The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species.Liver structure is considered to favor a tolerogenic environment.The peripheral tolerance mechanisms also pl...The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species.Liver structure is considered to favor a tolerogenic environment.The peripheral tolerance mechanisms also play a role in spontaneous tolerance to liver graft.In a clinical setting,the main challenge nowadays facing liver transplantation is minimization of immunosuppression with the goal of donor-specific tolerance.Mechanisms involved in tolerance to transplanted organs are complex and partly unknown.A significant mechanism in tolerance induction is chimerism.Chimerism can be induced through transplantation of allogeneic donor bone marrow/stem cells under appropriate host conditioning.This review focuses on the tolerance mechanisms in liver transplantation and highlights the role of chimerism and allogeneic bone marrow/stem cell transplantation in tolerance development.展开更多
Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleo...Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.展开更多
Chimerism is defined as the presence in a subject of more than one stable and genetically distinct cell line;cases reported so far include both patients with ambiguous genitalia and healthy subjects. The biological me...Chimerism is defined as the presence in a subject of more than one stable and genetically distinct cell line;cases reported so far include both patients with ambiguous genitalia and healthy subjects. The biological mechanisms, which may give origin to chimeras, are complex, and can be understood by analyzing DNA samples of the patients and their parents using molecular techniques. The objective of this study is to identify the mechanism of origin for the 2 cases we report. The first patient is a phenotipically normal girl with normal (external and internal) genitalia;the second patient had ambiguous genitalia and underwent surgery. DNA was purified from blood samples and, limited to Patient 1, from a sample of biliary cyst. Short tandem repeat polymorphisms were analyzed in order to identify the relative parental contribution to the patients. Molecular analyses carried out on the first patient are not fully informative because of two possible explanations (i.e. parthenogenetic and andrognetic chimera), while in the second case the presence of four alleles at some markers allowed us to identify a tetragametic chimera originnated from the fusion of two distinct embryos. Studies carried on one single tissue may not always be conclusive as they do not allow the precise identification of the mechanism of origin. In these cases, studies on more tissues are strongly suggested.展开更多
BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SO...BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.展开更多
Background Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation （HSCT） and sequential adoptive immunotherapy by do...Background Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation （HSCT） and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. Methods A panel of 29 selected sequence polymorphism （SP） markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Results Recipient genotype discrimination was possible in 97.0% （98 of 101） with a mean number of 2.5 （1-7） informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation （r） of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high （standard deviation 〈1.85%） which might significantly improve detection accuracy of changes in autologous signals early in the post-transplantation course of follow-up. The main advantage of the real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. Conclusion This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.展开更多
Background Chimerism analysis is an important tool for the surveillance of post-transplant engraftment. It offers the possibility of identifying impending graft rejection and recurrence of underlying malignant or non-...Background Chimerism analysis is an important tool for the surveillance of post-transplant engraftment. It offers the possibility of identifying impending graft rejection and recurrence of underlying malignant or non-malignant disease. Here we investigated the quantitative chimerism kinetics of 21 relapsed leukemia patients after allogeneic hematopoietic stem cell transplantation （HSCT）. Methods A panel of 29 selected sequence polymorphism （SP） markers was screened by real-time polymerase chain reaction （RT-PCR） to obtain the informative marker for every leukemia patient. Quantitative chimerism analysis of bone marrow （BM） samples of 21 relapsed patients and 20 patients in stable remission was performed longitudinally. The chimerisms of BM and peripheral blood （PB） samples of 14 patients at relapse were compared. Results Twenty-one patients experienced leukemia relapse at a median of 135 days （range, 30-720 days） after transplantation. High recipient chimerism in BM was found in all patients at relapse, and increased recipient chimerism in BM samples was observed in 90% （19/21） of patients before relapse. With 0.5% recipient DNA as the cut-off, median time between the detection of increased recipient chimerism and relapse was 45 days （range, 0-120 days）, with 76% of patients showing increased recipient chimerism at least 1 month prior to relapse. Median percentage of recipient DNA in 20 stable remission patients was 0.28%, 0.04%, 0.05%, 0.05%, 0.08%, and 0.05% at 1, 2, 3, 6, 9, and 12 months, respectively, after transplantation. This was concordant with other specific fusion transcripts and fluorescent in situ hybridization examination. The recipient chimerisms in BM were significantly higher than those in PB at relapse （P=-0.001）. Conclusions This SP-based RT-PCR assay is a reliable method for chimerism analysis. Chimerism kinetics in BM can be used as a marker of impending leukemia relapse, especially when no other specific marker is available. Based on our findings, we recommend examining not only PB samples but also BM samples in HSCT patients.展开更多
Background The blood vessels of a transplanted organ are the interface between donor and recipient. The endothelium in the blood vessels is thought to be the major target for graft rejection. Endothelial cells of a tr...Background The blood vessels of a transplanted organ are the interface between donor and recipient. The endothelium in the blood vessels is thought to be the major target for graft rejection. Endothelial cells of a transplanted organ can be of recipient origin after transplantation. In this study, we tested whether endothelial chimerism correlated with the graft rejection and cold ischemia. Methods We studied the biopsy samples from 34 renal transplants of female recipients who received the kidney from a male donor for the presence of endothelial cells of recipient origin. We examined the tissue sections of renal biopsy samples by fluorescence in situ hybridization （FISH） for the presence of endothelial cells containing two X chromosomes using a biotinylated Y chromosome probe and digoxigenin labelled X chromosome probe, and then analyzed the relationship between the endothelial cell chimerism and the rejection and cold ischemia. Results Endothelial chimerism was common and irrespective of rejections （P〉0.05）. The cold ischemic time of chimerism group was longer than no chimerism group （（14.83±4.03） hours vs （11.27±3.87） hours, P〈0.05）. Conclusions There is no correlation between the percentage of recipient endothelial cells in vascular endothelial cells and the type of graft rejection. The endothelium damaged by ischemic injury might be repaired by the endothelial cells from the recipient.展开更多
Objective: To determine the sensitivity and significance of B-cell chimerism for the detection of early engraftment, transplant rejection, and disease relapse. Methods: The dynamic monitoring of lineage-specific cell ...Objective: To determine the sensitivity and significance of B-cell chimerism for the detection of early engraftment, transplant rejection, and disease relapse. Methods: The dynamic monitoring of lineage-specific cell subtypes (B, T, and NK cells) was made in 20 B-cell acute lympho-blastic leukemia (B-ALL) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the early period after allo-HSCT, the latest establishment of B-cell complete chimerism (CC) was observed in a majority of patients. Results: The percentage of donor cells of B-cell lineage was lower than the percent of T-cell lineage in most of the mixed chimerism (MC) patients. During graft rejection, the frequency of patients with decreasing MC of B-, T-and NK-cell lineage were 5/5, 2/5, and 2/5. When disease relapsed, five patients showed a faster decrease of the donor percent of B-cells than of T-or NK-cells. Only one patient displayed a more rapid decrease in NK-cells than in T-or B-cells. Conclusion: Monitoring of B-cell chimerism after HSCT seems to be valuable for insuring complete engraftment, anticipating graft rejection, and relapse in B-ALL patients. Copyright ? 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).展开更多
Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the ...Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.展开更多
Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive micro...Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive microenvironments,CAR-T cell exhaustion,and unmanageable adverse events.Diverse modifications have been introduced into conventional CAR-T cells to overcome these obstacles;examples include addition of recognition sites to prevent immune escape,coupling of cytokine domains to enhance killing ability,blocking of immune checkpoint signals to resist tumor microenvironments,and inclusion of suicide systems or safety switches to improve safety and flexibility.With increasing understanding of the importance of metabolism and epigenetics in cancer and cytotherapy,glycolysis,methylation,and acetylation have become crucial CAR-T cell therapeutic targets.Universal and in situ CAR-T cells are also expected to be used in clinical applications,thus providing hope to patients with relapsed/refractory lymphomas.展开更多
Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This stud...Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This study aims to engineer chitosan-coated nanostructure lipid carriers(NLCs)loaded with gefitinib(GF)and simvastatin(SV)as CCT for HCC.Methods:Both GF and SV-loaded nanostructure lipids carriers(GFSVNLC)and chitosan-capped GF and SV-loaded nanostructure lipids carriers(CGFSVNLC)formulations were assembled by topdown techniques.Moreover,particle size(PS),zeta potential(ZP),and polydispersity index(PDI)were measured by Zetasizer.The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model.The cytotoxic,and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC.The effect of GF,SV,and NLC composition on JNK3,HDAC6,and telomerase was studied using molecular docking simulation(MDS).Results:The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent,CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP.Moreover,both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis.The treatment of HepG2 cells with GFSVNLC,and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50.Equally,the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV,GFSVNLC,and CGFSVNLC compared to the control group.Additionally,GF,SV,stearic acid(SA),and oleic acid(OA)modulate the activity of JNK3,HDAC6,and telomerase.Conclusions:This study suggests CGFSVNLC achieves codelivery,selective targeting,and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death.Mechanistically,CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival.CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.展开更多
Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CA...Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CAR-NK cell therapy has enabled the development of“off-the-shelf”products that bypass the lengthy and expensive cell manufacturing process1.展开更多
Glypican-3(GPC3)is a tumor-associated antigen that is specifically expressed in hepatocellular carcinoma(HCC)and having relatively low levels in normal tissues.This unique expression pattern positions GPC3 as a potent...Glypican-3(GPC3)is a tumor-associated antigen that is specifically expressed in hepatocellular carcinoma(HCC)and having relatively low levels in normal tissues.This unique expression pattern positions GPC3 as a potential target for precision therapy and drug development in HCC.Recent studies have shown significant advancements in GPC3-targeted therapies and immunotherapies,particularly for patients with advanced or treatment-resistant HCC.Although certain clinical trials have yielded suboptimal results,numerous ongoing studies continue to explore its therapeutic efficacy.This mini-review focuses on the latest research developments regarding GPC3 as a therapeutic target across various HCC treatment strategies,including monoclonal antibodies,bispecific antibodies,chimeric antigen receptor-T-cell therapies,and other innovative approaches.In addition,the limitations of GPC3-targeted therapies and their future application prospects in HCC treatment are discussed.The review particularly emphasizes the unmet need for future research directions,such as combination immuno-therapy strategies and novel drug designs.Through the integration of innovative technologies and clinical validation,GPC3 holds strong potential as a promising breakthrough in the treatment of HCC,offering new opportunities for enhancing patient outcomes and improving therapeutic efficacy.展开更多
Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related mortality worldwide1.The primary treatment options for this disease are surgical resection and liver transplantation.Unfortunately,most HCC ca...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related mortality worldwide1.The primary treatment options for this disease are surgical resection and liver transplantation.Unfortunately,most HCC cases are diagnosed in advanced stages and are inoperable.Even after surgery,the long-term prognosis remains unsatisfactory,because of a high recurrence rate.展开更多
Objective Acute myeloid leukemia(AML)is a highly heterogeneous disease,and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients.Consequently,there is an urgent need for a n...Objective Acute myeloid leukemia(AML)is a highly heterogeneous disease,and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients.Consequently,there is an urgent need for a novel therapeutic approach for AML.Methods DNMT3A mRNA and protein expression were confirmed in DNMT3A-mutant AML cells via RT-qPCR and Western blotting.Cell proliferation and apoptosis were assessed via CCK-8 and Annexin V/PI staining,respectively.Flow cytometry was used to analyze surface antigens and CD44v6 CAR-T-cell transfection efficiency.CD44v6-directed CAR plasmids were constructed,and lentiviruses were packaged.Methylation-specific PCR was used to evaluate differences in promoter methylation,whereas ELISA was used to measure cytokine secretion.Results In this study,we found that the DNMT3A-mutant group presented significantly increased expression of CD44v6 on the cell surface.Methylation of the CD44 promoter region was lower in the mutant group than in the control group.CD44v6 CAR-T cells exhibited specific cytotoxicity against DNMT3A-mutant AML cells.Furthermore,pretreatment with low concentrations of decitabine significantly enhanced the killing effect of CD44v6 CAR-T cells on DNMT3A-mutant AML cells(P<0.05).Additionally,decitabine treatment upregulated the expression of CD44v6 on the surface of DNMT3A-mutant AML cells(P<0.05).Conclusion CD44v6 is a promising CAR-T-cell therapy target in AML patients with DNMT3A mutations.Notably,treatment with decitabine resulted in increased CD44v6 expression on the cell surface of DNMT3A-mutant AML cells.This increase in CD44v6 expression facilitates improved recognition and targeting by CD44v6 CAR-T cells.展开更多
Autologous stem cell transplantation(ASCT)and chimeric antigen receptor T-cell(CAR-T)therapy represent pivotal treatments for hematologic malignancies,each with distinct strengths and limitations.ASCT reduces tumor bu...Autologous stem cell transplantation(ASCT)and chimeric antigen receptor T-cell(CAR-T)therapy represent pivotal treatments for hematologic malignancies,each with distinct strengths and limitations.ASCT reduces tumor burden through myeloablative conditioning but remains susceptible to relapse,while CAR-T therapy precisely targets malignant cells but encounters challenges,including cytokine release syndrome(CRS),immune effector cell-associated neurotoxicity syndrome(ICANS),and limited persistence.Emerging evidence suggests that combining ASCT with CAR-T therapy yields synergistic effects.ASCT reshapes the immune microenvironment,lowers immunosuppressive cells and CRS risk,while CAR-T eliminates residual disease and promotes immune recovery.Clinical trials in relapsed/refractory B-cell lymphomas and multiple myeloma demonstrate complete remission rates(CRR)of 72%-100%and two-year progression-free survival(PFS)rates of 59%-83%,with severe CRS/ICANS incidences below 10%.However,the precise mechanisms underlying this synergy,optimal timing of CAR-T infusion after ASCT,and ideal dosing regimens require further definition.Future research should prioritize large-scale,randomized controlled trials and establish standardized protocols for toxicity management to maximize therapeutic benefits.By integrating the complementary strengths of ASCT and CAR-T,this combination strategy represents a promising approach for improving outcomes in high-risk hematologic malignancies;however,additional studies are necessary to validate its efficacy and expand its clinical applicability.展开更多
Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the...Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.展开更多
Objective To develop a novel prognostic scoring system for severe cytokine release syndrome(CRS)in patients with B-cell acute lymphoblastic leukemia(B-ALL)treated with anti-CD19 chimeric antigen receptor(CAR)-T-cell t...Objective To develop a novel prognostic scoring system for severe cytokine release syndrome(CRS)in patients with B-cell acute lymphoblastic leukemia(B-ALL)treated with anti-CD19 chimeric antigen receptor(CAR)-T-cell therapy,aiming to optimize risk mitigation strategies and improve clinical management.Methods This single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023.These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data,documented CRS grading,and at least 3 months of follow-up.Data on patient demographics,treatment history,laboratory parameters,CAR-T-cell characteristics,safety,and efficacy endpoints were collected.CRS severity was graded according to the 2019 ASTCT consensus criteria.Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity,and a prognostic model was constructed.Results The overall incidence of CRS was 67.2%,with 13.6%having grade≥3(severe)CRS.Higher baseline and post-lymphodepletion minimal residual disease(MRD)levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS.Inflammatory markers(CRP,ferritin,and IL-6)and coagulation dysfunction(APTT)on day 7 post-infusion were also predictive of CRS severity.The prognostic model incorporating these factors demonstrated robust discriminatory ability,with an area under the ROC curve of 0.875.Conclusion This study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy.The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS.Further validation in larger,prospective cohorts is warranted.展开更多
This paper presents a novel neuro-adaptive cellular immunotherapy control strategy that leverages the high efficiency and applicability of chimeric antigen receptor-engineered T(CAR-T)cells in treating cancer.The prop...This paper presents a novel neuro-adaptive cellular immunotherapy control strategy that leverages the high efficiency and applicability of chimeric antigen receptor-engineered T(CAR-T)cells in treating cancer.The proposed real-time control strategy aims to maximize tumor regression while ensuring the safety of the treatment.A dynamic growth model of cancer cells under the influence of cellular immunotherapy is established for the first time,which aligns with clinical experimental results.Utilizing the backstepping method,a novel consensus reference model is designed to consider the characteristics of cancer cell changes during the treatment process and conform to clinical rules.The model is segmented and continuous,with cancer cells expected to decrease in a step-like manner.Furthermore,a prescribed performance mechanism is constructed to maintain the therapeutic effect of the proposed scheme while ensuring the transient performance of the system.Through the analysis of Lyapunov stability,all signals within the closed-loop system are proven to be semiglobally uniformly ultimately bounded(SGUUB).Simulation results demonstrate the effectiveness of the proposed control strategy,highlighting its potential for clinical application in cancer treatment.展开更多
Dear Editor,Thyroid-associated ophthalmopathy(TAO),or Graves’ophthalmopathy(GO),is a complex autoimmune condition characterized by eye symptoms such as proptosis,lid retraction,and periorbital swelling,often associat...Dear Editor,Thyroid-associated ophthalmopathy(TAO),or Graves’ophthalmopathy(GO),is a complex autoimmune condition characterized by eye symptoms such as proptosis,lid retraction,and periorbital swelling,often associated with thyroid dysfunction[1].Current drug treatments primarily include glucocorticoids,traditional immunosuppressants,and novel biologics such as Teprotumumab.While able to alleviate symptoms,they often do not adequately address irreversible conditions such as visual impairment and fi brosis,and it is diffi cult to avoid long-term medication side eff ects.In this context,exploring new therapeutic avenues for TAO to improve patients’prognosis and quality of life is meaningful.We proposed chimeric antigen receptor(CAR)-based therapy as a novel treatment orientation.展开更多
文摘The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species.Liver structure is considered to favor a tolerogenic environment.The peripheral tolerance mechanisms also play a role in spontaneous tolerance to liver graft.In a clinical setting,the main challenge nowadays facing liver transplantation is minimization of immunosuppression with the goal of donor-specific tolerance.Mechanisms involved in tolerance to transplanted organs are complex and partly unknown.A significant mechanism in tolerance induction is chimerism.Chimerism can be induced through transplantation of allogeneic donor bone marrow/stem cells under appropriate host conditioning.This review focuses on the tolerance mechanisms in liver transplantation and highlights the role of chimerism and allogeneic bone marrow/stem cell transplantation in tolerance development.
文摘Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.
文摘Chimerism is defined as the presence in a subject of more than one stable and genetically distinct cell line;cases reported so far include both patients with ambiguous genitalia and healthy subjects. The biological mechanisms, which may give origin to chimeras, are complex, and can be understood by analyzing DNA samples of the patients and their parents using molecular techniques. The objective of this study is to identify the mechanism of origin for the 2 cases we report. The first patient is a phenotipically normal girl with normal (external and internal) genitalia;the second patient had ambiguous genitalia and underwent surgery. DNA was purified from blood samples and, limited to Patient 1, from a sample of biliary cyst. Short tandem repeat polymorphisms were analyzed in order to identify the relative parental contribution to the patients. Molecular analyses carried out on the first patient are not fully informative because of two possible explanations (i.e. parthenogenetic and andrognetic chimera), while in the second case the presence of four alleles at some markers allowed us to identify a tetragametic chimera originnated from the fusion of two distinct embryos. Studies carried on one single tissue may not always be conclusive as they do not allow the precise identification of the mechanism of origin. In these cases, studies on more tissues are strongly suggested.
文摘BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.
文摘Background Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation （HSCT） and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. Methods A panel of 29 selected sequence polymorphism （SP） markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Results Recipient genotype discrimination was possible in 97.0% （98 of 101） with a mean number of 2.5 （1-7） informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation （r） of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high （standard deviation 〈1.85%） which might significantly improve detection accuracy of changes in autologous signals early in the post-transplantation course of follow-up. The main advantage of the real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. Conclusion This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.
文摘Background Chimerism analysis is an important tool for the surveillance of post-transplant engraftment. It offers the possibility of identifying impending graft rejection and recurrence of underlying malignant or non-malignant disease. Here we investigated the quantitative chimerism kinetics of 21 relapsed leukemia patients after allogeneic hematopoietic stem cell transplantation （HSCT）. Methods A panel of 29 selected sequence polymorphism （SP） markers was screened by real-time polymerase chain reaction （RT-PCR） to obtain the informative marker for every leukemia patient. Quantitative chimerism analysis of bone marrow （BM） samples of 21 relapsed patients and 20 patients in stable remission was performed longitudinally. The chimerisms of BM and peripheral blood （PB） samples of 14 patients at relapse were compared. Results Twenty-one patients experienced leukemia relapse at a median of 135 days （range, 30-720 days） after transplantation. High recipient chimerism in BM was found in all patients at relapse, and increased recipient chimerism in BM samples was observed in 90% （19/21） of patients before relapse. With 0.5% recipient DNA as the cut-off, median time between the detection of increased recipient chimerism and relapse was 45 days （range, 0-120 days）, with 76% of patients showing increased recipient chimerism at least 1 month prior to relapse. Median percentage of recipient DNA in 20 stable remission patients was 0.28%, 0.04%, 0.05%, 0.05%, 0.08%, and 0.05% at 1, 2, 3, 6, 9, and 12 months, respectively, after transplantation. This was concordant with other specific fusion transcripts and fluorescent in situ hybridization examination. The recipient chimerisms in BM were significantly higher than those in PB at relapse （P=-0.001）. Conclusions This SP-based RT-PCR assay is a reliable method for chimerism analysis. Chimerism kinetics in BM can be used as a marker of impending leukemia relapse, especially when no other specific marker is available. Based on our findings, we recommend examining not only PB samples but also BM samples in HSCT patients.
基金This study was supported by the grant from the Capital Medical Progressing and Research Funds(No.2005-3093).
文摘Background The blood vessels of a transplanted organ are the interface between donor and recipient. The endothelium in the blood vessels is thought to be the major target for graft rejection. Endothelial cells of a transplanted organ can be of recipient origin after transplantation. In this study, we tested whether endothelial chimerism correlated with the graft rejection and cold ischemia. Methods We studied the biopsy samples from 34 renal transplants of female recipients who received the kidney from a male donor for the presence of endothelial cells of recipient origin. We examined the tissue sections of renal biopsy samples by fluorescence in situ hybridization （FISH） for the presence of endothelial cells containing two X chromosomes using a biotinylated Y chromosome probe and digoxigenin labelled X chromosome probe, and then analyzed the relationship between the endothelial cell chimerism and the rejection and cold ischemia. Results Endothelial chimerism was common and irrespective of rejections （P〉0.05）. The cold ischemic time of chimerism group was longer than no chimerism group （（14.83±4.03） hours vs （11.27±3.87） hours, P〈0.05）. Conclusions There is no correlation between the percentage of recipient endothelial cells in vascular endothelial cells and the type of graft rejection. The endothelium damaged by ischemic injury might be repaired by the endothelial cells from the recipient.
文摘Objective: To determine the sensitivity and significance of B-cell chimerism for the detection of early engraftment, transplant rejection, and disease relapse. Methods: The dynamic monitoring of lineage-specific cell subtypes (B, T, and NK cells) was made in 20 B-cell acute lympho-blastic leukemia (B-ALL) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the early period after allo-HSCT, the latest establishment of B-cell complete chimerism (CC) was observed in a majority of patients. Results: The percentage of donor cells of B-cell lineage was lower than the percent of T-cell lineage in most of the mixed chimerism (MC) patients. During graft rejection, the frequency of patients with decreasing MC of B-, T-and NK-cell lineage were 5/5, 2/5, and 2/5. When disease relapsed, five patients showed a faster decrease of the donor percent of B-cells than of T-or NK-cells. Only one patient displayed a more rapid decrease in NK-cells than in T-or B-cells. Conclusion: Monitoring of B-cell chimerism after HSCT seems to be valuable for insuring complete engraftment, anticipating graft rejection, and relapse in B-ALL patients. Copyright ? 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
文摘Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.
基金supported by grants from the Science Technology Department of Zhejiang Province(Grant No.2021C03117)Noncommunicable Chronic DiseasesNational Science and Technology Major Project(Grant No.2023ZD0501300)+1 种基金National Natural Science Foundation of China(Grant No.82170219)Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ24H080009)。
文摘Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive microenvironments,CAR-T cell exhaustion,and unmanageable adverse events.Diverse modifications have been introduced into conventional CAR-T cells to overcome these obstacles;examples include addition of recognition sites to prevent immune escape,coupling of cytokine domains to enhance killing ability,blocking of immune checkpoint signals to resist tumor microenvironments,and inclusion of suicide systems or safety switches to improve safety and flexibility.With increasing understanding of the importance of metabolism and epigenetics in cancer and cytotherapy,glycolysis,methylation,and acetylation have become crucial CAR-T cell therapeutic targets.Universal and in situ CAR-T cells are also expected to be used in clinical applications,thus providing hope to patients with relapsed/refractory lymphomas.
基金Support Project(RSPD2024R1037),King Saud University,Riyadh,Saudi Arabia.
文摘Background:Hepatocellular carcinoma(HCC)is a health problem due to multi-drug resistance(MDR).Codelivery of multiple oncotherapy in one cargo as chimeric cancer therapy(CCT)is suggested as a solution for MDR.This study aims to engineer chitosan-coated nanostructure lipid carriers(NLCs)loaded with gefitinib(GF)and simvastatin(SV)as CCT for HCC.Methods:Both GF and SV-loaded nanostructure lipids carriers(GFSVNLC)and chitosan-capped GF and SV-loaded nanostructure lipids carriers(CGFSVNLC)formulations were assembled by topdown techniques.Moreover,particle size(PS),zeta potential(ZP),and polydispersity index(PDI)were measured by Zetasizer.The biosafety of GFSVNLC preparations was investigated by using erythrocytes as a biological model.The cytotoxic,and apoptotic effects of the prepared GFSVNLCs were investigated using HepG2 cell lines as a substitute model for HCC.The effect of GF,SV,and NLC composition on JNK3,HDAC6,and telomerase was studied using molecular docking simulation(MDS).Results:The present results revealed that the obtained GFSVNLC and CGFSVNLC have nanosized and consistent,CS coating shifts anionic ZP of GFSVNLC into CGFSVNLC with cationic ZP.Moreover,both formulations are biocompatible as indicated by their gentle effect on erythrocyte hemolysis.The treatment of HepG2 cells with GFSVNLC,and CGFSVNLC induced marked cell death compared to other groups with a decrease of IC50.Equally,the percentage of the apoptotic HepG2 cells was increased upon treatment of the cells with GFSV,GFSVNLC,and CGFSVNLC compared to the control group.Additionally,GF,SV,stearic acid(SA),and oleic acid(OA)modulate the activity of JNK3,HDAC6,and telomerase.Conclusions:This study suggests CGFSVNLC achieves codelivery,selective targeting,and enhancing the synergistic effect of GF and SV for inducing HepG2 cell death.Mechanistically,CGFSVNLC inhibits key cascades implicated in MDR and HepG2 cell survival.CGFSVNLC is promising for overcoming drug resistance mechanisms and improving therapeutic outcomes against HepG2 cells.
基金supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project(Grant No.2023ZD0501300)Science Technology Department of Zhejiang Province(Grant No.2021C03117)+2 种基金National Natural Science Foundation of China(Grant No.82350104 and 82170219)Natural Science Foundation of Zhejiang Province,China(Grant No.LY23H080004 and LY24H080001)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(Grant No.2021KY199)。
文摘Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CAR-NK cell therapy has enabled the development of“off-the-shelf”products that bypass the lengthy and expensive cell manufacturing process1.
文摘Glypican-3(GPC3)is a tumor-associated antigen that is specifically expressed in hepatocellular carcinoma(HCC)and having relatively low levels in normal tissues.This unique expression pattern positions GPC3 as a potential target for precision therapy and drug development in HCC.Recent studies have shown significant advancements in GPC3-targeted therapies and immunotherapies,particularly for patients with advanced or treatment-resistant HCC.Although certain clinical trials have yielded suboptimal results,numerous ongoing studies continue to explore its therapeutic efficacy.This mini-review focuses on the latest research developments regarding GPC3 as a therapeutic target across various HCC treatment strategies,including monoclonal antibodies,bispecific antibodies,chimeric antigen receptor-T-cell therapies,and other innovative approaches.In addition,the limitations of GPC3-targeted therapies and their future application prospects in HCC treatment are discussed.The review particularly emphasizes the unmet need for future research directions,such as combination immuno-therapy strategies and novel drug designs.Through the integration of innovative technologies and clinical validation,GPC3 holds strong potential as a promising breakthrough in the treatment of HCC,offering new opportunities for enhancing patient outcomes and improving therapeutic efficacy.
基金supported by the RGC Research Impact Fund(Grant No.R5008-22F).
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related mortality worldwide1.The primary treatment options for this disease are surgical resection and liver transplantation.Unfortunately,most HCC cases are diagnosed in advanced stages and are inoperable.Even after surgery,the long-term prognosis remains unsatisfactory,because of a high recurrence rate.
基金supported by the National Natural Science Foundation of China(No.82270177)Chen Xiaoping Foundation for the Development of Science and Technology of Hubei Province(CXPJJH122001-2221).
文摘Objective Acute myeloid leukemia(AML)is a highly heterogeneous disease,and molecular events such as DNMT3A gene mutations are associated with poor prognosis in AML patients.Consequently,there is an urgent need for a novel therapeutic approach for AML.Methods DNMT3A mRNA and protein expression were confirmed in DNMT3A-mutant AML cells via RT-qPCR and Western blotting.Cell proliferation and apoptosis were assessed via CCK-8 and Annexin V/PI staining,respectively.Flow cytometry was used to analyze surface antigens and CD44v6 CAR-T-cell transfection efficiency.CD44v6-directed CAR plasmids were constructed,and lentiviruses were packaged.Methylation-specific PCR was used to evaluate differences in promoter methylation,whereas ELISA was used to measure cytokine secretion.Results In this study,we found that the DNMT3A-mutant group presented significantly increased expression of CD44v6 on the cell surface.Methylation of the CD44 promoter region was lower in the mutant group than in the control group.CD44v6 CAR-T cells exhibited specific cytotoxicity against DNMT3A-mutant AML cells.Furthermore,pretreatment with low concentrations of decitabine significantly enhanced the killing effect of CD44v6 CAR-T cells on DNMT3A-mutant AML cells(P<0.05).Additionally,decitabine treatment upregulated the expression of CD44v6 on the surface of DNMT3A-mutant AML cells(P<0.05).Conclusion CD44v6 is a promising CAR-T-cell therapy target in AML patients with DNMT3A mutations.Notably,treatment with decitabine resulted in increased CD44v6 expression on the cell surface of DNMT3A-mutant AML cells.This increase in CD44v6 expression facilitates improved recognition and targeting by CD44v6 CAR-T cells.
基金supported by funding from the National KeyR&D Program of China(No.2022YFC2502604)the National Natural Science Foundation of China(No.82470194)+1 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2024-I2M-3-021)the ChenXiaoping Foundation for the development of Science and Technology of Hubei Province(No.CXPJJH122001-2221)。
文摘Autologous stem cell transplantation(ASCT)and chimeric antigen receptor T-cell(CAR-T)therapy represent pivotal treatments for hematologic malignancies,each with distinct strengths and limitations.ASCT reduces tumor burden through myeloablative conditioning but remains susceptible to relapse,while CAR-T therapy precisely targets malignant cells but encounters challenges,including cytokine release syndrome(CRS),immune effector cell-associated neurotoxicity syndrome(ICANS),and limited persistence.Emerging evidence suggests that combining ASCT with CAR-T therapy yields synergistic effects.ASCT reshapes the immune microenvironment,lowers immunosuppressive cells and CRS risk,while CAR-T eliminates residual disease and promotes immune recovery.Clinical trials in relapsed/refractory B-cell lymphomas and multiple myeloma demonstrate complete remission rates(CRR)of 72%-100%and two-year progression-free survival(PFS)rates of 59%-83%,with severe CRS/ICANS incidences below 10%.However,the precise mechanisms underlying this synergy,optimal timing of CAR-T infusion after ASCT,and ideal dosing regimens require further definition.Future research should prioritize large-scale,randomized controlled trials and establish standardized protocols for toxicity management to maximize therapeutic benefits.By integrating the complementary strengths of ASCT and CAR-T,this combination strategy represents a promising approach for improving outcomes in high-risk hematologic malignancies;however,additional studies are necessary to validate its efficacy and expand its clinical applicability.
基金Supported by the Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality,China,No.23ZR1458300Key Discipline Project of Shanghai Municipal Health System,China,No.2024ZDXK0004+1 种基金Doctoral Innovation Talent Base Project for Diagnosis and Treatment of Chronic Liver Diseases,China,No.RCJD2021B02Pujiang Project of Shanghai Magnolia Talent Plan,China,No.24PJD098.
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and remains a major treatment challenge,particularly in advanced and metastatic stages.Current standard treatments have limited efficacy,underscoring the urgent need for innovative strategies.Adoptive cell therapy(ACT),which involves in vitro expansion or genetic engineering of immune cells,is a promising approach to bolster anti-tumor immune responses.Key ACT modalities include chimeric antigen receptor(CAR)T cells,tumor-infiltrating lymphocytes(TILs),and T cell receptor(TCR)-engineered T cells.CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC.These challenges include antigen heterogeneity,an immunosuppressive tumor microenvironment,on-target off-tumor toxicity,among other factors.To address these limitations,combinatorial approaches,such as immune checkpoint inhibitors,cytokines,and advanced gene-editing tools like CRISPR/Cas9,are being actively explored.These strategies aim to enhance CAR-T cell specificity,improve resistance to immunosuppressive signals,and optimize in vivo functionality.This review summarizes ACT approaches for CRC,with a focus on CAR-T therapy.It briefly introduces TILs and TCR-T cells,while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.
基金supported by grants from the National Natural Science Foundation of China(No.82400212).
文摘Objective To develop a novel prognostic scoring system for severe cytokine release syndrome(CRS)in patients with B-cell acute lymphoblastic leukemia(B-ALL)treated with anti-CD19 chimeric antigen receptor(CAR)-T-cell therapy,aiming to optimize risk mitigation strategies and improve clinical management.Methods This single-center retrospective cohort study included 125 B-ALL patients who received anti-CD19 CAR-T-cell therapy from January 2017 to October 2023.These cases were selected from a cohort of over 500 treated patients on the basis of the availability of comprehensive baseline data,documented CRS grading,and at least 3 months of follow-up.Data on patient demographics,treatment history,laboratory parameters,CAR-T-cell characteristics,safety,and efficacy endpoints were collected.CRS severity was graded according to the 2019 ASTCT consensus criteria.Univariate and multivariate logistic regression analyses were conducted to identify factors associated with CRS severity,and a prognostic model was constructed.Results The overall incidence of CRS was 67.2%,with 13.6%having grade≥3(severe)CRS.Higher baseline and post-lymphodepletion minimal residual disease(MRD)levels and neutropenia on day 7 post-infusion were significantly associated with severe CRS.Inflammatory markers(CRP,ferritin,and IL-6)and coagulation dysfunction(APTT)on day 7 post-infusion were also predictive of CRS severity.The prognostic model incorporating these factors demonstrated robust discriminatory ability,with an area under the ROC curve of 0.875.Conclusion This study developed a novel prognostic scoring system for severe CRS in Chinese B-ALL patients receiving anti-CD19 CAR-T-cell therapy.The model integrates clinical and laboratory parameters to facilitate early identification and management of severe CRS.Further validation in larger,prospective cohorts is warranted.
基金supported in part by the National Natural Science Foundation of China(62203097)the National High-Level Talents Special Support Program(Youth Talent of Technological Innovation of TenThousands Talents Program)(QNBJ-2023-12)the Fundamental Research Funds for the Central Universities(N2404018)
文摘This paper presents a novel neuro-adaptive cellular immunotherapy control strategy that leverages the high efficiency and applicability of chimeric antigen receptor-engineered T(CAR-T)cells in treating cancer.The proposed real-time control strategy aims to maximize tumor regression while ensuring the safety of the treatment.A dynamic growth model of cancer cells under the influence of cellular immunotherapy is established for the first time,which aligns with clinical experimental results.Utilizing the backstepping method,a novel consensus reference model is designed to consider the characteristics of cancer cell changes during the treatment process and conform to clinical rules.The model is segmented and continuous,with cancer cells expected to decrease in a step-like manner.Furthermore,a prescribed performance mechanism is constructed to maintain the therapeutic effect of the proposed scheme while ensuring the transient performance of the system.Through the analysis of Lyapunov stability,all signals within the closed-loop system are proven to be semiglobally uniformly ultimately bounded(SGUUB).Simulation results demonstrate the effectiveness of the proposed control strategy,highlighting its potential for clinical application in cancer treatment.
基金supported by the Distinguished Young Scholars of the National Defense Biotechnology Foundation(01-SWKJYCJJ11).
文摘Dear Editor,Thyroid-associated ophthalmopathy(TAO),or Graves’ophthalmopathy(GO),is a complex autoimmune condition characterized by eye symptoms such as proptosis,lid retraction,and periorbital swelling,often associated with thyroid dysfunction[1].Current drug treatments primarily include glucocorticoids,traditional immunosuppressants,and novel biologics such as Teprotumumab.While able to alleviate symptoms,they often do not adequately address irreversible conditions such as visual impairment and fi brosis,and it is diffi cult to avoid long-term medication side eff ects.In this context,exploring new therapeutic avenues for TAO to improve patients’prognosis and quality of life is meaningful.We proposed chimeric antigen receptor(CAR)-based therapy as a novel treatment orientation.
