to “educate” Tregs to specifically suppress the reactive Tcon population. We incubated 2.5x105 donor derived Tregs with irradiated (3000 cGy) blood of aGVHD affected mice for 20 hours without further stimulation and injected the entire pool of these cells, termed educated Treg (eTregs), at day 7 or 8 after transplant and Tcon injection. Interestingly eTregs significantly improved aGVHD affected mouse survival (p = 0.0025 vs Tcons alone). BLI showed no difference between the groups (p = 0.85) because the treatment intervened after Tcon proliferation and activation was initiated. To evaluate eTreg impact on graft versus tumor (GVT) effects, we transplanted BALB/C mice with C57BL/6 TCD BM and 1x104/mouse luc+ A20 tumor cells along with 1x106/mouse donor Tcons and 2.5x105 eTregs. Mice that received TCD BM and A20 tumor cells alone died from progressive tumor growth, while mice that received Tcons died from GVHD without tumor engraftment. Further animals that received both Tcon and eTreg treatment did not have tumor engraftment demonstrating that eTregs do not impact Tcon mediated GVT effects. Further studies are ongoing to characterize the eTreg population as compared to nTreg, with respect to expression of activation markers and in functional assays. Our observations indicate that Tregs can be ex vivo educated to suppress in vivo reactive and proliferating Tcons. Moreover our data demonstrate that eTreg adoptive transfer is clinically feasible and promising. These findings may be relevant for the development of clinical grade Treg based cellular therapy for the treatment of conditions caused by immune dysregulation such as aGVHD and autoimmune diseases and for transplant tolerance induction. Disclosures: No relevant conflicts of interest to declare.

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