Allogeneic Cell Transplantation Research Articles

Non-human primate studies for cardiomyocyte transplantation-ready for translation?

Non-human primates (NHP) are valuable models for late translational pre-clinical studies, often seen as a last step before clinical application. The unique similarity between NHPs and humans is often the subject of ethical concerns. However, it is precisely this analogy in anatomy, physiology, and the immune system that narrows the translational gap to other animal models in the cardiovascular field. Cell and gene therapy approaches are two dominant strategies investigated in the research field of cardiac regeneration. Focusing on the cell therapy approach, several xeno- and allogeneic cell transplantation studies with a translational motivation have been realized in macaque species. This is based on the pressing need for novel therapeutic options for heart failure patients. Stem cell-based remuscularization of the injured heart can be achieved via direct injection of cardiomyocytes (CMs) or patch application. Both CM delivery approaches are in the late preclinical stage, and the first clinical trials have started. However, are we already ready for the clinical area? The present review concentrates on CM transplantation studies conducted in NHPs, discusses the main sources and discoveries, and provides a perspective about human translation.

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites.

The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20-25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells.

Clinical Outcomes and Treatment Patterns in Adults With FLT3-ITDmut+ Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the United States and Canada

Allogeneic hematopoietic cell transplantation (alloHCT) is used to treat patients with acute myeloid leukemia (AML) with internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITDmut+). However, the effect of different characteristics on outcomes after transplant is not fully understood. The aim of this study was to determine the impact of patient, disease, and transplant characteristics on clinical outcomes and trends in maintenance therapy for patients with FLT3-ITDmut+ AML who underwent their first alloHCT. This was an observational cohort study of adults ≥18 years who were recipients of human leukocyte antigen identical sibling, haploidentical, 8/8 or 7/8 unrelated, or cord blood donor alloHCT in the United States and Canada between 2014 and 2019. Patient, disease, and transplant characteristics were collected from Center for International Blood & Marrow Transplant Research between 2014 and 2022. Patients enrolled in the MORPHO clinical trial (NCT02997202) were excluded. Clinical outcomes were measured from the time of alloHCT by disease status: first complete remission (CR1), second or greater complete remission (≥CR2), or relapsed/refractory (R/R). The primary endpoints of this study were overall survival (OS) and leukemia-free survival (LFS). Key secondary endpoints included relapse after alloHCT, nonrelapse mortality (NRM), time from diagnosis to complete remission, time from complete remission to alloHCT, and maintenance therapy before and after alloHCT. Univariate analyses were conducted with Gray's test and log-rank test, while multivariable analyses were conducted using Cox proportional hazards models. A total of 3147 eligible patients (CR1, n = 2389; ≥CR2, n = 340; R/R, n = 418) were included. Most patient, disease, and transplant characteristics were similar between different disease statuses. In univariate analyses, disease status of CR1 compared with ≥CR2 or R/R was significantly (P < .001) associated with improved OS and LFS, and decreased probability of relapse; NRM likely differed across cohorts after alloHCT (P = .003). In multivariable analyses, patients with a disease status of ≥CR2 and R/R compared with CR1 had significantly shorter OS (hazard ratio [HR] 95% confidence interval [CI], 1.43 [1.19 to 1.72], P = .0001, and 2.14 [1.88 to 2.44], P < .0001, respectively). Patients with a disease status of CR1 at ≤2.6 months had better LFS compared with ≥CR2 and R/R (HR [95% CI], 2.03 [1.56 to 2.63], P < .0001 and 3.98 [3.07 to 5.17], P < .0001, respectively). Patients with a ≥CR2 or R/R disease status at ≤2.6 months had an increased likelihood of relapse compared with CR1 (HR [95% CI], 2.46 [1.82 to 3.33], P < .0001 and 4.68 [3.46 to 6.34], P < .0001, respectively). Disease status was not significantly associated with NRM. We also identified several additional patient, disease, and transplant characteristics that may have been associated with inferior OS and/or LFS and greater relapse and/or NRM. Maintenance therapy usage after alloHCT increased from 2014 to 2019 primarily due to increased FLT3 inhibitor use. In this largest study to date of patients from the United States and Canada with FLT3-ITDmut+ AML, disease status of CR1 at the time of alloHCT was associated with better clinical outcomes. Additional factors were identified that may also impact clinical outcomes, and in total, have the potential to inform clinical decision-making.

Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.

Effect of peptides of trophoblastic Β1 glycoprotein on peripheral and local T-regulatory lymphocytes level in Wistar rats with allogeneous bone marrow cell transplantation

Objective. The range of peptide drugs is expanding, but no drug with immunosuppressive activity has yet been found. Considering the fact that the trophoblastic β1-glycoprotein (PSG) is a fetoplacental protein with immunosuppressive activity, short peptide fragments of this protein were studied in the formation of an immune response in a situation of allogeneic cell transplantation. To study the effect of PSG peptides (YECE, YQCE, YVCS, and YACS) on the levels of peripheral and local T-regulatory cells (Treg) during the formation of an immune response to the introduction of allogeneic bone marrow cells (BM) in a dynamic experiment on Wistar rats.&#x0D; Materials and methods. We used an original host-versus-graft model in male Wistar rats without preconditioning of recipients. Animals were injected with PSG peptide fragment composition against a background of allogeneic intraperitoneal transplantation of BM cells in a dynamic experiment, in which the following parameters were evaluated: the level of peripheral "true" Tregs (CD4+CD25+FOXP3+), CD4+CD25-FOXP3+ cells, and FOXP3 expression in mesenteric lymph nodes. Material was collected on days 3 and 21 of the experiment.&#x0D; Results. PSG peptide administration against a background of allogeneic BM cells was found to reduce the absolute and relative amount of Treg in the peripheral blood of rats on days 3 and 21 of the experiment. PSG peptides against the background of the introduction of allogeneic BM cells reduced the absolute and relative amounts of CD4+CD25-FOXP3+ cells on the day 3 of the experiment. The introduction of PSG peptides against the background of the introduction of BM cells resulted in a relative decrease in FOXP3 expression in the T zone of mesenteric lymph nodes on the day 21 of the experiment.&#x0D; Conclusions. Thus, the PSG peptides did not have the expected effect on the level of peripheral and local Treg cells; moreover, the presence of the peptides led to a decrease in the number of these cells.

VEXAS syndrome: complete molecular remission after hypomethylating therapy

The VEXAS syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While various therapeutic strategies have been explored in case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation is considered the only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of the underlying UBA1 mutant clone outside the context of allogeneic HCT. Both patients received treatment with the hypomethylating agent azacitidine, and deep molecular remission triggered treatment de-escalation and even cessation with sustained molecular remission in one of them. Prospective studies are necessary to clarify which VEXAS patients will benefit most from hypomethylating therapy and to understand the variability in the response to different treatment strategies.

Engineering the best transplant outcome for high-risk acute myeloid leukemia: the donor, the graft and beyond

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies.

Induction of local immunosuppression in allogeneic cell transplantation by cell-type-specific expression of PD-L1 and CTLA4Ig

Immune rejection has long hindered allogeneic cell transplantation therapy. Current genetic modification approaches, including direct targeting of major histocompatibility complex or constitutive expression of immune inhibitory molecules, exhibit drawbacks such as severe adverse effects or elevated tumorigenesis risks. To overcome these limitations, we introduce an innovative approach to induce cell-type-specific immune tolerance in differentiated cells. By engineering human embryonic stem cells, we ensure the exclusive production of the immune inhibitory molecules PD-L1/CTLA4Ig in differentiated cells. Using this strategy, we generated hepatocyte-like cells expressing PD-L1 and CTLA4Ig, which effectively induced local immunotolerance. This approach was evaluated in a humanized mouse model that mimics the human immune system dynamics. We thus demonstrate a robust and selective induction of immunotolerance specific to hepatocytes, improving graft survival without observed tumorigenesis. This precise immune tolerance strategy holds great promise for advancing the development of stem cell-based therapeutics in regenerative medicine.

Development of a compact NMR system to measure pO2 in a tissue-engineered graft

Cellular macroencapsulation devices, known as tissue engineered grafts (TEGs), enable the transplantation of allogeneic cells without the need for life-long systemic immunosuppression. Islet containing TEGs offer promise as a potential functional cure for type 1 diabetes. Previous research has indicated sustained functionality of implanted islets at high density in a TEG requires external supplementary oxygen delivery and an effective tool to monitor TEG oxygen levels. A proven oxygen-measurement approach employs a 19F oxygen probe molecule (a perfluorocarbon) implanted alongside therapeutic cells to enable oxygen- and temperature- dependent NMR relaxometry. Although the approach has proved effective, the clinical translation of 19F oxygen relaxometry for TEG monitoring will be limited by the current inaccessibility and high cost of MRI. Here, we report the development of an affordable, compact, and tabletop 19F NMR relaxometry system for monitoring TEG oxygenation. The system uses a 0.5 T Halbach magnet with a bore diameter (19 cm) capable of accommodating the human arm, a potential site of future TEG implantation. 19F NMR relaxometry was performed while controlling the temperature and oxygenation levels of a TEG using a custom-built perfusion setup. Despite the magnet’s nonuniform field, a pulse sequence of broadband adiabatic full-passage pulses enabled accurate 19F longitudinal relaxation rate (R1) measurements in times as short as ∼2 min (R1 vs oxygen partial pressure and temperature (R2 > 0.98)). The estimated sensitivity of R1 to oxygen changes at 0.5 T was 1.62-fold larger than the sensitivity previously reported for 16.4 T. We conclude that TEG oxygenation monitoring with a compact, tabletop 19F NMR relaxometry system appears feasible.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for AML Patients with KMT2A Rearrangement: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Acute myeloid leukemia (AML) patients with KMT2A rearrangement (KMT2Ar, except for t(9;11)(p21.3;q23.3)/MLLT3::KMT2A) are classified as adverse risk in the 2022 European LeukemiaNet (ELN) classification. There is uncertainty on their outcome following allogeneic cell transplantation (allo-HCT). We compared, in an European Society for Blood and Marrow Transplantation (EBMT) global multi-center registry-based analysis, outcomes following an allogeneic stem cell transplantation (allo-HCT) with either a matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAPLO). Methods Data from 586 AML patients with KMT2Ar receiving a first allo-HCT in 183 EBMT centers from 2010-2022 were analyzed. All patients achieved first complete remission (CR1) before transplantation. Patients with t(9;11), without details on translocation, receiving mismatched UD (&amp;lt;10/10), umbilical cord blood, or grafts with ex-vivo manipulation were excluded. Univariant analysis and Cox regression models were used. Results KMT2A rearranged AML patients received allo-HCT from 201 MSD, 256 10/10 MUD, and 129 HAPLOs. For KMT2Ar type, t(6;11), t(11;19), t(10;11) or other translocations account for 27.8%, 37.5%, 23.9% and 10.8%, respectively. Peripheral blood was the major graft source (83.2%), and myeloablative conditioning accounted for the majority (60.2%) of all allo-HCTs. Engraftment rates were comparable in the three cohorts (MSD 99.5%, MUD 98.4% and HAPLO 96.9% p=0.17). AML relapse was the major cause of death in each donor cohort. On univariate analysis, HAPLO was associated with a lower 2-year relapse incidence (RI) (MSD 41.1%, MUD 37.2%, HAPLO 20%) but a higher 2-year non-relapse mortality (NRM) (MSD 6.1%, MUD 19.3%, HAPLO 21.3%) compared with MSD and MUD. The 180-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was lower in MSD (18.8%) than in MUD (31.3%) or HAPLO groups (26.5%), respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were comparable among the three cohorts. Lower RI was observed in patients with t(11;19) compared with t(6;11) or t(10;11). Complex karyotype (CK) (at least 3 abnormalities) or monosomal karyotype (MK) were both associated with higher RI compared with those without. In addition, in-vivo T cell depletion was related to lower intensive chronic GVHD (cGVHD) incidence. On multivariate analysis, HAPLO HCT was associated with lower RI (hazard ratio [HR=0.46], 95% CI 0.28-0.77; p&amp;lt;0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p&amp;lt;0.01) compared with MSD, while HAPLO had no significant impact on LFS, OS and GRFS. MUD HCT was associated with higher incidence of grade II-IV aGVHD (HR=1.82, 95% CI 1.19-2,78; p&amp;lt;0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p&amp;lt;0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p&amp;lt;0.05) compared with MSD (reference). Concerning translocation type, t(11;19) was associated with a lower RI (HR=0.64, 95% CI 0.43-0.94; p=0.022), a better LFS (HR=0.66, 95% CI 0.48-0.91; p=0.012), OS (HR=0.63, 95% CI 0.45-0.89; p=0.008) and GRFS (HR=0.75, 95% CI 0.57-1; p=0.049) compared with t(6;11)(reference). Translocations other than t(6;11), t(11;19) or t(10;11) were related to a lower RI (HR=0.45, 95% CI 0.24-0.87) and better OS (HR=0.57, 95% CI 0.34-0.95) compared to t(6;11). MK was associated with higher RI (HR=1.59, 95% CI 1.04-2.45; p&amp;lt;0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p&amp;lt;0.05). Conclusions For AML patients with KMT2Ar, HAPLO HCT was associated with a lower RI but higher NRM, leading to similar LFS, OS and GRFS compared with MUD and MSD HCTs. In the setting of allo-HCT, t(11;19) seems to be associated with favorable outcomes compared with other KMT2Ar.

Exopolysaccharide-Treated Dendritic Cells Effectively Ameliorate Acute Graft-versus-Host Disease

Graft-versus-host disease (GVHD) is a primary and often lethal complication of allogenic hematopoietic stem cell transplantation (HSCT). Prophylactic regimens for GVHD are given as standard pretransplantation therapy; however, up to 50% of these patients develop acute GVHD (aGVHD) and require additional immunosuppressive intervention. Using a mouse GVHD model, we previously showed that injecting mice with exopolysaccharide (EPS) from Bacillus subtilis prior to GVHD induction significantly increased 80-day survival after transplantation of complete allogeneic major histocompatibility complex-mismatched cells. To ask whether EPS might also inhibit GVHD in humans, we used humanized NSG-HLA-A2 mice and induced GVHD by i.v. injection of A2neg human peripheral blood mononuclear cells (PBMCs). Because we could not inject human donors with EPS, we transferred EPS-pretreated dendritic cells (DCs) to inhibit aGVHD. We derived these DCs from CD34+ human cord blood cells, treated them with EPS, and then injected them together with PBMCs into the NSG-HLA-A2 mice. We found that all mice that received untreated DCs were dead by day 35, whereas 25% of mice receiving EPS-treated DCs (EPS-DCs) survived. This DC cell therapy could be readily translatable to humans, because we can generate large numbers of human EPS-DCs and use them as an "off the shelf" treatment for patients undergoing HSCT.

The Current Status of Allogenic Islet Cell Transplantation.

Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell transplantation despite chronic immunosuppression. The Edmonton Protocol, however, remains limited by two obstacles: scarce organ donor availability and risks associated with chronic immunosuppression. To overcome these challenges, the search has begun for an alternative cell source. In 2006, pluripotency genomic factors, coined "Yamanaka Factors," were discovered, which reprogram mature somatic cells back to their embryonic, pluripotent form (iPSC). iPSCs can then be differentiated into specialized cell types, including islet cells. This discovery has opened a gateway to a personalized medicine approach to treating diabetes, circumventing the issues of donor supply and immunosuppression. In this review, we present a brief history of allogenic islet cell transplantation from the early days of pancreatic remnant transplantation to present work on encapsulating stem cell-derived cells. We review data on long-term outcomes and the ongoing challenges of allogenic islet cell and stem cell-derived islet cell transplant.

Secondary Malignancies in Patients after Allogeneic Hematopoietic Cell Transplantation at Triple the Incidence of Malignancies in Their Family Donors

The primary end point of this retrospective study was to determine the incidence, risk factors and clinical outcome of secondary malignancies in 951 patients who were given an allogeneic Hemopoietic Cell Transplantation (HCT) and to compare them with the incidence of malignancy observed in the cohort of 761 stem cell family donors. With a median follow-up of 20 years, 74 HCT recipients (40 males) developed SM at a median of 16.09 years since transplant and at a median age of 47 years. The 35-yr cumulative incidence of SM was 17.0% (95% confidence interval, 12.8-21.6%). In univariate analysis, factors associated with increased incidence of SM were cumulative (limited and extensive) chronic graft-versus-host disease (cGvHD) and duration of cumulative cGvHD &gt;24 months. By multivariate analysis, cumulative cGvHD was the only independent risk factor for SM. Patients with cGvHD had 2.85x higher risk as compared to patients without cGvHD (P&lt;0.001). With a median follow-up of 18 years, 13 family donors (7 males) out of 761 developed malignancy at a median of 15.04 years since stem cell donation and at a median age of 55 years. As compared to the cumulative incidence of SM observed in the cohort of transplant recipients, the cumulative incidence of malignancy in family donors at 35 years since stem cell donation was statistically lower [5.8% vs 17.0% (P=0.001)]. This study demonstrates that HCT recipients have a significantly higher incidence of developing post-transplant malignancy as compared to family donors and that cGvHD is a strong risk factor for SM development.

Effect of Short PSG Peptides on Inflammatory Markers in Allogeneic Bone Marrow Cell Transplantation in Wistar Rats.

Short linear peptide fragments of placental trophoblastic β1-glycoprotein (PSG) (YECE, YQCE, YVCS, and YACS) were studied in the context of their immunomodulatory effects at the level of inflammatory markers. The original host-versus-graft model was used in male Wistar rats without prior conditioning of recipient bone marrow. A composition of PSG peptide fragments was injected to animals after allogeneic transplantation of bone marrow cells in a dynamic experiment, inflammatory markers α1-acid glycoprotein (AGP, orosomucoid), α2-macroglobulin (α2M) were assayed by ELISA, and biochemical parameters (total protein, glucose, creatinine, and urea) were measured. The levels of α2M and AGP increased in response to allotransplantation, whereas administration of PSG peptides normalized serum α2M levels by the end of the experiment. The decrease in α2M level coincided with the independent effect of PSG peptide administration. The levels of total protein, glucose, creatinine, and urea in rat serum after allotransplantation were reduced throughout the experiment. Administration of PSG peptides contributed to normalization of serum total protein, creatinine, and urea levels by the end of the experiment. Administration of PSG peptides after allogeneic transplantation of bone marrow suspension contributed to normalization of the levels of α2M, total protein, creatinine, and urea, which can be interpreted as an anti-inflammatory effect of these peptides.

POSTER: AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

POSTER: AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

CTLA4-Ig alleviates the allogeneic immune responses against insulin-producing cells in a murine model of cell transplantation.

The adoptive transfer of insulin-producing cells (IPCs) is one of the promising treatments for insulin-dependent diabetes mellitus. While the use of allogeneic cell resources is inevitable in the case of a series of patients, alloimmune responses are a major barrier ahead of the successful implementation of allogeneic therapeutic cells. This study is aimed at evaluating the potential of CTLA4-Ig, as an approved immunomodulatory biologic, in protecting the IPCs against allogeneic immune responses. The C57BL/6 and BALB/c mice were used to establish a murine model of allogeneic cell transplantation. The mouse bone-marrow-derived mesenchymal stem cells were in vitro differentiated into IPCs, and the in vitro as well as the in vivo immune responses against IPCs were evaluated in the presence and absence of CTLA4-Ig. The allogeneic IPCs induced the in vitro activation of CD4+ T-cells, IFN-γ release, and the proliferation of lymphocytes, which all were controlled by CTLA4-Ig. Upon in vivo transfer of IPC into an allogeneic host, the splenic CD4+ and CD8+ T-cells exhibited a significant activation, and there was a significant donor-specific antibody response. Either of the mentioned cellular and humoral responses were modulated by a CTLA4-Ig regimen. This regimen also reduced the infiltration of CD3+ T-cells into the IPC injection site along with the improved overall survival of diabetic mice. CTLA4-Ig could be a complementary therapy for improving the efficacy of allogeneic IPC therapy through modulating the cellular and humoral responses that can lead to prolonged durability of IPCs within an allogeneic host.

Correction of T-Cell Repertoire and Autoimmune Diabetes in NOD Mice by Non-myeloablative T-Cell Depleted Allogeneic HSCT.

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated the ability of this relatively safe transplant modality to eliminate autoimmune T-cell clones in the NOD mouse model which spontaneously develop T1DM. Our results demonstrate that using this approach, marked durable chimerism is attained, without any transplant-related mortality, and with a very high rate of diabetes prevention. TCR sequencing of transplanted mice showed profound changes in the T-cell repertoire and decrease in the prevalence of specific autoimmune T-cell clones directed against pancreatic antigens. This approach could be considered as strategy to treat people destined to develop T1DM but with residual beta cell function, or as a platform for prevention of beta cell destruction after transplantation of allogenic beta cells.

The European landscape on allogeneic haematopoeietic cell transplantation in Chronic Lymphocytic Leukaemia between 2009 and 2019: a perspective from the Chronic Malignancies Working Party of the EBMT.

Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009-2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2-3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness.

Immune Responses to Sequential Binocular Transplantation of Allogeneic Retinal Progenitor Cells to the Vitreous Cavity in Mice.

Intravitreal transplantation of allogeneic human retinal progenitor cells (hRPCs) holds promise as a treatment for blinding retinal degenerations. Prior work has shown that neural progenitors are well-tolerated as allografts following single injections; however, sequential delivery of allogeneic cells raises the potential risk of host sensitization with subsequent immune rejection of grafts. The current study was designed to assess whether an immune response would be induced by repeated intravitreal transplants of allogeneic RPCs utilizing the mouse animal model. We injected murine retinal progenitor cells (gmRPCs), originally derived from donors with a C57BL/6 genetic background, into BALB/c recipient mice in order to provide safety data as to what might be expected following repeated treatment of patients with allogeneic human cell product. Immune responses to gmRPCs were mild, consisting of T cells, B cells, neutrophils, and natural killer cells, with macrophages clearly the predominating. Animals treated with repeat doses of gmRPCs did not show evidence of sensitization, nor was there immune-mediated destruction of the grafts. Despite the absence of immunosuppressive treatments, allogeneic gmRPC grafts survived following repeat dosing, thus providing support for the preliminary observation that repeated injection of allogeneic RPCs to the vitreous cavity is tolerated in patients with retinitis pigmentosa.