scholarly journals Low donor chimerism may be sufficient to prevent demyelination in adrenoleukodystrophy

JIMD Reports ◽  
2021 ◽  
Author(s):  
Takahiro Ikeda ◽  
Yuta Kawahara ◽  
Akihiko Miyauchi ◽  
Hitomi Niijima ◽  
Rieko Furukawa ◽  
...  
Keyword(s):  
Donor Chimerism

scholarly journals OP0307 A NOVEL TARGETED APPROACH TO ACHIEVE IMMUNE SYSTEM RESET: CD45-TARGETED ANTIBODY DRUG CONJUGATES AMELIORATE DISEASE IN PRECLINICAL AUTOIMMUNE DISEASE MODELS AND ENABLE AUTO-HSCT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 190-191
Author(s):  
G. Gillard ◽  
J. Proctor ◽  
S. Hyzy ◽  
O. Mikse ◽  
T. Lamothe ◽  
...  
Keyword(s):  
Single Dose ◽  
Immune System ◽  
Autoimmune Disease ◽  
Disease Onset ◽  
Effector Function ◽  
Disease Models ◽  
Cell Transplant ◽  
Site Specific ◽  
Donor Chimerism ◽  
Multiple Sclerosis Patients

Background:Resetting the immune system through autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment in selected patients with autoimmune diseases. AutoHSCT can induce long-term remission with 80% progression free survival in multiple sclerosis patients (Muraro 2017, Burt 2019). Use of autoHSCT in scleroderma patients has achieved superior outcomes in two randomized studies compared to standard of care (Tyndall 2014, Sullivan 2018). These impressive results are achieved by a combination of the eradication of autoreactive immune effector cells and re-establishment of self-tolerance, i.e., immune system reset. However, only a small fraction of eligible patients undergo autoHSCT, largely due to toxicity associated with current conditioning protocols.Objectives:As part of our goal to enable more patients to benefit from immune system reset, we have generated novel anti-human CD45 ADCs that cross react with nonhuman primates (NHP) and an anti-mouse CD45 ADC to model the approach in mouse models of AID.Methods:The human-targeted CD45-ADC is an affinity-matured mAb that targets an epitope present on all human CD45 isoforms, is cross-reactive with NHP CD45, and is conjugated to a payload that efficiently kills both quiescent and cycling cells. This ADC is engineered to eliminate Fc-mediated effector function, enable site-specific conjugation of linker/payload, and enable rapid clearance. This ADC was evaluated in vitro and in vivo in hNSG and NHPs. The murine tool ADC specifically targets the CD45.2 isoform of mouse CD45, and is also engineered to eliminate effector function, allow for site-specific conjugation of linker payload, and be rapidly cleared. The payload for this murine tool ADC is potent and preferentially kills dividing cells. This ADC was tested for the ability to enable immune reset and ameliorate autoimmune disease in multiple disease models.Results:The anti-human CD45-ADC showed efficient killing of human HSCs and human and cyno PBMC, including CD3+cells from healthy donors and patients with MS. In hNSG, single doses of the CD45-ADC were well-tolerated and led to substantial depletion of human cells. In NHPs, single doses of CD45-ADC were well tolerated and depleted both peripheral lymphocytes and HSCs. Administration of a single dose of anti-human CD45-ADC to hNSGs with sclerodermatous xenoGVHD resulted in depletion of human T cells and resolution of symptoms. A single-dose of the anti-mouse CD45-ADC enabled full myeloablation and complete durable donor chimerism with congenic HSCT at 16 weeks. In a murine immunization model of MS, MOG-induced EAE, a single dose of the CD45-ADC followed by congenic HSCT prior to disease onset enabled full donor chimerism, significantly delayed disease onset and reduced disease severity. We are generating additional data in an adoptive transfer model of EAE to confirm and extend these results. In a murine model of arthritis, therapeutic treatment with a single dose of the CD45-ADC followed by congenic HSCT enabled complete donor chimerism and halted disease progression, comparable to with the effects of an anti-TNFα antibody. The ADC is being further evaluated in a model of type 1 diabetes and those data will be presented. These data demonstrate that CD45-ADC conditioning followed by congenic HSCT is sufficient for full myeloablation and immune reset.Conclusion:These results demonstrate that targeted immune depletion with a single dose of CD45-ADC can enable auto-HSCT and immune reset in multiple AID indications without toxic side effects. Targeted conditioning with CD45-ADC may represent a better tolerated approach for removing disease-causing cells as part of immune reset through auto-HSCT and enable more patients to benefit.Disclosure of Interests:Geoffrey Gillard Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Jennifer Proctor Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Sharon Hyzy Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Oliver Mikse Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Tahirih Lamothe Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Sean McDonough Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Nicholas Clark Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Rahul Palchaudhuri Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Anjali Bhat Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Melissa Brooks Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Ganapathy Sarma Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Prashant Bhattarai Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Pranoti Sawant Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Brad Pearse Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Charlotte McDonagh Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Tony Boitano Shareholder of: Magenta, Employee of: Magenta, Michael Cooke Shareholder of: Magenta, Employee of: Magenta

scholarly journals 313: A cDNA-based assay for donor-chimerism analysis of epidermal langerhans cells

2007 ◽  
Vol 13 (2) ◽  
pp. 114
Author(s):  
S. Bakhtiar ◽  
K. Bender ◽  
T. Schmitt ◽  
C. Moench ◽  
A. Konur ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Donor Chimerism ◽  
Chimerism Analysis ◽  
Epidermal Langerhans Cells

Do We Need Full Donor Chimerism? How Alloreactive Cell Therapies without Substantial Engraftment Might Treat Hematologic Cancers

2017 ◽  
Vol 18 (3) ◽  
pp. 281-295 ◽  
Author(s):  
Elizabeth Krakow ◽  
Hui-Sheng Ai ◽  
Brian Shaffer ◽  
Jean-Sebastien Delisle ◽  
Kai-Xun Hu ◽  
...  
Keyword(s):  
Cell Therapies ◽  
Donor Chimerism

scholarly journals Risk Factors for Primary and Secondary Graft Failure in Allogenic Hematopoietic Cell Transplantation: A Single Center Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2046-2046
Author(s):  
Zeyad Al-Shaibani ◽  
Eshrak AL-Shaibani ◽  
Mats Remberger ◽  
Wilson Lam ◽  
Arjun Law ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Hematopoietic Cell Transplantation ◽  
Donor Lymphocyte Infusion ◽  
Malignant Diseases ◽  
Single Center ◽  
Donor Chimerism ◽  
Increased Risk

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for high risk hematological diseases and sustained engraftment of the donor stem cells is essential for transplant success. Graft failure (GF) is a rare, but serious complication post allo-HCT. In the presented study we aimed to assess the incidence, risk factors in a single-center population and as well the impact on transplant outcome. Methods: Between 01 January 2015 and 31 December 2018, 557 patients underwent allo-HCT at our center. Data was collected retrospectively and updated in June 2019. Cases were included regardless of the underlying diagnosis, disease status prior to transplant, preparative regimen, or stem cell source. Primary graft failure was defined as failure to achieve an absolute neutrophil count (ANC) of >500/ µL by 28 days after bone marrow (BM) or peripheral blood stem cell (PB) transplantation. In contrast, secondary graft failure was defined as cytopenias after initial engraftment (ANC <500/µL), with (a) donor chimerism of less than 5% or (b) falling donor chimerism with intervention such as second transplant or donor lymphocyte infusion (DLI) or (c) patient death due to cytopenias, and fall in donor chimerism, even if chimerism was >5%. Exclusion criteria for diagnosis of GF were (a) disease relapse (b) graft versus host disease or (c) other causes of cytopenias such as, viral infections, or drug induced. Outcomes examined included overall survival (OS), cumulative incidence of GF, non-relapse mortality (NRM) and cause of death. Results: Baseline characteristics are summarized in (Table 1). GF was seen in 43 (7.7%) patients. Of these 43 patients, 9 (21%) had primary GF, and 34 (79%) had secondary GF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (0.8- 3.0%) at day 100 and 6.5% (4.5-8.8%) at day 800. The median survival of patients following primary GF was 41 days versus 144 days in secondary GF. At one hundred days OS in primary GF was 22% and in secondary GF was 64%. The 1y and 2y OS for secondary GF was 33% and 28% respectively (Figure 1-A). Multivariable analysis demonstrated that the (a) diagnosis/transplant indication (MDS, myelofibrosis, lymphoma or non-malignant diseases) and (b) donor type (HLA-mismatched unrelated or haploidentical) were the only factors significantly associated with increased GF (Table 2). We determined the effect of more than one of these risk factors on the occurrence of graft failure as seen in (Figure 1-B). In the absence of any of the risk factors, the incidence of GF was 3.6%. If one risk factor was present, the incidence of GF was 9.9%, and if 2 risk factors were present, the incidence of GF was 24.5%. In primary GF, 5 patients underwent second allo-HCT. In secondary GF, 15 patients (44%) underwent a second allo-HCT and another 8 patients received donor lymphocyte infusion. All the patients with primary GF died because of graft failure and its associated complications. In secondary GF, 22 patients (51%) died, 30% of causes related to infections. Conclusions: Our study showed an increased risk for graft failure following the use of mismatched unrelated or haploidentical donors for diseases such as lymphoma, myelofibrosis, myelodysplastic syndrome and non-malignant diseases. As well, we found that a presence of two risk factors puts patients at clinically significant increased risk of graft failure. More intense conditioning therapy should be considered for patients with one but in particular two risk factors. Disclosures Michelis: CSL Behring: Other: Financial Support.

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