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 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
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
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
A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an or...A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.展开更多
Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving resear...Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.展开更多
Classical Hodgkin lymphoma(cHL)is characterized by rare Hodgkin/Reed-Sternberg(HRS)tumor cells that uniformly express cluster of differentiation(CD)30 molecules and orchestrate an immunosuppressive tumor microenvironm...Classical Hodgkin lymphoma(cHL)is characterized by rare Hodgkin/Reed-Sternberg(HRS)tumor cells that uniformly express cluster of differentiation(CD)30 molecules and orchestrate an immunosuppressive tumor microenvironment,making CD30 an attractive and selective therapeutic target.We summarize the biological rationale for CD30 as a therapeutic target and the preclinical and clinical evidence across major platforms:antibody-drug conjugates(brentuximab vedotin),monoclonal antibodies(including acimtamig and its combinations with Natural Killer cells),second-and third-generation chimeric antigen receptor(CAR)-T cells,and alternative modalities.Particular attention is given to standardized response assessment(IWG,Lugano,RECIL criteria),which enables appropriate cross-trial comparisons.Taken together,the data indicate that beyond the established role of brentuximab vedotin,CD30-directed CAR-T cells and bispecific antibodies demonstrate high activity in refractory cHL,especially when used with fludarabine-containing lymphodepletion,combined with programmed cell death 1(PD-1)receptor blockade as a strategy to eradicate minimal residual disease.Key challenges include durable effector-cell persistence and optimization of sequencing and combinations;notably,loss of CD30 as an escape mechanism appears uncommon.Integrating mechanistic insights into HRS biology with clinical trial data highlights strategies to enhance the efficacy,safety,and accessibility of CD30-directed immunotherapy.This review aims to provide a concise overview of CD30-targeted approaches in cHL,emphasizing therapeutic outcomes and the evolution of CAR-T technologies.展开更多
The paradigm of cancer treatment has been reshaped by chimeric antigen receptor(CAR)αβT cell therapy,yet its full potential remains constrained by fundamental limitations.While conventional CARαβT cells have achie...The paradigm of cancer treatment has been reshaped by chimeric antigen receptor(CAR)αβT cell therapy,yet its full potential remains constrained by fundamental limitations.While conventional CARαβT cells have achieved notable success in hematological malignancies,their broader application is hindered by the high cost and delays of autologous manufacturing,as well as the critical risk of graft-vs-host disease(GvHD).In addition,their efficacy against solid tumors is often compromised by the immunosuppressive tumor microenvironment(TME).As a promising solution,γδT cells are being developed as an alternative CAR platform.Their intrinsic ability to recognize transformed cells in a major histocompatibility complex(MHC)-independent manner minimizes the risk of GvHD and supports the creation of safe,effective allogeneic therapies.Building on this unique biology,the therapeutic efficacy of CARγδT cells is being enhanced through advanced engineering strategies.Key innovations include“armoring”technologies,such as cytokine secretion,checkpoint blockade,and metabolic rewiring,to overcome local immunosuppression and improve persistence,as well as the use of induced pluripotent stem cells(iPSCs)to generate standardized products from a renewable and consistent source.This expanding technological toolbox is also enabling novel applications beyond oncology.For example,chimeric autoantibody receptor(CAAR)constructs built onγδT cells integrate both classical and emerging insights into CARγδT cell therapy,highlighting innovations that are driving the field toward safer,more versatile,and longer-lasting treatments for cancer and autoimmunity.In light of these advancements,this review provides an overview of the current understanding ofγδT cell biology and highlights emerging engineering strategies that enhance the efficacy and durability of CARγδT cells across oncologic and autoimmune contexts.展开更多
Background:In patients with autoimmune hemolytic anemia(AIHA),the risk of relapse is high owing to persistent autoreactive B-cell activity.Multirefractory AIHA is a more advanced stage of disease that is defined by a ...Background:In patients with autoimmune hemolytic anemia(AIHA),the risk of relapse is high owing to persistent autoreactive B-cell activity.Multirefractory AIHA is a more advanced stage of disease that is defined by a lack of response to at least three lines of therapy.CD19-directed chimeric antigen receptor(CAR)T-cell therapy results in profound B-cell depletion and may be a useful approach to achieving drug-free remission in multirefractory AIHA.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
The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting...The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.展开更多
This review aims to explore the development,challenges,and future directions of UCAR cell therapy as a scalable alternative to autologous CAR-T for cancer treatment.Consequently,limitations of autologous CAR-T,includi...This review aims to explore the development,challenges,and future directions of UCAR cell therapy as a scalable alternative to autologous CAR-T for cancer treatment.Consequently,limitations of autologous CAR-T,including long production,variable quality,and cost,drive off-the-shelf UCAR development to standardize manufacturing and improve access.Current UCAR-T cell strategies focus on mitigating the risks of graft-vs.-host disease and host-vs.-graft rejection through advanced gene editing technologies,including clustered regularly interspaced short palindromic repeat-associated system Cas9-mediated knockout of the T cell receptor,human leukocyte antigen,and cluster of differentiation 52(CD52).Beyond conventional T cells,cell types such as double-negative T cells,γδT cells,and virus-specific T cells are being engineered with CARs to improve tumor targeting and minimize off-tumor toxicity.UCAR-T therapy is frequently used for hematologic malignancies,including acute lymphoblastic leukemia,non-Hodgkin lymphoma,andmultiplemyeloma,with efficacy and safety supported by numerous clinical studies.Although trials for solid tumors(e.g.,CYAD-101,CTX130)show modest responses,challenges such as tumor heterogeneity and T cell exhaustion remain.Future research should focus on optimizing gene editing precision,integrating combination therapies,and advancing scalable manufacturing platforms.With expanded targets and cell types,UCAR therapies show promise for both hematologic and solid tumors,reshaping cancer treatment and patient outcomes.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.
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.
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A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.
基金supported by Key Research and Development Plan of Hunan Province(2024DK2006)the Fundamental Research Funds for the Central Universities of Central South University(1053320221769)+2 种基金Hunan Provincial Respiratory Disease Rehabilitation and Nursing Engineering Research Center Innovation Capacity Building Project(No.202012)the Zhangjiajie Science and Technology Development Key Special Project(No.202304)the National Key Clinical Specialty Major Scientific Research Project(No.20230382).
文摘Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.
基金supported by the Kazan Federal University Strategic Academic Leadership Program(PRIORITY-2030).
文摘Classical Hodgkin lymphoma(cHL)is characterized by rare Hodgkin/Reed-Sternberg(HRS)tumor cells that uniformly express cluster of differentiation(CD)30 molecules and orchestrate an immunosuppressive tumor microenvironment,making CD30 an attractive and selective therapeutic target.We summarize the biological rationale for CD30 as a therapeutic target and the preclinical and clinical evidence across major platforms:antibody-drug conjugates(brentuximab vedotin),monoclonal antibodies(including acimtamig and its combinations with Natural Killer cells),second-and third-generation chimeric antigen receptor(CAR)-T cells,and alternative modalities.Particular attention is given to standardized response assessment(IWG,Lugano,RECIL criteria),which enables appropriate cross-trial comparisons.Taken together,the data indicate that beyond the established role of brentuximab vedotin,CD30-directed CAR-T cells and bispecific antibodies demonstrate high activity in refractory cHL,especially when used with fludarabine-containing lymphodepletion,combined with programmed cell death 1(PD-1)receptor blockade as a strategy to eradicate minimal residual disease.Key challenges include durable effector-cell persistence and optimization of sequencing and combinations;notably,loss of CD30 as an escape mechanism appears uncommon.Integrating mechanistic insights into HRS biology with clinical trial data highlights strategies to enhance the efficacy,safety,and accessibility of CD30-directed immunotherapy.This review aims to provide a concise overview of CD30-targeted approaches in cHL,emphasizing therapeutic outcomes and the evolution of CAR-T technologies.
基金supported by the National Research Foundation of Korea(NRF)through the Ministry of Education(2021R1I1A3059820)(to Jea-Hyun Baek).
文摘The paradigm of cancer treatment has been reshaped by chimeric antigen receptor(CAR)αβT cell therapy,yet its full potential remains constrained by fundamental limitations.While conventional CARαβT cells have achieved notable success in hematological malignancies,their broader application is hindered by the high cost and delays of autologous manufacturing,as well as the critical risk of graft-vs-host disease(GvHD).In addition,their efficacy against solid tumors is often compromised by the immunosuppressive tumor microenvironment(TME).As a promising solution,γδT cells are being developed as an alternative CAR platform.Their intrinsic ability to recognize transformed cells in a major histocompatibility complex(MHC)-independent manner minimizes the risk of GvHD and supports the creation of safe,effective allogeneic therapies.Building on this unique biology,the therapeutic efficacy of CARγδT cells is being enhanced through advanced engineering strategies.Key innovations include“armoring”technologies,such as cytokine secretion,checkpoint blockade,and metabolic rewiring,to overcome local immunosuppression and improve persistence,as well as the use of induced pluripotent stem cells(iPSCs)to generate standardized products from a renewable and consistent source.This expanding technological toolbox is also enabling novel applications beyond oncology.For example,chimeric autoantibody receptor(CAAR)constructs built onγδT cells integrate both classical and emerging insights into CARγδT cell therapy,highlighting innovations that are driving the field toward safer,more versatile,and longer-lasting treatments for cancer and autoimmunity.In light of these advancements,this review provides an overview of the current understanding ofγδT cell biology and highlights emerging engineering strategies that enhance the efficacy and durability of CARγδT cells across oncologic and autoimmune contexts.
文摘Background:In patients with autoimmune hemolytic anemia(AIHA),the risk of relapse is high owing to persistent autoreactive B-cell activity.Multirefractory AIHA is a more advanced stage of disease that is defined by a lack of response to at least three lines of therapy.CD19-directed chimeric antigen receptor(CAR)T-cell therapy results in profound B-cell depletion and may be a useful approach to achieving drug-free remission in multirefractory AIHA.
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 National Natural Science Foundation of China(No.32371394)the National Key R&D Program of China(No.2021YFD1800600)+3 种基金the Special Projects in Key Areas of Colleges and Universities in Guangdong Province(No.2022ZDZX2046)the Open Project of State Key Laboratory of Respiratory Disease(No.SKLRD-OP-202502)the Postdoctoral Fellowship Program of CPSF(No.GZC20230619)Postdoctoral startup funding of Guangzhou Medical University(No.Q0301–130)。
文摘The inherent low immunogenicity and immunosuppressive metabolism of solid tumors significantly attenuate the immunotherapeutic effect and restrict the immune response.In this work,an endoplasmic reticulum(ER)targeting photodynamic oxidizer(designated as PhotoOx)is fabricated to boost the antitumor immunity by integrating photodynamic therapy(PDT)induced immunogenic cell death(ICD)with indoleamine 2,3-dioxygenase 1(IDO1)inhibition.Among which,an ER targeting photosensitizer-peptide conjugate called PhotoPe is rationally designed for optimal functionality and amphiphilicity,which could self-assemble into nano-micelles co-delivering chlorin e6 and NLG919.PhotoOx exhibits a good stability to enable ER targeting drug delivery,which could induce ER rupture to intensify PDT induced ICD and release damage associated molecular patterns(DAMPs).Furthermore,PhotoOx could effectively initiate immunological cascades,leading to the suppression of regulatory T cells(Tregs)and activation of CD8^(+)T cells when combines with IDO inhibition.Furthermore,the multi-synergistic effects of PhotoOx activate a robust systemic anti-tumor immune response,resulting in the eradication of lung and liver metastases.Such a medication strategy might inspire the rational design of biomedicine for precise drug delivery,which also provides a sophisticated mechanism for addressing the challenges of solid tumor treatment.
文摘This review aims to explore the development,challenges,and future directions of UCAR cell therapy as a scalable alternative to autologous CAR-T for cancer treatment.Consequently,limitations of autologous CAR-T,including long production,variable quality,and cost,drive off-the-shelf UCAR development to standardize manufacturing and improve access.Current UCAR-T cell strategies focus on mitigating the risks of graft-vs.-host disease and host-vs.-graft rejection through advanced gene editing technologies,including clustered regularly interspaced short palindromic repeat-associated system Cas9-mediated knockout of the T cell receptor,human leukocyte antigen,and cluster of differentiation 52(CD52).Beyond conventional T cells,cell types such as double-negative T cells,γδT cells,and virus-specific T cells are being engineered with CARs to improve tumor targeting and minimize off-tumor toxicity.UCAR-T therapy is frequently used for hematologic malignancies,including acute lymphoblastic leukemia,non-Hodgkin lymphoma,andmultiplemyeloma,with efficacy and safety supported by numerous clinical studies.Although trials for solid tumors(e.g.,CYAD-101,CTX130)show modest responses,challenges such as tumor heterogeneity and T cell exhaustion remain.Future research should focus on optimizing gene editing precision,integrating combination therapies,and advancing scalable manufacturing platforms.With expanded targets and cell types,UCAR therapies show promise for both hematologic and solid tumors,reshaping cancer treatment and patient outcomes.
