T细胞表面含有特异性的T细胞受体(T cell receptors,TCR),能够识别不同的肿瘤抗原,从而实现对癌变细胞的杀伤和清除。TCR工程化T细胞(TCR-engineered T cells,TCR-T)治疗即是通过钓取针对肿瘤细胞的特异性TCR,并应用基因工程技术改造T细...T细胞表面含有特异性的T细胞受体(T cell receptors,TCR),能够识别不同的肿瘤抗原,从而实现对癌变细胞的杀伤和清除。TCR工程化T细胞(TCR-engineered T cells,TCR-T)治疗即是通过钓取针对肿瘤细胞的特异性TCR,并应用基因工程技术改造T细胞,输注体内后可达到治疗肿瘤的目的。尽管TCR-T治疗取得一定成果,但是还存在治疗毒性、T细胞浸润有限、抗原特异性不佳等问题,需要不断优化TCR-T治疗的安全性和有效性。因此,本文阐述了目前国内外关于实体肿瘤TCR-T治疗的研究现状以及存在的问题与对策。展开更多
Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful...Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.展开更多
Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destructi...Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destruction of other cells and their high safety when used as autologous T cells.Several studies and clinical tests have been conducted to demonstrate its potential as a novel therapy.However,previous research has mainly focused on antigens;these common targets for TCR-T are tumor-associated antigens,which exhibit expression not only in tumor cells but also in normal cells,resulting in off-target risk and not considering the heterogeneity of different patients.In contrast,neoantigens offer superior specificity as they are uniquely expressed on tumor cells due to genomic alterations.Given the frequent occurrence and notable role of genetic mutations in tumorigenesis and tumor progression,identification and targeting of neoantigens is a valuable therapeutic direction.This perspective delves into various antigen classifications,including their characteristics and advantages,as well as strategies for identifying and validating neoantigens that have emerged from numerous research studies.These insights are crucial for guiding the search for new neoantigens.We also review significant and representative studies involving TCR-T and other immunotherapies that target neoantigens to assess the therapeutic effectiveness of TCR-T therapy.Moreover,we discuss the challenges and complexities inherent in TCR-T therapy and propose potential solutions for these issues.In this perspective,we aim to provide fresh perceptions and strategies for cancer treatment by highlighting the potential of TCR-T and exploring its challenges and future directions.It also seeks to propel the development of precision medicine and personalized therapy,offering hope for more effective and targeted cancer treatments in the future.展开更多
文摘T细胞表面含有特异性的T细胞受体(T cell receptors,TCR),能够识别不同的肿瘤抗原,从而实现对癌变细胞的杀伤和清除。TCR工程化T细胞(TCR-engineered T cells,TCR-T)治疗即是通过钓取针对肿瘤细胞的特异性TCR,并应用基因工程技术改造T细胞,输注体内后可达到治疗肿瘤的目的。尽管TCR-T治疗取得一定成果,但是还存在治疗毒性、T细胞浸润有限、抗原特异性不佳等问题,需要不断优化TCR-T治疗的安全性和有效性。因此,本文阐述了目前国内外关于实体肿瘤TCR-T治疗的研究现状以及存在的问题与对策。
基金supported by the Botha-Chan Research Fund,the Office of the Assistant Secretary of Defense for Health Affairs through award no.HT9425-24-1-0623(I.R.)the Brain Tumor Funders'Collaborative,the Ellie Kavalieros DIPG Research Fund+6 种基金the UPMC Children’s Hospital of Pittsburgh Foundation(G.K.,I.R.)the Children’s Brain Tumor Network(I.F.P.),a stipend from the Central South University Xiangya School of Medicine and University of Pittsburgh(Z.X.)by grant NS117742 from the National Institute of Health(T.G.F.)support from the Jesse H.&Mary Jones Gibbs Endowed Chair(T.G.F)supported in part by the University of Pittsburgh Center for Research Computing,RRID:SCR_022735through NIH award number S10OD028483Work performed in the UPMC Hillman Cancer Center Tissue and Research Pathology Services Shared Resource Facility and the services and instruments used in this project were supported,in part,by the University of Pittsburgh and the NCI of the NIH under Award Number P30CA047904.
文摘Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
文摘Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destruction of other cells and their high safety when used as autologous T cells.Several studies and clinical tests have been conducted to demonstrate its potential as a novel therapy.However,previous research has mainly focused on antigens;these common targets for TCR-T are tumor-associated antigens,which exhibit expression not only in tumor cells but also in normal cells,resulting in off-target risk and not considering the heterogeneity of different patients.In contrast,neoantigens offer superior specificity as they are uniquely expressed on tumor cells due to genomic alterations.Given the frequent occurrence and notable role of genetic mutations in tumorigenesis and tumor progression,identification and targeting of neoantigens is a valuable therapeutic direction.This perspective delves into various antigen classifications,including their characteristics and advantages,as well as strategies for identifying and validating neoantigens that have emerged from numerous research studies.These insights are crucial for guiding the search for new neoantigens.We also review significant and representative studies involving TCR-T and other immunotherapies that target neoantigens to assess the therapeutic effectiveness of TCR-T therapy.Moreover,we discuss the challenges and complexities inherent in TCR-T therapy and propose potential solutions for these issues.In this perspective,we aim to provide fresh perceptions and strategies for cancer treatment by highlighting the potential of TCR-T and exploring its challenges and future directions.It also seeks to propel the development of precision medicine and personalized therapy,offering hope for more effective and targeted cancer treatments in the future.
