Multiple myeloma(MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel ...Multiple myeloma(MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen(BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease(MRD) negative patients, will also be discussed.展开更多
Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and...Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new ap- proach for multiple myeloma （MM） immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow （BM） Cells of 25 MM patients and 18 healthy vol- unteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% （7/25）, 80% （20/25）, 40% （10/25） and 68% （17/25）, respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% （20/25） MM patients, and that of at least one CTA in 88% （22/25）. The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II （P〈0.05）. No statistically significant differences were observed in the mRNA expression levels of MAGE-C 1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM （P〉0.05）. In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immuno- therapy in the future.展开更多
Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy...Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.展开更多
Chimeric antigen receptor(CAR)T-cell therapy is an effective new treatment strategy for hematologic malignancies.The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for mul...Chimeric antigen receptor(CAR)T-cell therapy is an effective new treatment strategy for hematologic malignancies.The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for multiple myeloma(MM),and the initial results of CAR T cell therapy have been encouraging.CAR T-cell therapy target antigens that have been clinically evaluated in MM;these antigens include CD19,B cell maturation antigen(BCMA),CD38,and CD138.A barrier to the widespread use of CAR T-cell therapy is its toxicity,primarily cytokine release syndrome(CRS),and neurologic toxicity.This study reports a patient with refractory MM who also developed megakaryocyte aplastic thrombocytopenia after receiving CAR T-cell therapy;such a case or the unusual side effects involving medications are yet unreported.There are risks in using cyclosporine and other immunosuppressants that may lead to MM recurrence as the use of such substances is contradictory to previous treatments;therefore,we temporarily administered platelet infusion as supportive care.Thus far,the condition of the patient has been steady and the patient regularly takes blood test in the hospital.展开更多
As a non-specific modulator of macrophage, multiplied muramyl dipeptide (MMD) is solid-phase synthesized by application of standard Fmoc chemistry strategy. Tarn's multiple antigen system (MAS) is used as our four...As a non-specific modulator of macrophage, multiplied muramyl dipeptide (MMD) is solid-phase synthesized by application of standard Fmoc chemistry strategy. Tarn's multiple antigen system (MAS) is used as our four branched-linker on Lysine.展开更多
背景嵌合抗原受体(CAR)-T细胞免疫疗法已在多发性骨髓瘤(MM)中取得较好的疗效,最常见的靶点为B细胞成熟抗原(BCMA)。单靶点CAR-T细胞免疫疗法的缺点是会导致疾病抵抗和复发,可能与抗原逃逸有关。为此,改进开发了双靶点CAR-T细胞治疗复...背景嵌合抗原受体(CAR)-T细胞免疫疗法已在多发性骨髓瘤(MM)中取得较好的疗效,最常见的靶点为B细胞成熟抗原(BCMA)。单靶点CAR-T细胞免疫疗法的缺点是会导致疾病抵抗和复发,可能与抗原逃逸有关。为此,改进开发了双靶点CAR-T细胞治疗复发难治多发性骨髓瘤(RRMM),此方面尚缺乏系统的临床分析。目的对RRMM患者应用双靶点CAR-T细胞免疫疗法治疗的有效性及安全性进行Meta分析。方法计算机检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网7个数据库中有关双靶点CAR-T细胞治疗RRMM的单组率研究,检索时限为建库至2023-02-06。由2名研究人员使用自制的数据表单来提取收集数据,并采用非随机对照试验方法学评价指标进行文献质量评价。采用R Studio软件进行数据分析。结果共纳入9篇文献,包括200例既往接受过多线治疗的RRMM患者。双靶点CAR-T细胞疗法根据不同靶点可分为4类:BCMA+CD19、BCMA+CD38,BCMA+跨膜剂与钙调节亲环素配体的相互作用者(TACI)、BCMA+人信号淋巴细胞激活分子家族成员7(CS1),其中BCMA+CD19靶点的研究较多。根据输注形式不同CAR-T细胞疗法可分为4类:双特异性CAR-T细胞、联合或序贯输注两种不同CAR-T细胞、双顺反子结构、共转导。Meta分析显示,双靶点CAR-T细胞治疗RRMM的总缓解率(ORR)为90.0%(95%CI=0.849~0.943),完全缓解率(CRR)为54.6%(95%CI=0.416~0.673),微小残留病(MRD)阴性率为75.6%(95%CI=0.489~0.952),髓外病变(EMD)总缓解率为55.1%(95%CI=0.234~0.851),最后一次随访时的复发率为29.7%(95%CI=0.141~0.454),最后一次随访时的生存率为75.6%(95%CI=0.554~0.915),3~4级细胞释放因子综合征(CRS)发生率为16.4%(95%CI=0.094~0.245),神经毒性(ICANS)发生率为4.0%(95%CI=0~0.120)。敏感性分析提示结果稳定。Egger's检验结果显示,ORR(P=0.03)及EMD总缓解率(P=0.02)提示存在一定的偏倚风险;CRR(P=0.53)、MRD阴性率(P=0.79)、最后一次随访时的复发率(P=0.71)、生存率(P=0.98)、3~4级CRS发生率(P=0.90)、ICANS发生率(P=0.30)提示不存在发表偏倚。结论双靶点CAR-T细胞免疫治疗RRMM显示出良好的疗效和安全性,未来需要多中心、大样本、更长随访期的研究来进一步评估其疗效和安全性。展开更多
A fundamental goal in cellular signaling is to understand allosteric communication, the process by which sig-nals originating at one site in a protein propagate reliably to affect distant functional sites. The general...A fundamental goal in cellular signaling is to understand allosteric communication, the process by which sig-nals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Statistical coupling analysis （SCA） is a statistical technique that uses evolutionary data of a protein family to measure correlation between distant functional sites and suggests allosteric communication. In proteins, very distant and small interactions between collections of amino acids provide the communication which can be important for signaling process. In this paper, we present the SCA of protein alignment of the esterase family （pfam ID： PF00756） containing the sequence of antigen 85C secreted by Mycobacterium tuberculosis to identify a subset of interacting residues. Clustering analysis of the pairwise correlation highlighted seven important residue positions in the esterase family alignments. These resi-dues were then mapped on the crystal structure of antigen 85C （PDB ID： 1DQZ）. The mapping revealed corre-lation between 3 distant residues （Asp38, Leu123 and Met125） and suggests allosteric communication between them. This information can be used for a new drug against this fatal disease.展开更多
文摘Multiple myeloma(MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen(BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease(MRD) negative patients, will also be discussed.
基金supported by the Natural Science Foundation of Hubei Province,China(No.2012FK04452)
文摘Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new ap- proach for multiple myeloma （MM） immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow （BM） Cells of 25 MM patients and 18 healthy vol- unteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% （7/25）, 80% （20/25）, 40% （10/25） and 68% （17/25）, respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% （20/25） MM patients, and that of at least one CTA in 88% （22/25）. The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II （P〈0.05）. No statistically significant differences were observed in the mRNA expression levels of MAGE-C 1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM （P〉0.05）. In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immuno- therapy in the future.
基金the National Natural Science Foundation of China(No.81873452)the Clinical Research Program of Huazhong University of Science and Technology Affiliated Tongji Hospital(No.2020003).
文摘Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.
文摘Chimeric antigen receptor(CAR)T-cell therapy is an effective new treatment strategy for hematologic malignancies.The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for multiple myeloma(MM),and the initial results of CAR T cell therapy have been encouraging.CAR T-cell therapy target antigens that have been clinically evaluated in MM;these antigens include CD19,B cell maturation antigen(BCMA),CD38,and CD138.A barrier to the widespread use of CAR T-cell therapy is its toxicity,primarily cytokine release syndrome(CRS),and neurologic toxicity.This study reports a patient with refractory MM who also developed megakaryocyte aplastic thrombocytopenia after receiving CAR T-cell therapy;such a case or the unusual side effects involving medications are yet unreported.There are risks in using cyclosporine and other immunosuppressants that may lead to MM recurrence as the use of such substances is contradictory to previous treatments;therefore,we temporarily administered platelet infusion as supportive care.Thus far,the condition of the patient has been steady and the patient regularly takes blood test in the hospital.
基金These studies were granted by the National Natural Science Foundation of China (39600183).
文摘As a non-specific modulator of macrophage, multiplied muramyl dipeptide (MMD) is solid-phase synthesized by application of standard Fmoc chemistry strategy. Tarn's multiple antigen system (MAS) is used as our four branched-linker on Lysine.
文摘背景嵌合抗原受体(CAR)-T细胞免疫疗法已在多发性骨髓瘤(MM)中取得较好的疗效,最常见的靶点为B细胞成熟抗原(BCMA)。单靶点CAR-T细胞免疫疗法的缺点是会导致疾病抵抗和复发,可能与抗原逃逸有关。为此,改进开发了双靶点CAR-T细胞治疗复发难治多发性骨髓瘤(RRMM),此方面尚缺乏系统的临床分析。目的对RRMM患者应用双靶点CAR-T细胞免疫疗法治疗的有效性及安全性进行Meta分析。方法计算机检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网7个数据库中有关双靶点CAR-T细胞治疗RRMM的单组率研究,检索时限为建库至2023-02-06。由2名研究人员使用自制的数据表单来提取收集数据,并采用非随机对照试验方法学评价指标进行文献质量评价。采用R Studio软件进行数据分析。结果共纳入9篇文献,包括200例既往接受过多线治疗的RRMM患者。双靶点CAR-T细胞疗法根据不同靶点可分为4类:BCMA+CD19、BCMA+CD38,BCMA+跨膜剂与钙调节亲环素配体的相互作用者(TACI)、BCMA+人信号淋巴细胞激活分子家族成员7(CS1),其中BCMA+CD19靶点的研究较多。根据输注形式不同CAR-T细胞疗法可分为4类:双特异性CAR-T细胞、联合或序贯输注两种不同CAR-T细胞、双顺反子结构、共转导。Meta分析显示,双靶点CAR-T细胞治疗RRMM的总缓解率(ORR)为90.0%(95%CI=0.849~0.943),完全缓解率(CRR)为54.6%(95%CI=0.416~0.673),微小残留病(MRD)阴性率为75.6%(95%CI=0.489~0.952),髓外病变(EMD)总缓解率为55.1%(95%CI=0.234~0.851),最后一次随访时的复发率为29.7%(95%CI=0.141~0.454),最后一次随访时的生存率为75.6%(95%CI=0.554~0.915),3~4级细胞释放因子综合征(CRS)发生率为16.4%(95%CI=0.094~0.245),神经毒性(ICANS)发生率为4.0%(95%CI=0~0.120)。敏感性分析提示结果稳定。Egger's检验结果显示,ORR(P=0.03)及EMD总缓解率(P=0.02)提示存在一定的偏倚风险;CRR(P=0.53)、MRD阴性率(P=0.79)、最后一次随访时的复发率(P=0.71)、生存率(P=0.98)、3~4级CRS发生率(P=0.90)、ICANS发生率(P=0.30)提示不存在发表偏倚。结论双靶点CAR-T细胞免疫治疗RRMM显示出良好的疗效和安全性,未来需要多中心、大样本、更长随访期的研究来进一步评估其疗效和安全性。
文摘A fundamental goal in cellular signaling is to understand allosteric communication, the process by which sig-nals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Statistical coupling analysis （SCA） is a statistical technique that uses evolutionary data of a protein family to measure correlation between distant functional sites and suggests allosteric communication. In proteins, very distant and small interactions between collections of amino acids provide the communication which can be important for signaling process. In this paper, we present the SCA of protein alignment of the esterase family （pfam ID： PF00756） containing the sequence of antigen 85C secreted by Mycobacterium tuberculosis to identify a subset of interacting residues. Clustering analysis of the pairwise correlation highlighted seven important residue positions in the esterase family alignments. These resi-dues were then mapped on the crystal structure of antigen 85C （PDB ID： 1DQZ）. The mapping revealed corre-lation between 3 distant residues （Asp38, Leu123 and Met125） and suggests allosteric communication between them. This information can be used for a new drug against this fatal disease.
