Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell ac...Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.展开更多
Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alter...Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.展开更多
Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shar...Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches(e.g.,daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing(fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies(clone MM12 T or clone MM27) or proteins(H02 H or H08 H) were used to block CD38 or the CAR single-chain variable fragment(scFv) domain, respectively, on the T cell surface.The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-a, IFN-g and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.展开更多
Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s t...Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.展开更多
Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T(CAR-T)cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma(r/r NHL)have not been well characterized.In ...Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T(CAR-T)cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma(r/r NHL)have not been well characterized.In this study,we found that the different sites of extranodal involvement may affect response,overall survival(OS),and progression-free survival(PFS)in patients with r/r NHL treated with anti-CD19 CAR-T cells.In a cohort of 32 treated patients,12(37.5%)and 8(25%)patients exhibited soft tissue lymphoma and bone marrow(BM)infiltrations,respectively,and 13(41%)patients exhibited infiltration at other sites.The factors that may affect prognosis were identified through multivariable analysis.As an independent risk factor,soft tissue infiltration was the only factor significantly correlated with adverse prognosis(P<0.05),whereas other factors did not reach statistical significance.Furthermore,the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy.PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone.Thus,anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.展开更多
γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unc...γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.展开更多
Recently,bispecific T-cell engagers(BiTEs)and chimeric antigen receptor-modified T cells(CAR-Ts)have been shown to have high therapeutic efficacy in hematological tumors.CD87 is highly expressed in solid tumors with a...Recently,bispecific T-cell engagers(BiTEs)and chimeric antigen receptor-modified T cells(CAR-Ts)have been shown to have high therapeutic efficacy in hematological tumors.CD87 is highly expressed in solid tumors with an oncogenic function.To assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas(iNFPAs),we first examined CD87 expression and its effects on the metabolism of iNFPA cells.We generated CD87-specific BiTE and CAR/IL-12 T cells,and their cytotoxic effects on iNFPAs cells and in mouse models were determined.CD87 had high expression in i NFPA tissue and cell samples but was undetected in noncancerous brain samples.CD87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects,decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental mice.Overall,the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells.展开更多
Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike ...Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.展开更多
近年来嵌合抗原受体T细胞(CAR T)在临床治疗淋巴系统白血病方面取得了突破性进展,为细胞免疫疗法治疗肿瘤开辟了新的途径。该疗法的关键是将识别淋巴细胞白血病CD19抗原的基因导入淋巴细胞,使其能够在输注给患者后特异性地杀伤体内白血...近年来嵌合抗原受体T细胞(CAR T)在临床治疗淋巴系统白血病方面取得了突破性进展,为细胞免疫疗法治疗肿瘤开辟了新的途径。该疗法的关键是将识别淋巴细胞白血病CD19抗原的基因导入淋巴细胞,使其能够在输注给患者后特异性地杀伤体内白血病细胞。如果将同样的细胞免疫疗法原理用于其他肿瘤,还需要给淋巴细胞导入另外的特异性靶标基因。近期研究发现,高迁移率组蛋白N2(high mobility group chromosal protein N2,HM GN2)是淋巴细胞识别肿瘤抗原的极好的靶标,是CD8+T细胞的抗肿瘤效应分子,对髓系白血病、乳腺癌、宫颈癌等多种肿瘤细胞具有趋向性和特异性结合识别能力,有望用于制备特异性识别肿瘤的淋巴细胞,治疗更多类型的白血病和肿瘤。本文论述了HMGN的结构和功能,以及HMGN2在白血病和肿瘤细胞中的趋化性和抗肿瘤作用。展开更多
基金supported by grants from the National Natural Science Foundation of China(No.82020108004)the Hospital-level Clinical Innovation Military-Civilian Special Project of Army Medical University(No.2018JSLC0020)+1 种基金Chongqing Science and Technology Innovation Leading Talent(No.CSTCCXLJRC201718)Natural Science Foundation of Chongqing Innovation Group Science Program(No.cstc2021jcyj-cxttX0001).
文摘Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.
基金the National Natural Science Foundation of China(Nos.81830007,82130004,81600155,and 81670716)Clinical Research Plan of SHDC(No.2020CR1032B),Shanghai Rising-Star Program(No.19QA145600)+5 种基金Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai(No.2017YQ075)Talent(Class A)of Guangci Excellence Youth Plan(No.GCQN-2019-A16)Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2020CR1032B)Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(Nos.20152206 and 20152208)China CAR-T Clinical Research Fund Project(No.CARTFR-05)Samuel Waxman Cancer Research Foundation.
文摘Anti-CD19 chimeric antigen receptor(CAR)-T cell therapy has achieved 40%–50%long-term complete response in relapsed or refractory diffuse large B-cell lymphoma(DLBCL)patients.However,the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation.A multi-center phase I/II trial of anti-CD19 CD28z CAR-T(FKC876,ChiCTR1800019661)was conducted.Among 22 evaluable DLBCL patients,seven achieved complete remission,10 experienced partial remissions,while four had stable disease by day 29.Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients,and compared at different stages of treatment.M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells,leading to CAR-T cell therapy failure and disease progression in DLBCL.Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy,during both cell expansion and disease progression,which could not be altered by infiltrating CAR-T cells.Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments.Thus,our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.
基金supported by the grants from the National Natural Science Foundation of China (Nos. 81830002 and 31870873 to W.D.H.)the National Key Research and Development Program of China (Nos. 2016YFC1303501 and 2016YFC1303504 to WDH, and No. 2017YFC0909803 to W.Y.)
文摘Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches(e.g.,daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing(fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies(clone MM12 T or clone MM27) or proteins(H02 H or H08 H) were used to block CD38 or the CAR single-chain variable fragment(scFv) domain, respectively, on the T cell surface.The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-a, IFN-g and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.
基金This study was supported by grants from the Shanghai Municipal Hospital New Frontier Technology Joint Research Project(No.SHDC12015108)the National Natural Science Foundation of China(Nos.81830004,31301118,and 81272325)the Fundamental Research Funds for the Central Universities(No.22120170004).
文摘Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.
基金This study was supported by grants from the Municipal Hospital Frontier Technology Joint Project of Shanghai City(No.SHDC12015108)the National Natural Science Foundation of China(Nos.81830004 and 31301118).
文摘Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T(CAR-T)cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma(r/r NHL)have not been well characterized.In this study,we found that the different sites of extranodal involvement may affect response,overall survival(OS),and progression-free survival(PFS)in patients with r/r NHL treated with anti-CD19 CAR-T cells.In a cohort of 32 treated patients,12(37.5%)and 8(25%)patients exhibited soft tissue lymphoma and bone marrow(BM)infiltrations,respectively,and 13(41%)patients exhibited infiltration at other sites.The factors that may affect prognosis were identified through multivariable analysis.As an independent risk factor,soft tissue infiltration was the only factor significantly correlated with adverse prognosis(P<0.05),whereas other factors did not reach statistical significance.Furthermore,the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy.PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone.Thus,anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.
基金supported by grants from the National Natural Science Foundation of China(Nos.32270915,31970843,82071791,U20A20374,and 81972886)National Key Research and Development Program of China(No.2022YFC3602004)+4 种基金CAMS Initiative for Innovative Medicine(Nos.2021-I2M-1-005,2021-I2M-1-035,and 2021-I2M-1-053)Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00028)CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses(No.3332020035)Changzhou Science and Technology Support Plan(No.CE20215008)Beijing Municipal Commission of Science and Technology Fund for Innovative Drug(No.Z221100007922040)
文摘γδT cells are a kind of innate immune T cell.They have not attracted sufficient attention because they account for only a small proportion of all immune cells,and many basic factors related to these cells remain unclear.However,in recent years,with the rapid development of tumor immunotherapy,γδT cells have attracted increasing attention because of their ability to exert cytotoxic effects on most tumor cells without major histocompatibility complex(MHC)restriction.An increasing number of basic studies have focused on the development,antigen recognition,activation,and antitumor immune response ofγδT cells.Additionally,γδT cell-based immunotherapeutic strategies are being developed,and the number of clinical trials investigating such strategies is increasing.This review mainly summarizes the progress of basic research and the clinical application ofγδT cells in tumor immunotherapy to provide a theoretical basis for further the development ofγδT cell-based strategies in the future.
基金supported by the National Key Research and Development Program of China(2021YFE0114300)the National Key Basic Research Program of China(973 Program)(2014CB541603)+1 种基金the National High Technology Research and Development Program of China(863 Program)(2013AA020106)the National Natural Science Foundation of China(82171475,82170799)。
文摘Recently,bispecific T-cell engagers(BiTEs)and chimeric antigen receptor-modified T cells(CAR-Ts)have been shown to have high therapeutic efficacy in hematological tumors.CD87 is highly expressed in solid tumors with an oncogenic function.To assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas(iNFPAs),we first examined CD87 expression and its effects on the metabolism of iNFPA cells.We generated CD87-specific BiTE and CAR/IL-12 T cells,and their cytotoxic effects on iNFPAs cells and in mouse models were determined.CD87 had high expression in i NFPA tissue and cell samples but was undetected in noncancerous brain samples.CD87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects,decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental mice.Overall,the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells.
基金support from the Center for Cellular Immunotherapiesthe Abramson Cancer Center at the Perelman School of Medicine,University of Pennsylvania+1 种基金the Parker Institute for Cancer ImmunotherapyPeking University
文摘Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.
文摘近年来嵌合抗原受体T细胞(CAR T)在临床治疗淋巴系统白血病方面取得了突破性进展,为细胞免疫疗法治疗肿瘤开辟了新的途径。该疗法的关键是将识别淋巴细胞白血病CD19抗原的基因导入淋巴细胞,使其能够在输注给患者后特异性地杀伤体内白血病细胞。如果将同样的细胞免疫疗法原理用于其他肿瘤,还需要给淋巴细胞导入另外的特异性靶标基因。近期研究发现,高迁移率组蛋白N2(high mobility group chromosal protein N2,HM GN2)是淋巴细胞识别肿瘤抗原的极好的靶标,是CD8+T细胞的抗肿瘤效应分子,对髓系白血病、乳腺癌、宫颈癌等多种肿瘤细胞具有趋向性和特异性结合识别能力,有望用于制备特异性识别肿瘤的淋巴细胞,治疗更多类型的白血病和肿瘤。本文论述了HMGN的结构和功能,以及HMGN2在白血病和肿瘤细胞中的趋化性和抗肿瘤作用。
