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
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
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
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
T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus（EBV） associated malignancies.The EBV latent membrane protein 1（LMP1） is a 66-KD integral membrane protein enco...T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus（EBV） associated malignancies.The EBV latent membrane protein 1（LMP1） is a 66-KD integral membrane protein encoded by EBV that consists of transmembrane-spanning loops.Previously,we have identified a functional signal chain variable fragment（scFv） that specifically recognizes LMP1 through phage library screening.Here,we constructed a LMP1 specific chimeric antigen receptor containing anti-LMP1 scFv,the CD28 signalling domain,and the CD3ζchain（HELA/CAR）.We tested its functional ability to target LMP1 positive nasopharyngeal carcinoma cells.HELA/CAR cells were efficiently generated using lentivirus vector encoding the LMP1-specific chimeric antigen receptor to infect activated human CD3＋ T cells.The HELA/CAR T cells displayed LMP1 specific cytolytic action and produced IFN-γ and IL-2 in response to nasopharyngeal carcinoma cells overexpressing LMP1.To demonstrate in vivo anti-tumor activity,we tested the HELA/CAR T cells in a xenograft model using an LMP1 overexpressing tumor.Intratumoral injection of anti-LMP1 HELA/CAR-T cells significantly reduced tumor growth in vivo.These results show that targeting LMP1 using HELA/CAR cells could represent an alternative therapeutic approach for patients with EBV-positive cancers.展开更多
Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic ...Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.展开更多
Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therap...Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.展开更多
c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-...c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-specific chimeric antigen receptor(CAR)is an attractive strategy in treating c-Met-positive HCC.This study aimed to systematically evaluate the inhibitory effects of 2^(nd)-and 3^(rd)-generation c-Met CAR-T cells on hepatocellular carcinoma(HCC)cells.Here,2^(nd)-and 3^(rd)-generation c-Met CARs containing an anti-c-Met singlechain variable fragment(scFv)as well as the CD28 signaling domain and CD3ζ(c-Met-28-3ζ),the CD137 signaling domain and CD3ζ(c-Met-137-3ζ),or the CD28 and CD137 signaling domains and CD3ζ(c-Met-28-137-3ζ)were constructed,and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo.All c-Met CARs were stably expressed on T cell membrane,and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro.c-Met-28-137-3ζCAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-Met-28-3ζCAR-T cells and c-Met-137-3ζCAR-T cells.Compared with c-Met low-expressed cells,c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.Moreover,c-Met-28-137-3ζCAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.This study suggests that 3^(rd)-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2^(nd)-generation c-Met CAR-T cells,thereby providing a promising therapeutic intervention for c-Met-positive HCC.展开更多
Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the in...Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the introduction of novel agents such as immunomodulatory drugs(IMiDs)and proteasome inhibitors(PIs)have doubled the median overall survival to eight years,relapsed and refractory diseases are still frequent events in the course of MM.To achieve a durable and deep remission,immunotherapy modalities have been developed for relapsed/refractory multiple myeloma(RRMM).Among these approaches,chimeric antigen receptor(CAR)T-cell therapy is the most promising star,based on the results of previous success in B-cell neoplasms.In this immunotherapy,autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure.Tisagenlecleucel and Axicabtagene,targeting the CD19 antigen,are the two pacesetters of CAR T-cell products.They were approved by the US Food and Drug Administration(FDA)in 2017 for the treatment of acute lymphocytic leukemia(ALL)and diffuse large B-cell lymphoma(DLBCL).Their development enabled unparalleled efficacy in combating hematopoietic neoplasms.In this review article,we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.展开更多
With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunother...With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunotherapy,CARs have been exploited to modify the function of natural killer(NK)cells against a variety of tumors,including hepatocellular carcinoma(HCC).CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells,independent of major histocompatibility complex matching or prior priming.In this review,we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.展开更多
Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementi...Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.展开更多
BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete respons...BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.展开更多
We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral produce...We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral producer cells were established in the GALV-based PG13 packaging cell line. Ficoll purified human peripheral blood lymphocytes (PBL) were virally transduced using an optimized protocol incorporating activation with immobilized anti-CD3/anti-CD28 monoclonal anti- bodies, followed by viral infection in the presence of fibronectin fragment CH296. Transduced cells were co-cultured with human tumor cell lines that overexpress (SK-OV-3) or underexpress (MCF7) p185HER2 to assay for antigen specific im- mune responses. Both CM+ and CD8+ T-cells transduced with the N29γ or N29ζ chTCR demonstrated HER2-specific anti- gen responses, as determined by release of Th1 like cytokines, and cellular cytotoxicity assays. Our results support the fea- sibility of adoptive immunotherapy with genetically modified T-cells expressing a chTCR specific for p185HER2.展开更多
Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by t...Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by the inclusion of an antigen-specific binding region within the synthetic CAR construct.The advantage of cells with programmed specificity has been demonstrated clinically in the field of oncology,and it is clear that such cells have greater accuracy,potency,and reduced off-target therapeutic effects compared with their unmodified counterparts.In contrast to conventional T cells(Tconvs),regulatory T cells(Tregs)play a major role in suppressing immune activation and regulating the host immune response.CAR expression within Tregs has been proposed as a therapy for autoimmune and inflammatory diseases,graft-versus-host disease(GVHD),and organ transplant rejectio n.In the latter,they hold immense potential as mediators of immune tolerance for recipients of allotransplants.However,current research into CAR-Treg engineering is extremely limited,and there is uncertainty regarding optimal design for therapeutic use.This review examines the rationale behind the development of CAR-Tregs,their significance for human transplantation,potential designs,safety considerations,and comparisons of CAR-Tregs in transplantation models to date.展开更多
We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test th...We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two routine tumor cell lines： MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor ceils： MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.展开更多
BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing ap...BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing approximately 1%-2%of lymphoma.Approximately 30%–40%of patients are refractory to frontline therapy or relapse after complete remission.Refractory DLBCL responds poorly to other lines of chemotherapy,and experiences short-term survival.CASE SUMMARY We present a 41-year-old male patient who was diagnosed with PT-DLBCL.Further disease progression was observed after multiline chemotherapy.Chimeric antigen receptor T cells(CAR-T)therapy salvaged the patient.Unfortunately,a new mass was observed in the right adrenal area after six months.The patient was administered programmed cell death protein-1(PD-1)inhibitor therapy and maintained progression-free survival at more than 17 mo of follow-up.CONCLUSION Our findings support the potential benefit of CAR-T combined with PD-1 inhibitor therapies in this type of relapsed and refractory PT-DLBCL.展开更多
BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)...BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema.A large mass was detected in the pelvis,and pathology indicated non-Hodgkin diffuse large B-cell lymphoma.After three cycles of the R-CHOP chemotherapeutic regimen,the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine.Pathological examination of the nodules indicated DLBCL again.The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma.We recommended CAR-T cell treatment.Before treatment,the patient’s T cell function and expression of immune detection points were tested.Expression of PD-1 was obviously increased(52.7%)on cluster of differentiation(CD)3+T cells.The PD-1 inhibitor(3 mg/kg)was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide.CAR-CD19 T cells of 3×10^(6)/kg and CAR-CD22 T cells 1×10^(6)/kg were infused,respectively.The therapeutic effect was significant,and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable.Presently,the patient has been disease-free for more than 12 mo.CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cellsimproved therapeutic efficacy in B-cell lymphoma.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
Urological tumors represent a significant global health challenge,with conventional therapies often proving insufficient to control disease progression.Recent breakthroughs in cellular immunotherapy,particularly in ch...Urological tumors represent a significant global health challenge,with conventional therapies often proving insufficient to control disease progression.Recent breakthroughs in cellular immunotherapy,particularly in chimeric antigen receptor(CAR)-T cell,CAR–natural killer cell,and CAR-macrophage therapies,have demonstrated remarkable potential for treating these malignancies.Ongoing research is ac-tively refining CAR-based strategies to enhance their precision in targeting tumor-associated antigens.This review comprehensively summarizes the applications of CAR cell therapy in the following 3 major urological tumors:renal cell carcinoma,bladder cancer,and prostate cancer.Furthermore,we analyzed the current advantages and limitations of these approaches and propose potential strate-gies for optimization focused on CAR-T cells.This review will provide future directions in this field and contribute to the development of more effective treatments for patients with urological cancer.展开更多
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 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 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 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 in part by grants from the Special Fund of Clinical Medicine in Jiangsu Province(BL2013038)the Graduate Student Innovation Fund(CXZZ12_0563)
文摘T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus（EBV） associated malignancies.The EBV latent membrane protein 1（LMP1） is a 66-KD integral membrane protein encoded by EBV that consists of transmembrane-spanning loops.Previously,we have identified a functional signal chain variable fragment（scFv） that specifically recognizes LMP1 through phage library screening.Here,we constructed a LMP1 specific chimeric antigen receptor containing anti-LMP1 scFv,the CD28 signalling domain,and the CD3ζchain（HELA/CAR）.We tested its functional ability to target LMP1 positive nasopharyngeal carcinoma cells.HELA/CAR cells were efficiently generated using lentivirus vector encoding the LMP1-specific chimeric antigen receptor to infect activated human CD3＋ T cells.The HELA/CAR T cells displayed LMP1 specific cytolytic action and produced IFN-γ and IL-2 in response to nasopharyngeal carcinoma cells overexpressing LMP1.To demonstrate in vivo anti-tumor activity,we tested the HELA/CAR T cells in a xenograft model using an LMP1 overexpressing tumor.Intratumoral injection of anti-LMP1 HELA/CAR-T cells significantly reduced tumor growth in vivo.These results show that targeting LMP1 using HELA/CAR cells could represent an alternative therapeutic approach for patients with EBV-positive cancers.
文摘Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.
基金supported by grants from the National Key Research and Development Program of China(Grant No.2020YFA0707704)the National Key Research and Development Program of China(Grant No.2016YFC1303800)+1 种基金the Jilin Scientific and Technological Development Program(CN)(Grant No.20190303146SF)the National Natural Science Foundation of China(Grant No.81874052).
文摘Cytokine release syndrome(CRS)is a major obstacle to the widespread clinical application of chimeric antigen receptor(CAR)T cell therapies.CRS can also be induced by infections(such as SARS-CoV-2),drugs(such as therapeutic antibodies),and some autoimmune diseases.Myeloid-derived macrophages play key roles in the pathogenesis of CRS,and participate in the production and release of the core CRS cytokines,including interleukin(IL)-1,IL-6,and interferon-γ.In this review,we summarize the roles of macrophages in CRS and discuss new developments in macrophage activation and the related mechanisms of cytokine regulation in CRS.
基金grants from National Natural Science Foundation of China(81773268)Collaborative Innovation Center for Cancer Personalized Medicine,China(JX21817902/005).
文摘c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-specific chimeric antigen receptor(CAR)is an attractive strategy in treating c-Met-positive HCC.This study aimed to systematically evaluate the inhibitory effects of 2^(nd)-and 3^(rd)-generation c-Met CAR-T cells on hepatocellular carcinoma(HCC)cells.Here,2^(nd)-and 3^(rd)-generation c-Met CARs containing an anti-c-Met singlechain variable fragment(scFv)as well as the CD28 signaling domain and CD3ζ(c-Met-28-3ζ),the CD137 signaling domain and CD3ζ(c-Met-137-3ζ),or the CD28 and CD137 signaling domains and CD3ζ(c-Met-28-137-3ζ)were constructed,and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo.All c-Met CARs were stably expressed on T cell membrane,and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro.c-Met-28-137-3ζCAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-Met-28-3ζCAR-T cells and c-Met-137-3ζCAR-T cells.Compared with c-Met low-expressed cells,c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.Moreover,c-Met-28-137-3ζCAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.This study suggests that 3^(rd)-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2^(nd)-generation c-Met CAR-T cells,thereby providing a promising therapeutic intervention for c-Met-positive HCC.
文摘Multiple myeloma(MM),considered an incurable hematological malignancy,is characterized by its clonal evolution of malignant plasma cells.Although the application of autologous stem cell transplantation(ASCT)and the introduction of novel agents such as immunomodulatory drugs(IMiDs)and proteasome inhibitors(PIs)have doubled the median overall survival to eight years,relapsed and refractory diseases are still frequent events in the course of MM.To achieve a durable and deep remission,immunotherapy modalities have been developed for relapsed/refractory multiple myeloma(RRMM).Among these approaches,chimeric antigen receptor(CAR)T-cell therapy is the most promising star,based on the results of previous success in B-cell neoplasms.In this immunotherapy,autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure.Tisagenlecleucel and Axicabtagene,targeting the CD19 antigen,are the two pacesetters of CAR T-cell products.They were approved by the US Food and Drug Administration(FDA)in 2017 for the treatment of acute lymphocytic leukemia(ALL)and diffuse large B-cell lymphoma(DLBCL).Their development enabled unparalleled efficacy in combating hematopoietic neoplasms.In this review article,we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.
基金The National Natural Science Foundation of China,No.81972673.
文摘With the advance of genome engineering technology,chimeric antigen receptors(CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors.Although initially designed for T cells in tumor immunotherapy,CARs have been exploited to modify the function of natural killer(NK)cells against a variety of tumors,including hepatocellular carcinoma(HCC).CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells,independent of major histocompatibility complex matching or prior priming.In this review,we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.
基金funded by 2023 Sichuan Scientific and Technological Achievements Transformation Project.Project Number:2023JDZH0024.
文摘Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.
文摘BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.
文摘We have developed and tested chimeric T-cell receptors (TCR) specific for p185HER2. In these experiments, retroviral vectors expressing the N29γ or N29ζ receptors were constructed in pRET6. Amphotropic viral producer cells were established in the GALV-based PG13 packaging cell line. Ficoll purified human peripheral blood lymphocytes (PBL) were virally transduced using an optimized protocol incorporating activation with immobilized anti-CD3/anti-CD28 monoclonal anti- bodies, followed by viral infection in the presence of fibronectin fragment CH296. Transduced cells were co-cultured with human tumor cell lines that overexpress (SK-OV-3) or underexpress (MCF7) p185HER2 to assay for antigen specific im- mune responses. Both CM+ and CD8+ T-cells transduced with the N29γ or N29ζ chTCR demonstrated HER2-specific anti- gen responses, as determined by release of Th1 like cytokines, and cellular cytotoxicity assays. Our results support the fea- sibility of adoptive immunotherapy with genetically modified T-cells expressing a chTCR specific for p185HER2.
基金supported by the European Union’s Horizon 2020 Research and Innovation Program(RESHAPE,825392)to Joanna Hester and Fadi Issasupported by the Restore Research Trust。
文摘Chimeric antigen receptors(CARs)are a breakthrough in genetic engineering that have revolutio nized the field of adoptive cellular therapy(ACT).Cells expressing these receptors are rerouted to a predefined target by the inclusion of an antigen-specific binding region within the synthetic CAR construct.The advantage of cells with programmed specificity has been demonstrated clinically in the field of oncology,and it is clear that such cells have greater accuracy,potency,and reduced off-target therapeutic effects compared with their unmodified counterparts.In contrast to conventional T cells(Tconvs),regulatory T cells(Tregs)play a major role in suppressing immune activation and regulating the host immune response.CAR expression within Tregs has been proposed as a therapy for autoimmune and inflammatory diseases,graft-versus-host disease(GVHD),and organ transplant rejectio n.In the latter,they hold immense potential as mediators of immune tolerance for recipients of allotransplants.However,current research into CAR-Treg engineering is extremely limited,and there is uncertainty regarding optimal design for therapeutic use.This review examines the rationale behind the development of CAR-Tregs,their significance for human transplantation,potential designs,safety considerations,and comparisons of CAR-Tregs in transplantation models to date.
文摘We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two routine tumor cell lines： MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor ceils： MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.
文摘BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing approximately 1%-2%of lymphoma.Approximately 30%–40%of patients are refractory to frontline therapy or relapse after complete remission.Refractory DLBCL responds poorly to other lines of chemotherapy,and experiences short-term survival.CASE SUMMARY We present a 41-year-old male patient who was diagnosed with PT-DLBCL.Further disease progression was observed after multiline chemotherapy.Chimeric antigen receptor T cells(CAR-T)therapy salvaged the patient.Unfortunately,a new mass was observed in the right adrenal area after six months.The patient was administered programmed cell death protein-1(PD-1)inhibitor therapy and maintained progression-free survival at more than 17 mo of follow-up.CONCLUSION Our findings support the potential benefit of CAR-T combined with PD-1 inhibitor therapies in this type of relapsed and refractory PT-DLBCL.
文摘BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema.A large mass was detected in the pelvis,and pathology indicated non-Hodgkin diffuse large B-cell lymphoma.After three cycles of the R-CHOP chemotherapeutic regimen,the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine.Pathological examination of the nodules indicated DLBCL again.The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma.We recommended CAR-T cell treatment.Before treatment,the patient’s T cell function and expression of immune detection points were tested.Expression of PD-1 was obviously increased(52.7%)on cluster of differentiation(CD)3+T cells.The PD-1 inhibitor(3 mg/kg)was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide.CAR-CD19 T cells of 3×10^(6)/kg and CAR-CD22 T cells 1×10^(6)/kg were infused,respectively.The therapeutic effect was significant,and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable.Presently,the patient has been disease-free for more than 12 mo.CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cellsimproved therapeutic efficacy in B-cell lymphoma.
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 Special Fund for the Taishan Scholars Project(tsqn202211324)the Key Research and Development Program of Shandong Province(2021CXGC011101).
文摘Urological tumors represent a significant global health challenge,with conventional therapies often proving insufficient to control disease progression.Recent breakthroughs in cellular immunotherapy,particularly in chimeric antigen receptor(CAR)-T cell,CAR–natural killer cell,and CAR-macrophage therapies,have demonstrated remarkable potential for treating these malignancies.Ongoing research is ac-tively refining CAR-based strategies to enhance their precision in targeting tumor-associated antigens.This review comprehensively summarizes the applications of CAR cell therapy in the following 3 major urological tumors:renal cell carcinoma,bladder cancer,and prostate cancer.Furthermore,we analyzed the current advantages and limitations of these approaches and propose potential strate-gies for optimization focused on CAR-T cells.This review will provide future directions in this field and contribute to the development of more effective treatments for patients with urological cancer.
