Human Transplantation Research Articles

Human iPSC-liver organoid transplantation reduces fibrosis through immunomodulation.

Donor organ shortages for transplantation remain a serious global concern, and alternative treatment is in high demand. Fetal cells and tissues have considerable therapeutic potential as, for example, organoid technology that uses human induced pluripotent stem cells (hiPSCs) to generate unlimited human fetal-like cells and tissues. We previously reported the in vivo vascularization of early fetal liver-like hiPSC-derived liver buds (LBs) and subsquent improved survival of recipient mice with subacute liver failure. Here, we show hiPSC-liver organoids (LOs) that recapitulate midgestational fetal liver promote de novo liver generation when grafted onto the surface of host livers in chemical fibrosis models, thereby recovering liver function. We found that fetal liver, a hematopoietic tissue, highly expressed macrophage-recruiting factors and antifibrotic M2 macrophage polarization factors compared with the adult liver, resulting in fibrosis reduction because of CD163+ M2-macrophage polarization. Next, we created midgestational fetal liver-like hiPSC-LOs by fusion of hiPSC-LBs to induce static cell-cell interactions and found that these contained complex structures such as hepatocytes, vasculature, and bile ducts after transplantation. This fusion allowed the generation of a large human tissue suitable for transplantation into immunodeficient rodent models of liver fibrosis. hiPSC-LOs showed superior liver function compared with hiPSC-LBs and improved survival and liver function upon transplantation. In addition, hiPSC-LO transplantation ameliorated chemically induced liver fibrosis, a symptom of liver cirrhosis that leads to organ dysfunction, through immunomodulatory effects, particularly on CD163+ phagocytic M2-macrophage polarization. Together, our results suggest hiPSC-LO transplantation as a promising therapeutic option for liver fibrosis.

Efficacy of chemically induced human hepatic progenitor cells from diseased liver against nonalcoholic steatohepatitis model.

Numerous chemical reprogramming techniques have been reported, rendering them applicable to regenerative medicine research. The aim of our study was to evaluate the therapeutic potential of human CLiP derived from clinical specimens transplanted into a nonalcoholic steatohepatitis (NASH) mouse model of liver fibrosis. We successfully generated chemically induced liver progenitor (CLiP), which exhibited progenitor-like characteristics, through stimulation with low-molecular-weight compounds. We elucidated their cell differentiation ability and therapeutic effects. However, the therapeutic efficacy of human CLiP generated from clinical samples on liver fibrosis, such as liver cirrhosis, remains unproven. Following a 4 week period, transplanted human CLiP in the NASH model differentiated into mature hepatocytes and demonstrated suppressive effects on liver injury markers (i.e., aspartate transaminase and alanine transaminase). Although genes related to inflammation and fat deposition did not change in the human CLiP transplantation group, liver fibrosis-related factors (Acta2 and Col1A1) showed suppressive effects on gene expression following transplantation, with approximately a 60% reduction in collagen fibers. Importantly, human CLiP could be efficiently induced from hepatocytes isolated from the cirrhotic liver, underscoring the feasibility of using autologous hepatocytes to produce human CLiP. Our findings demonstrate the effectiveness of human CLiP transplantation as a viable cellular therapy for liver fibrosis, including NASH liver. These results hold promise for the development of liver antifibrosis therapy utilizing human CLiP within the field of liver regenerative medicine.

Future directions for xenotransplantation in lungs.

Advancements in preclinical xenotransplant studies have opened doors for clinical heart and kidney xenotransplantation. This review assesses recent progress in lung xenotransplantation research and its potential clinical implications. The efficacy of the humanized von Willebrand factor in reducing platelet sequestration in ex-vivo and in-vivo lung xenotransplant models was showcased. Combining human tissue factor pathway inhibitor and CD47 expression with selectin and integrin inhibition delayed neutrophil and platelet sequestration. Enhanced expression of human complement regulatory proteins and thrombomodulin in genetically engineered pig lungs improved graft survival by reducing platelet activation and modulating coagulation disruptions. Knocking out the CMAH gene decreased antibody-mediated inflammation and coagulation activation, enhancing compatibility for human transplantation. Furthermore, CMAH gene knockout in pigs attenuated sialoadhesin-dependent binding of human erythrocytes to porcine macrophages, mitigating erythrocyte sequestration and anemia. Meanwhile, in-vivo experiments demonstrated extended survival of xenografts for up to 31 days with multiple genetic modifications and comprehensive treatment strategies. Experiments have uncovered vital insights for successful xenotransplantation, driving further research into immunosuppressive therapy and genetically modified pigs. This will ultimately pave the way for clinical trials designed to improve outcomes for patients with end-stage lung disease.

Antibody Mediated Rejection and T-cell Mediated Rejection Molecular Signatures Using Next-Generation Sequencing in Kidney Transplant Biopsies.

Recently, interest in transcriptomic assessment of kidney biopsies has been growing. This study investigates the use of NGS to identify gene expression changes and analyse the pathways involved in rejection. An Illumina bulk RNA sequencing on the polyadenylated RNA of 770 kidney biopsies was conducted. Differentially-expressed genes (DEGs) were determined for AMR and TCMR using DESeq2. Genes were segregated according to their previous descriptions in known panels (microarray or the Banff Human Organ Transplant (B-HOT) panel) to obtain NGS-specific genes. Pathway enrichment analysis was performed using the Reactome and Kyoto Encyclopaedia of Genes and Genomes (KEGG) public repositories. The differential gene expression using NGS analysis identified 6,141 and 8,478 transcripts associated with AMR and TCMR. While most of the genes identified were included in the microarray and the B-HOT panels, NGS analysis identified 603 (9.8%) and 1,186 (14%) new specific genes. Pathways analysis showed that the B-HOT panel was associated with the main immunological processes involved during AMR and TCMR. The microarrays specifically integrated metabolic functions and cell cycle progression processes. Novel NGS-specific based transcripts associated with AMR and TCMR were discovered, which might represent a novel source of targets for drug designing and repurposing.

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P<0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P=0.027; P=0.003; P=0.035; P=0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P<0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Quality Assessment by Bile Composition in Normothermic Machine Perfusion of Rat Livers.

Background: The persistent challenge of organ scarcity in liver transplantation leads to an escalating dependence on organs obtained from extended criteria donors (ECD). Normothermic machine perfusion (NMP) is used for improved preservation. Due to the mimicked invivo conditions during normothermic machine perfusion, the liver is metabolically active, which allows quality assessment during perfusion. Bile seems to be of rising interest in clinical studies, as it is easily collectible for analysis. As there are currently no data on biliary bile acids during NMP, the primary objective of this study was to use our experimental rodent NMP model to assess changes in bile composition through organ damage during perfusion to inform clinical evaluation of donor organs during NMP. Methods: Thirty livers from male Sprague-Dawley rats in five groups underwent 6 h of NMP using either erythrocyte-supplemented DMEM or Steen solution, with or without 30 min of warm ischemia time (WIT). We conducted regular measurements of AST, ALT, LDH, and urea levels in the perfusate at 3-hour intervals. Bile samples were analyzed for biliary pH, LDH, and gamma glutamyltransferase, as well as biliary bile acids via mass spectrometry and UHPLC. Results: Compared with regular livers, liver injury parameters were significantly higher in our donation after circulatory death (DCD) model. Bile production was significantly reduced in livers exposed to WIT, and the bile showed a significantly more alkaline pH. This correlated with the concentration of total bile acids, which was significantly higher in livers experiencing WIT. However, regular livers produced a higher total amount of biliary bile acids during perfusion. Taurocholic acid and its metabolites were most prominent. Secondary bile acids were significantly reduced during perfusion due to the missing enterohepatic circulation. Conclusions: WIT-induced liver injury affects bile composition within our small-animal NMP model. We hypothesize this phenomenon to be attributed to the energy-driven nature of bile secretion, potentially explaining why DCD livers produce less, yet more concentrated, bile. Our results may inform clinical studies, in which biliary bile acids might have a potential as a quantifiable viability marker in human NMP liver transplantation studies.

Uterus Transplantation: the Translational Evolution of a Clinical Breakthrough.

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important preclinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore criteria and describe the different procedures of preparation, surgeries, postoperative monitoring, and use of assisted reproduction in human uterus transplantation. We review the worldwide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore criteria and strict alignment with the IDEAL concept have resulted in the establishment of uterus transplantation as a novel, safe, and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.

Immune modulation permits tolerance and engraftment in a murine model of late-gestation transplantation

AbstractIn utero hematopoietic cell transplantation is an experimental nonmyeloablative therapy with potential applications in hematologic disorders, including sickle cell disease (SCD). Its clinical utility has been limited due to the early acquisition of T-cell immunity beginning at ∼14 weeks gestation, posing significant technical challenges and excluding treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days postcoitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable with that of the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T-cell depletion followed by central tolerance induction confirmed by donor–specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrated the successful application of this approach in the Townes mouse model of SCD. These findings confirm the developing fetal T-cell response as a barrier to LGT and support transient T-cell depletion as a safe and effective immunomodulatory strategy to overcome it.

Lymphotoxin β receptor and tertiary lymphoid organs shape acute and chronic allograft rejection.

Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αβ/lymphotoxin β receptor (LTαβ/LTβR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαβ/LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.

The transcriptional repressor B cell lymphoma 6 regulates CXCR3 chemokine and human leukocyte antigen II expression in endothelial cells

Interferon gamma (IFN-γ) induces an endothelial proimmunogenic phenotype through the JAK/STAT1 pathway, which can shape the activation of alloreactive leukocytes in transplant rejection. In immune cells, the DNA-binding protein B cell lymphoma 6 (BCL6) controls the transcription of inflammatory genes. This study tested if BCL6 modulates IFN-γ-induced gene expression in endothelial cells. In vitro, BCL6 was IFN-γ-inducible in primary human endothelium, along with CXCR3 chemokines and human leukocyte antigen (HLA). BCL6, HLA II, and CXCL9 were also increased in human cardiac transplants during acute rejection. Knockdown of BCL6 augmented, whereas overexpression and BTB domain inhibitors (BCL6-BTBi) suppressed, HLA II and CXCR3 chemokine expression but not HLA I. Further, BCL6 had a greater effect on HLA-DR and DP but was less involved in regulating HLA-DQ expression. The effect correlated with BCL6 binding motifs in or near affected genes. The BCL6 DNA recognition sequence was highly similar to that of STAT1, and BTBi reduced STAT1’s transcriptional activity in vitro. Our results show for the first time that BCL6 selectively controls IFN-γ-induced endothelial gene expression, advancing our understanding of the endogenous mechanisms regulating donor immunogenicity.

Cardiac Xenotransplantation: A Narrative Review.

Cardiac xenotransplantation (cXT) has emerged as a solution to heart donor scarcity, prompting an exploration of its scientific, ethical, and regulatory facets. The review begins with genetic modifications enhancing pig hearts for human transplantation, navigating through immunological challenges, rejection mechanisms, and immune responses. Key areas include preclinical milestones, complement cascade roles, and genetic engineering to address hyperacute rejection. Physiological counterbalance systems, like human thrombomodulin and endothelial protein C receptor upregulation in porcine xenografts, highlight efforts for graft survival enhancement. Evaluating pig and baboon donors and challenges with non-human primates illuminates complexities in donor species selection. Ethical considerations, encompassing animal rights, welfare, and zoonotic disease risks, are critically examined in the cXT context. The review delves into immune control mechanisms with aggressive immunosuppression and clustered regularly interspaced palindromic repeats associated protein 9 (CRISPR/Cas9) technology, elucidating hyperacute rejection, complement activation, and antibody-mediated rejection intricacies. CRISPR/Cas9's role in creating pig endothelial cells expressing human inhibitor molecules is explored for rejection mitigation. Ethical and regulatory aspects emphasize the role of committees and international guidelines. A forward-looking perspective envisions precision medical genetics, artificial intelligence, and individualized heart cultivation within pigs as transformative elements in cXT's future is also explored. This comprehensive analysis offers insights for researchers, clinicians, and policymakers, addressing the current state, and future prospects of cXT.

The Legality Of Human Organ Transplantation In Maqashidiah Perspective (A Study Of Fazlur Rahman’s Thought)

In the Qur'an, the prohibition of pigs is absolute, but the shari'ah realizes the preservation of Ḥifẓ an-Nafs (preserving life). Through an examination of Fazlur Rahman's thoughts, this study aims to look at the legality of transplantation through the eyes of contextual interpretation and contemporary Muslim thinkers. This research is literature research with qualitative method and sociology of religion approach. The purpose of shari'ah is to safeguard the interests of humans, damaging the honour of corpses is an individual benefit, while maintaining the safety of the living is a general benefit. Fazlur Rahman's understanding of deduction and induction states that reasoning starts from the specific to the general because that is the more general benefit that is prioritised. The benefits that can realise the five elements of the principle of the establishment of a law (Maqashid Sharia), namely the benefits that can protect religion, soul, offspring, mind, and property. The values of Maqashid Sharia are clearly illustrated in Fazlur Rahman's thoughts and decisions in punishing human organ transplants. This legality eliminates doubts in religion which indirectly eliminates doubts from an ethical point of view.

Combination of reduced post-transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft-versus-host disease in human leukocyte antigen-haploidentical peripheral blood stem-cell transplantation.

We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100mg/kg) (35.0%vs. 26.6%, p=0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p=0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD.

Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

1504-P: AdoShell, a Nonfibrotic Encapsulation System for Human Islets Transplantation, Shows Promising Results for Clinical Application as a Cure for People with Type 1 Diabetes

1504-P: AdoShell, a Nonfibrotic Encapsulation System for Human Islets Transplantation, Shows Promising Results for Clinical Application as a Cure for People with Type 1 Diabetes

A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia–reperfusion injury by integrating bioinformatics and machine learning algorithms

BackgroundLiver ischemia–reperfusion injury (LIRI) is closely associated with immune infiltration, which commonly occurs after liver surgery, especially liver transplantation. Therefore, it is crucial to identify the genes responsible for LIRI and develop effective therapeutic strategies that target immune response. Methylation modifications in mRNA play various crucial roles in different diseases. This study aimed to identify potential methylation-related markers in patients with LIRI and evaluate the corresponding immune infiltration.MethodsTwo Gene Expression Omnibus datasets containing human liver transplantation data (GSE12720 and GSE151648) were downloaded for integrated analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to investigate the functional enrichment of differentially expressed genes (DEGs). Differentially expressed methylation-related genes (DEMRGs) were identified by overlapping DEG sets and 65 genes related to N6-methyladenosine (m6A), 7-methylguanine (m7G), 5-methylcytosine (m5C), and N1-methyladenosine (m1A). To evaluate the relationship between DEMRGs, a protein–protein interaction (PPI) network was utilized. The core DEMRGs were screened using three machine learning algorithms: least absolute shrinkage and selection operator, random forest, and support vector machine-recursive feature elimination. After verifying the diagnostic efficacy using the receiver operating characteristic curve, we validated the expression of the core DEMRGs in clinical samples and performed relative cell biology experiments. Additionally, the immune status of LIRI was comprehensively assessed using the single sample gene set enrichment analysis algorithm. The upstream microRNA and transcription factors of the core DEMRGs were also predicted.ResultsIn total, 2165 upregulated and 3191 downregulated DEGs were identified, mainly enriched in LIRI-related pathways. The intersection of DEGs and methylation-related genes yielded 28 DEMRGs, showing high interaction in the PPI network. Additionally, the core DEMRGs YTHDC1, METTL3, WTAP, and NUDT3 demonstrated satisfactory diagnostic efficacy and significant differential expression and corresponding function based on cell biology experiments. Furthermore, immune infiltration analyses indicated that several immune cells correlated with all core DEMRGs in the LIRI process to varying extents.ConclusionsWe identified core DEMRGs (YTHDC1, METTL3, WTAP, and NUDT3) associated with immune infiltration in LIRI through bioinformatics and validated them experimentally. This study may provide potential methylation-related gene targets for LIRI immunotherapy.

Human Amniotic Epithelial Cell Transplantation is Safe and Well Tolerated in Patients with Compensated Cirrhosis: A First-in-Human Trial.

Placenta-derived human amniotic epithelial cells (hAEC) exhibit anti-inflammatory and anti-fibrotic effects in cirrhosis models. We conducted a first-in-human phase I clinical trial to assess the safety and tolerability of hAEC in adults with compensated cirrhosis. We examined increasing and repeated doses of hAEC in 9 patients in 3 cohorts. Cohort 1 patients received 0.5 × 106/kg hAEC in one IV infusion. Cohort 2 patients received 1 × 106/kg hAEC in one IV infusion. The patients in cohort 3 received 1 × 106/kg hAEC on days 0 and 28. Here, we report follow-up to post-infusion day 56 (D56), during which no serious adverse events occurred. Six patients experienced no study-related adverse events, while 3 patients reported mild (grade 1) headaches that were possibly infusion-related. A transient decrease in serum platelet count occurred in all patients, which returned to baseline screening values by day 5. FIB-4 values to assess fibrosis were significantly lower at D56. Although not statistically significant, serum AST levels and liver stiffness measurements at D56 were lower than those at baseline. The hepatic venous pressure gradient, a measure of portal hypertension, declined in 4 patients, did not change in 3 patients, and increased in 2 patients. In conclusion, intravenous infusion of allogeneic hAEC in patients with compensated cirrhosis at the doses used in this study was safe and well tolerated, with no difference observed between 1 and 2 doses. Decreased hepatic inflammation, liver stiffness, and portal hypertension support larger studies aimed at identifying patients who may benefit from this therapy. Clinical Trial registration: The trial was prospectively entered on the Australian Clinical Trials Registry (ANZCTR12616000437460).

Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial

IntroductionAcute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment...

A phase 1 study to evaluate the safety and preliminary efficacy of minnelide given alone or in combination with paclitaxel in advanced gastric cancer.

4033 Background: Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor. Studies using pancreatic cancer cell lines and human xenograft transplants demonstrated that Minnelide prevents tumor progression, increases survival, and causes tumor regression. This study aims to evaluate the safety and antitumor activity of Minnelide and its combination with paclitaxel in patients with advanced gastric cancer (AGC). Methods: This open-label, single-center, dose-escalation phase I study recruited adult patients with previously treated advanced gastric cancer. Patients received Minnelide per oral (PO) daily starting with 1.0 mg for 3weeks and 1week rest schedule, escalating to 1.25mg, and 1.5mg. In combination Regimen, patients received Minnelide starting at a dose of 0.25 mg and escalating by 0.25mg to 1.25mg plus paclitaxel 60-80 mg/m2 intravenously on Day 1, 8, and 15 of each cycle, administered in 4-week cycles. The primary objective was to assess the safety and determine the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy using RECIST v1.1, and survival analysis. Results: Among Regimen A (n = 11), two patients experienced dose-limiting toxicity (DLTs) (Minnelide 1.5 mg: Grade 3 abdominal pain). No DLTs occurred in combination treatment, Regimen B &amp; C (n=25). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4%) and abdominal pain (11.1%). In Regimen C, 71.5% achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. Notably, patients without previous exposure to paclitaxel (n = 4) in the last 2 cohorts of Regimen C, had a confirmed ORR of 50.0%, DCR of 75.0%, the median PFS was 5.3 months (95% CI NE-NE) and the median OS has not reached as some of the patients are still receiving treatment. Conclusions: The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on this Phase I experience a Phase II will be initiated in AGC patients. Clinical trial information: NCT05566834 .

Evaluating longitudinal cytomegalovirus-specific humoral immune responses and association with DNAemia risk in seropositive lung transplant recipients

BackgroundCytomegalovirus (CMV) is the most common viral infection among lung transplant recipients and is associated with chronic lung allograft dysfunction. There is a need for better therapeutics as well as biomarkers to enable effective stratification of CMV seropositive patient risk for developing CMV DNAemia to inform prophylaxis duration. MethodsCMV-specific IgG binding and functional responses were evaluated in a discovery cohort of longitudinal plasma samples from 51 CMV seropositive human lung transplant recipients, collected as part of the CTOT-20 and CTOT-22 consortium studies. Pre-transplant plasma from an additional 43 CMV seropositive lung transplant recipients were evaluated as a validation cohort. ResultsIn the discovery cohort with longitudinal samples, pre-transplant plasma IgG binding to CMV surface glycoproteins gH/gL, gH/gL/gO, and pentameric complex (PC), as well as neutralization of CMV in epithelial cells are associated with increased risk of CMV DNAemia post-prophylaxis. However, these results were not confirmed by the validation cohort. ConclusionWhile quantification of pre-transplant CMV-specific antibody responses showed association with DNAemia in the discovery cohort, additional clinical variables and/or known risk factors for CMV, such as patient CMV-specific T-cell responses, may need to be considered in combination with humoral immunity to effectively stratify risk of CMV DNAemia.