Refractory and/or relapsed (r/r) diffuse large B-cell lymphomas after treatment with two lines of systemic chemoimmunotherapy exhibit diversity in genetics, tissue biology, and pathology, as well as poor prognosis. Patient TCRαβ cells engineered with a CD19-specific chimeric antigen receptor (CAR) have shown promising clinical outcomes in r/r diffuse large B-cell lymphoma. The ZUMA-1 study, the JULIET study, and the TRANSCEND NHL 001 study of three prototype 19CAR-T cells have indicated an overall response rate of 52–82%, a complete response rate of 40–58%, and a 12-month progression-free survival of 33.2%–46.6%, with clinically manageable treatment related toxicity. At the 5-year follow-up, relapse was observed in approximately 57% of patients within 1 year. Understanding of the risk factors for non-response remains insufficient. In addition to intrinsic tumor resistance, such as aberrant apoptotic signaling, downregulation or loss of tumor-associated antigens (TAA), an immunosuppressive tumor microenvironment, and CAR-T cell exhaustion in vivo have been suggested to be important risk factors. Mechanisms underlying 19CAR-T cell exhaustion under chronic TAA exposure, and limited 19CAR-T cell trafficking and infiltration into the tumor mass have been reported. Moreover, tumor escape in the presence of low TAA density remains a challenge in 1928ζ CAR-T cell treatment. In this review, we provide an overview of modified modular CAR elements and their synergistic effects in controlling T-cell function. We then briefly discuss novel strategies against tumors with low TAA density, such as bispecific tandem or loop CAR recognition domains, the development of human leukocyte antigen-independent synthetic TCRαβ double-chain receptors integrated into the constant region of the TCRα chain, and armored CAR-T cells targeting the tumor microenvironment.
在接受两种系统化疗免疫治疗后，难治性和/或复发(r/r)弥漫性大b细胞淋巴瘤在遗传学、组织生物学和病理学方面表现出多样性，并且预后较差。cd19特异性嵌合抗原受体(CAR)修饰的患者TCRαβ细胞在r/r弥漫性大b细胞淋巴瘤中显示出良好的临床效果。ZUMA-1研究、JULIET研究和TRANSCEND NHL 001研究表明，三种原型19CAR-T细胞的总缓解率为52-82%，完全缓解率为40-58%，12个月无进展生存期为33.2%-46.6%，具有临床可控的治疗相关毒性。在5年随访中，大约57%的患者在1年内复发。对无反应的危险因素的了解仍然不足。除了固有的肿瘤抵抗，如异常的凋亡信号，肿瘤相关抗原(TAA)的下调或缺失，免疫抑制的肿瘤微环境和体内CAR-T细胞衰竭被认为是重要的危险因素。慢性TAA暴露下19CAR-T细胞衰竭的机制，以及有限的19CAR-T细胞运输和浸润到肿瘤肿块中已经有报道。此外，低TAA密度下的肿瘤逃逸在1928ζ CAR-T细胞治疗中仍然是一个挑战。在这篇综述中，我们概述了修饰的模块化CAR元件及其在控制t细胞功能中的协同作用。然后，我们简要地讨论了针对低TAA密度肿瘤的新策略，如双特异性串联或环状CAR识别域，整合到TCRα链恒定区域的人类白细胞抗原非依赖性合成TCRαβ双链受体的开发，以及靶向肿瘤微环境的装甲CAR- t细胞。
{"title":"T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma","authors":"Rong Luan, B. Deng","doi":"10.15212/hod-2022-0009","DOIUrl":"https://doi.org/10.15212/hod-2022-0009","url":null,"abstract":"Refractory and/or relapsed (r/r) diffuse large B-cell lymphomas after treatment with two lines of systemic chemoimmunotherapy exhibit diversity in genetics, tissue biology, and pathology, as well as poor prognosis. Patient TCRαβ cells engineered with a CD19-specific chimeric antigen receptor (CAR) have shown promising clinical outcomes in r/r diffuse large B-cell lymphoma. The ZUMA-1 study, the JULIET study, and the TRANSCEND NHL 001 study of three prototype 19CAR-T cells have indicated an overall response rate of 52–82%, a complete response rate of 40–58%, and a 12-month progression-free survival of 33.2%–46.6%, with clinically manageable treatment related toxicity. At the 5-year follow-up, relapse was observed in approximately 57% of patients within 1 year. Understanding of the risk factors for non-response remains insufficient. In addition to intrinsic tumor resistance, such as aberrant apoptotic signaling, downregulation or loss of tumor-associated antigens (TAA), an immunosuppressive tumor microenvironment, and CAR-T cell exhaustion in vivo have been suggested to be important risk factors. Mechanisms underlying 19CAR-T cell exhaustion under chronic TAA exposure, and limited 19CAR-T cell trafficking and infiltration into the tumor mass have been reported. Moreover, tumor escape in the presence of low TAA density remains a challenge in 1928ζ CAR-T cell treatment. In this review, we provide an overview of modified modular CAR elements and their synergistic effects in controlling T-cell function. We then briefly discuss novel strategies against tumors with low TAA density, such as bispecific tandem or loop CAR recognition domains, the development of human leukocyte antigen-independent synthetic TCRαβ double-chain receptors integrated into the constant region of the TCRα chain, and armored CAR-T cells targeting the tumor microenvironment.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127698543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CAR-T cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CAR-T cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CAR-T cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CAR-T cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CAR-T cell therapy to overcome immunosuppressive TME and improve the efficacy of CAR-T cell therapy in the treatment of MM.
{"title":"Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment","authors":"Jian Cui, G. An, L. Qiu","doi":"10.15212/hod-2022-0008","DOIUrl":"https://doi.org/10.15212/hod-2022-0008","url":null,"abstract":"Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CAR-T cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CAR-T cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CAR-T cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CAR-T cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CAR-T cell therapy to overcome immunosuppressive TME and improve the efficacy of CAR-T cell therapy in the treatment of MM.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133093077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. An, Ruifeng Hou, Huanhuan Guan, Zhihui Li, Tong Wu, Shuangyou Liu
To date, no ideal CAR-T product is available for treating acute myeloid leukemia (AML). Recently, CD7 CAR-T therapy has shown promising efficiency in treating T-cell acute lymphoblastic leukemia. Because the CD7 antigen is also expressed on the myeloid blasts of some patients with AML, it might serve as a target for immunotherapy in AML. Herein, we administered CD7-specific CAR-T cells into a 20-year-old woman with AML with CD7 expression. She had a history of multiple relapses (with extramedullary disease, EMD) and treatments (radiation and allogeneic hematopoietic cell transplantation). The most recent relapse indicated a high disease burden with multifocal EMD. After a combination regimen of azacytidine, venetoclax and ruxolitinib, she showed minimal residual disease-positive remission in the bone marrow (BM), and EMD remained present. Subsequently, donor-derived CD7 CAR-T cells infused at a dose of 5.5×105/kg completely eliminated all disease in the BM and extramedullary areas. Grade I cytokine release syndrome occurred with no neurotoxicity. CD7 CAR-T cells were detectable in the peripheral blood and BM. Fifty-five days after T-cell infusion, she underwent a second allogeneic hematopoietic cell transplantation and has survived in disease-free remission for more than 7 months.
{"title":"CD7 CAR-T therapy for an AML patient with CD7 expression","authors":"L. An, Ruifeng Hou, Huanhuan Guan, Zhihui Li, Tong Wu, Shuangyou Liu","doi":"10.15212/hod-2022-0007","DOIUrl":"https://doi.org/10.15212/hod-2022-0007","url":null,"abstract":"To date, no ideal CAR-T product is available for treating acute myeloid leukemia (AML). Recently, CD7 CAR-T therapy has shown promising efficiency in treating T-cell acute lymphoblastic leukemia. Because the CD7 antigen is also expressed on the myeloid blasts of some patients with AML, it might serve as a target for immunotherapy in AML. Herein, we administered CD7-specific CAR-T cells into a 20-year-old woman with AML with CD7 expression. She had a history of multiple relapses (with extramedullary disease, EMD) and treatments (radiation and allogeneic hematopoietic cell transplantation). The most recent relapse indicated a high disease burden with multifocal EMD. After a combination regimen of azacytidine, venetoclax and ruxolitinib, she showed minimal residual disease-positive remission in the bone marrow (BM), and EMD remained present. Subsequently, donor-derived CD7 CAR-T cells infused at a dose of 5.5×105/kg completely eliminated all disease in the BM and extramedullary areas. Grade I cytokine release syndrome occurred with no neurotoxicity. CD7 CAR-T cells were detectable in the peripheral blood and BM. Fifty-five days after T-cell infusion, she underwent a second allogeneic hematopoietic cell transplantation and has survived in disease-free remission for more than 7 months.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123254410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential treatment for patients with B-cell lymphoma in whom standard therapy has failed. The U.S. Food and Drug Administration (FDA) has approved anti-CD19 CAR T-cell products for B-cell lymphoma. However, growing experience has shown that treatment has limitations, such as relapses due to tumour mutations or CD19 antigen loss, unexpanded CAR T-cells, and/or poor persistence of CAR T-cells. Understanding the limitations of CAR T-cell therapy is essential to achieve the full potential of this therapeutic strategy. In this review, we analyse factors potentially affecting the efficacy of CAR T-cell therapy, explore the mechanisms of resistance to CD19 CAR T-cell therapy in B-cell lymphoma, and summarise potential strategies to overcome treatment barriers.
嵌合抗原受体(CAR) t细胞疗法已成为标准治疗失败的b细胞淋巴瘤患者的潜在治疗方法。美国食品和药物管理局(FDA)已批准抗cd19 CAR - t细胞产品治疗b细胞淋巴瘤。然而，越来越多的经验表明，治疗有局限性，如由于肿瘤突变或CD19抗原丢失、CAR - t细胞未扩增和/或CAR - t细胞持久性差而复发。了解CAR - t细胞疗法的局限性对于充分发挥这种治疗策略的潜力至关重要。在这篇综述中，我们分析了可能影响CAR - t细胞治疗疗效的因素，探讨了b细胞淋巴瘤对CD19 CAR - t细胞治疗的耐药机制，并总结了克服治疗障碍的潜在策略。
{"title":"Exploring the mechanisms of CD19 CAR T-cell failure and salvage strategies in B-cell lymphoma","authors":"Fan Yang, Rui Liu, K. Hu","doi":"10.15212/hod-2022-0004","DOIUrl":"https://doi.org/10.15212/hod-2022-0004","url":null,"abstract":"Chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential treatment for patients with B-cell lymphoma in whom standard therapy has failed. The U.S. Food and Drug Administration (FDA) has approved anti-CD19 CAR T-cell products for B-cell lymphoma. However, growing experience has shown that treatment has limitations, such as relapses due to tumour mutations or CD19 antigen loss, unexpanded CAR T-cells, and/or poor persistence of CAR T-cells. Understanding the limitations of CAR T-cell therapy is essential to achieve the full potential of this therapeutic strategy. In this review, we analyse factors potentially affecting the efficacy of CAR T-cell therapy, explore the mechanisms of resistance to CD19 CAR T-cell therapy in B-cell lymphoma, and summarise potential strategies to overcome treatment barriers.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128325037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimeric antigen receptor T cell (CAR-T) therapy has substantial efficacy in the treatment of relapsed and/or refractory hematological malignancies. However, despite this outstanding performance, various CAR-T complications challenge treatment success during the entire process of CAR-T therapy. Short-term (within 28 days) complications with a high incidence include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and CAR-T associated coagulopathy. Many other complications may also occur during mid- (28–100 days) and long-term (>100 days) follow-up. Determining how to identify and standardize the management of adverse events in CAR-T therapy in an accurately and timely manner is crucial for its wide application. This review focuses on time periods after CAR-T cell therapy, and discusses the occurrence and management of adverse events, with an aim to improve the safety management of CAR-T cell therapy.
{"title":"Whole-process management of complications during CAR-T therapy","authors":"Yingying Li, H. Mei","doi":"10.15212/hod-2022-0005","DOIUrl":"https://doi.org/10.15212/hod-2022-0005","url":null,"abstract":"Chimeric antigen receptor T cell (CAR-T) therapy has substantial efficacy in the treatment of relapsed and/or refractory hematological malignancies. However, despite this outstanding performance, various CAR-T complications challenge treatment success during the entire process of CAR-T therapy. Short-term (within 28 days) complications with a high incidence include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome and CAR-T associated coagulopathy. Many other complications may also occur during mid- (28–100 days) and long-term (>100 days) follow-up. Determining how to identify and standardize the management of adverse events in CAR-T therapy in an accurately and timely manner is crucial for its wide application. This review focuses on time periods after CAR-T cell therapy, and discusses the occurrence and management of adverse events, with an aim to improve the safety management of CAR-T cell therapy.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127169095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CD19-targeted chimeric antigen receptor (CAR)-T cell therapy has shown high potential for treating B-cell hematological malignancies and has been approved by the US FDA. However, CAR-T cell therapy for T-cell hematologic malignancies poses feasibility challenges, including the difficulty of obtaining sufficient healthy cells from patients, CAR-T cell fratricide, and the risk of immunodeficiency. In this review, we discuss bottlenecks and possible solutions in CAR-T cell therapy for T-cell acute lymphoblastic leukemias, as well as future directions in this field.
{"title":"CAR-T Cell therapy in T-cell malignancies: limitations and solutions","authors":"Lingling Shan, Xiaoming Feng, Jing Pan","doi":"10.15212/hod-2022-0002","DOIUrl":"https://doi.org/10.15212/hod-2022-0002","url":null,"abstract":"CD19-targeted chimeric antigen receptor (CAR)-T cell therapy has shown high potential for treating B-cell hematological malignancies and has been approved by the US FDA. However, CAR-T cell therapy for T-cell hematologic malignancies poses feasibility challenges, including the difficulty of obtaining sufficient healthy cells from patients, CAR-T cell fratricide, and the risk of immunodeficiency. In this review, we discuss bottlenecks and possible solutions in CAR-T cell therapy for T-cell acute lymphoblastic leukemias, as well as future directions in this field.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126971145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment, particularly for hematopoietic malignancies. CAR T-cell therapy is a living drug with fundamentally different characteristics from those of other therapies. For example, CAR T-cell therapy efficacy may not increase with dose, and dose-limiting toxicity is rarely observed in the therapeutic dose range. Consequently, the conventional trial design paradigm is not suitable for the development of CAR T-cell therapy. Here, we review and introduce the phase I-II trial design paradigm to optimize the dose of CAR T-cell therapy on the basis of both toxicity and efficacy. We describe several novel Bayesian model-assisted designs, including BOIN12 and U-BOIN, which are simple to implement and have excellent operating characteristics for identifying the optimal biological dose for CAR T-cell therapy. Examples and software are provided to facilitate the use of these novel designs to accelerate the development of CAR T-cell therapy.
{"title":"Novel bayesian adaptive early phase designs to accelerate the development of CAR T-cell therapy","authors":"Ying Yuan, Kai Chen","doi":"10.15212/hod-2022-0003","DOIUrl":"https://doi.org/10.15212/hod-2022-0003","url":null,"abstract":"Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment, particularly for hematopoietic malignancies. CAR T-cell therapy is a living drug with fundamentally different characteristics from those of other therapies. For example, CAR T-cell therapy efficacy may not increase with dose, and dose-limiting toxicity is rarely observed in the therapeutic dose range. Consequently, the conventional trial design paradigm is not suitable for the development of CAR T-cell therapy. Here, we review and introduce the phase I-II trial design paradigm to optimize the dose of CAR T-cell therapy on the basis of both toxicity and efficacy. We describe several novel Bayesian model-assisted designs, including BOIN12 and U-BOIN, which are simple to implement and have excellent operating characteristics for identifying the optimal biological dose for CAR T-cell therapy. Examples and software are provided to facilitate the use of these novel designs to accelerate the development of CAR T-cell therapy.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127515386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Central nervous system lymphoma (CNSL) includes primary and secondary subtypes. It is associated with poor prognosis even after aggressive therapies. Primary CNSL involves mainly the brain, eyes, leptomeninges and spinal cord, without evidence of systemic non-Hodgkin’s lymphoma (NHL). Secondary CNSL refers to involvement of the CNS secondary to systemic NHL. Chimeric antigen receptor T (CAR-T) cells are genetically engineered T-cells directed against tumor target antigens. CAR-T-cells have shown encouraging results in treating B-cell malignancies. Clinical data on CAR-T-cells in CNSL treatment are limited, because of concerns regarding the immunoprivileged status of the CNS and the possibility of immune effector cell-associated neurotoxicity syndrome. Clinical trials on CAR-T therapy for CNSL are increasingly being conducted to evaluate its efficiency and safety since CAR-T-cells have been detected in the cerebrospinal fluid from a patient with PMBCL who received CAR-T-cell therapy. Current data suggest that CAR-T-cells are an emerging therapeutic modality for CNSL with clinical benefits and acceptable adverse effects. However, whether CAR-T therapy may be a promising therapeutic avenue remains controversial, because evidence from large-scale randomized clinical trials remains lacking. Herein, we provide a review of existing clinical data on CAR-T-cell therapy for CNSL, discuss the limitations of CAR-T-cells in CNSL treatment and hypothesize strategies to overcome these challenges.
{"title":"Chimeric antigen receptor engineered T-cell therapy for central nervous system lymphoma","authors":"Tiantian Sun, Mi Zhou, Liang Huang","doi":"10.15212/hod-2022-0001","DOIUrl":"https://doi.org/10.15212/hod-2022-0001","url":null,"abstract":"Central nervous system lymphoma (CNSL) includes primary and secondary subtypes. It is associated with poor prognosis even after aggressive therapies. Primary CNSL involves mainly the brain, eyes, leptomeninges and spinal cord, without evidence of systemic non-Hodgkin’s lymphoma (NHL). Secondary CNSL refers to involvement of the CNS secondary to systemic NHL. Chimeric antigen receptor T (CAR-T) cells are genetically engineered T-cells directed against tumor target antigens. CAR-T-cells have shown encouraging results in treating B-cell malignancies. Clinical data on CAR-T-cells in CNSL treatment are limited, because of concerns regarding the immunoprivileged status of the CNS and the possibility of immune effector cell-associated neurotoxicity syndrome. Clinical trials on CAR-T therapy for CNSL are increasingly being conducted to evaluate its efficiency and safety since CAR-T-cells have been detected in the cerebrospinal fluid from a patient with PMBCL who received CAR-T-cell therapy. Current data suggest that CAR-T-cells are an emerging therapeutic modality for CNSL with clinical benefits and acceptable adverse effects. However, whether CAR-T therapy may be a promising therapeutic avenue remains controversial, because evidence from large-scale randomized clinical trials remains lacking. Herein, we provide a review of existing clinical data on CAR-T-cell therapy for CNSL, discuss the limitations of CAR-T-cells in CNSL treatment and hypothesize strategies to overcome these challenges.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130589526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CRISPR/Cas-based gene editing is an innovative biotechnology that has revolutionized genetic engineering in recent years. The process involves induction of a double-strand break (DSB) at the desired DNA site and subsequent cellular repair. Two primary mechanisms drive DSB repair: non-homologous end joining and homologous recombination-mediated repair. Non-homologous end joining, the primary mode of DSB repair, is a simple high-efficiency process that is susceptible to errors, and unpredictable nucleotide insertion or deletion mutations. In contrast, point mutations account for more than 50% of human genetic disorders and are the most frequent type of genetic variation in nature. Base editing is a precise gene editing approach in which a single DNA base is substituted without introduction of DSBs or use of a repair template. This technique has promising therapeutic potential in gene therapy, owing to its high efficiency and controllable editing results. Since the invention of the first base editing tools, the technique has rapidly developed and undergone clinical trials. This review summarizes progress in gene therapy through base editing, including DNA and RNA base editing, with particular emphasis on recent clinical trial and preclinical research advancements, current limitations and remaining challenges, and prospects for further research and applications.
{"title":"Base editing therapy forges ahead","authors":"Wen Jiang, Rui Yang","doi":"10.15212/hod-2023-0001","DOIUrl":"https://doi.org/10.15212/hod-2023-0001","url":null,"abstract":"CRISPR/Cas-based gene editing is an innovative biotechnology that has revolutionized genetic engineering in recent years. The process involves induction of a double-strand break (DSB) at the desired DNA site and subsequent cellular repair. Two primary mechanisms drive DSB repair: non-homologous end joining and homologous recombination-mediated repair. Non-homologous end joining, the primary mode of DSB repair, is a simple high-efficiency process that is susceptible to errors, and unpredictable nucleotide insertion or deletion mutations. In contrast, point mutations account for more than 50% of human genetic disorders and are the most frequent type of genetic variation in nature. Base editing is a precise gene editing approach in which a single DNA base is substituted without introduction of DSBs or use of a repair template. This technique has promising therapeutic potential in gene therapy, owing to its high efficiency and controllable editing results. Since the invention of the first base editing tools, the technique has rapidly developed and undergone clinical trials. This review summarizes progress in gene therapy through base editing, including DNA and RNA base editing, with particular emphasis on recent clinical trial and preclinical research advancements, current limitations and remaining challenges, and prospects for further research and applications.","PeriodicalId":107466,"journal":{"name":"Hematology and Oncology Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123137968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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