精准医疗(precision medicine)作为一种全新的医学概念与医疗模式,已日益在恶性肿瘤临床治疗中显示其价值。精准细胞免疫治疗(precision cell immunotherapy,PCIT)是基于肿瘤患者基因检测,筛选可引起强烈免疫反应的新抗原(neoantigen),...精准医疗(precision medicine)作为一种全新的医学概念与医疗模式,已日益在恶性肿瘤临床治疗中显示其价值。精准细胞免疫治疗(precision cell immunotherapy,PCIT)是基于肿瘤患者基因检测,筛选可引起强烈免疫反应的新抗原(neoantigen),进而寻找并富集针对新抗原的精准T细胞(precision T cell for neo-antigen,PNA-T),扩增后回输患者的治疗新策略。相对于其他精准医学治疗方式,精准细胞免疫治疗具有比较独特的优势,有望成为中国肿瘤精准医学治疗的重要突破口。本文围绕肿瘤精准细胞免疫治疗面临的机遇与挑战,从概念、特点、流程、技术难点等方面进行了详细阐述,并对比了其与转基因嵌合抗原受体T细胞(chimeric antigen recepor T cell,CAR-T)的异同,勾勒出肿瘤精准细胞免疫治疗的美好前景。展开更多
Chimeric antigen receptor T cell(CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors(CAR).The CAR-T cell is an effector...Chimeric antigen receptor T cell(CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors(CAR).The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies,including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma. Solid tumors including melanoma, breast cancer and sarcoma offer great promise in CAR-T cell research and development. CD19 CAR-T cell is most commonly used, and other targets, including CD20, CD30, CD38 and CD138 are being studied. Although this novel therapy is promising, there are several disadvantages. In this review we discuss the applications of CAR-T cells in different hematological malignancies, and pave a way for future improvement on the effectiveness and persistence of these adoptive cell therapies.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
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor imm...Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.展开更多
Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause o...Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.展开更多
文摘精准医疗(precision medicine)作为一种全新的医学概念与医疗模式,已日益在恶性肿瘤临床治疗中显示其价值。精准细胞免疫治疗(precision cell immunotherapy,PCIT)是基于肿瘤患者基因检测,筛选可引起强烈免疫反应的新抗原(neoantigen),进而寻找并富集针对新抗原的精准T细胞(precision T cell for neo-antigen,PNA-T),扩增后回输患者的治疗新策略。相对于其他精准医学治疗方式,精准细胞免疫治疗具有比较独特的优势,有望成为中国肿瘤精准医学治疗的重要突破口。本文围绕肿瘤精准细胞免疫治疗面临的机遇与挑战,从概念、特点、流程、技术难点等方面进行了详细阐述,并对比了其与转基因嵌合抗原受体T细胞(chimeric antigen recepor T cell,CAR-T)的异同,勾勒出肿瘤精准细胞免疫治疗的美好前景。
基金supported by grants from the National Natural Science Foundation of China (Nos. 31670880 and 31370868)the Guangdong Natural Science Fund for Distinguished Young Scholars (No. 2016A030306004)+2 种基金Guangdong Special Support Program for Youth Science and Technology Innovation Talents (No. 2015TQ01R473)Guangzhou Pearl River New Star Program (No. 201610010064)Guangdong Innovative Research Team Program (No. 2011Y035)
文摘Chimeric antigen receptor T cell(CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors(CAR).The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies,including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma. Solid tumors including melanoma, breast cancer and sarcoma offer great promise in CAR-T cell research and development. CD19 CAR-T cell is most commonly used, and other targets, including CD20, CD30, CD38 and CD138 are being studied. Although this novel therapy is promising, there are several disadvantages. In this review we discuss the applications of CAR-T cells in different hematological malignancies, and pave a way for future improvement on the effectiveness and persistence of these adoptive cell therapies.
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.
基金Supported by(in part)Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B(No.17fk0310116h0001) from the Japan Agency for Medical Research and Development(AMED)Extramural Collaborative Research Grant of Cancer Research Institute,Kanazawa University
文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
基金NIH/NCI grants(R01CA168912 and R01CA235159)Augusta University intramural grant。
文摘Liver cancers, majority of which are primary hepatocellular carcinoma(HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years,immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells,have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes(TCRTs) and the chimeric antigen receptor genes(CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.
