Neurological toxicities associated with chimeric antigen receptor T-cell therapy
Daniel B. RubinHusain DanishAli Basil AliKaren LiSarah LaRoseAndrew D. MonkDavid J. CotéLauren SpendleyAngela H. KimMatthew RobertsonMatthew TorreTimothy R. SmithSaef IzzyCaron A. JacobsonJong Woo LeeHenrikas Vaitkevicius
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Abstract:
Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.Although chimeric antigen receptor (CAR)-T therapy has produced remarkable clinical responses for patients with relapsed or refractory hematological malignancies, setbacks were experienced, including antigen escape and heterogeneity, its efficacy and safety issues. In recent years, researchers at home and abroad are addressing the current obstacles by digging deeply into structural optimization of CAR gene in order to solve the problems of CAR-T cell therapy. In this review, we mainly illustrate the ectodomain structure, transmemberane domain, and endodomain structure, and new designs which promote persistence of CAR-T cells in vivo, so as to provide new ideas for improving the safety and the efficacy of CAR-T cell therapy.嵌合抗原受体T细胞结构设计的研究进展.嵌合抗原受体（CAR）-T细胞疗法在复发难治性血液恶性肿瘤中的应用已经取得了令人鼓舞的临床疗效，但在靶向杀伤特异性、有效性以及安全性等方面均存在一定的挑战。近年来，国内外研究人员为解决CAR-T细胞疗法所存在的问题在CAR基因结构优化方面进行了深入的研究。本文主要阐述CAR基因中胞外结构域、跨膜区和胞内结构域的优化以及新型CAR基因设计，为进一步提高CAR-T细胞疗法的安全性和有效性提供新信息。.
Ectodomain
Cell therapy
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Chimeric antigen receptor T (CAR-T) cell immunotherapy shows potential and guarantee for clinical application in solid tumor treatment, although a section of difficulties must be overcome. Compared with conventional antitumor therapies, the advantages of CAR-T cell treatment include high specificity, great killing power, and long-term effectiveness. But various difficulties in treating solid tumors by CAR-T immunotherapy include intracellular signaling of CARs, immune escape due to antigenic heterogeneity of malignant tumors, physical or cytokine barriers that prevent CAR-T cell entry or limit their persistence, tumor microenvironment of other immunosuppressive molecules, and side effects. This paper describes CAR-T immunotherapy's mechanisms, development, and applications and discusses the status, difficulties, solutions, and future directions of treating solid tumors by CAR-T immunotherapy.
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Cellular immunotherapy is recognized as the fourth tumor treatment after surgery, radiotherapy and chemotherapy.Chimeric antigen receptor (CAR)-T-cell therapy belongs to adoptive cellular immunotherapy.CAR-T not only has made great breakthroughs in cancer treatment, but also has good application prospects in the treatment of infectious diseases and autoimmune diseases.This article reviews the development history, clinical applications, current problems and the latest research progress of CAR-T cell immunotherapy.
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Chimeric antigen receptor; T cell; Immunotherapy; Tumor
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Chimeric antigen receptor modified T cell (CAR T) cytotherapy is a modified technology of T cell immunotherapy. It has achieved encouraging breakthroughs in the treatment of hematological malignancies. Recent studies had shown that CAR T cells can also be used in the treatment of solid tumors. However, it's indispensable to understand its bottlenecks, including regulating CAR T cell expansion, survival time, metastasis, and prognosis in vivo, to establish a feasible and effective CART-based solid tumor therapy model. Therefore, we summarized the advances, challenges and possible solutions for CAR T therapy to treat solid tumors, and then prospected in the future clinical treatment.嵌合抗原受体修饰T细胞(CAR T)技术是经过改造后的T细胞免疫治疗，在治疗血液系统恶性肿瘤中取得显著效果。近年来，CAR T细胞同样可应用于实体肿瘤的治疗。然而，如何有效地将CAR T细胞免疫疗法转化到实体肿瘤治疗中，需要认识其在实体肿瘤临床治疗中的瓶颈，包括调节CAR T细胞体内扩增、存活时间、转移以及在肿瘤组织内的转归等因素。文章阐述了近年来CAR T细胞治疗实体肿瘤的研究现状、CAR T细胞治疗过程中遇到的一些瓶颈以及可能的解决办法，并对未来CAR T细胞治疗实体肿瘤的发展趋势进行分析和展望。.
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Neurological dysfunction in AIDS is common, occurring in as many as eighty percent of children. Thus, it is important to recognize the central nervous system imaging appearance of HIV, in particular those of HIV encephalopathy, as this is an AIDS defining illness and with distinct neuro-imaging features essential for early diagnosis and timely therapeutic interventionTo identify the clinical features in HIV-1 infection of the central nervous system and their associated neuroradiological correlates.Retrospective review of the records of all children with HIV-1 encephalopathy identified among children with neurological and developmental problems and who were on follow up at a child development and neurology clinic in an African city.A total of 22 children (10 male and 12 female) with HIV-1 encephalopathy were identified among 2382 children with various forms of neurological and developmental problems and who were on follow up at a child development and neurology clinic for a little bit over eight years period. All the children acquired the infection vertically. The age range of these children was between 10 months to 14 years. The median age was 5.6 years. The mean duration of symptom was 3.2 years. Global delay or regression in development along with signs of pyramidal tract involvement and seizures were the commonest clinical signs observed in these children. Neuro-behavioral problems were commonly observed among preschool and school aged children. In older children and preadolescents focal seizures with or with out neurologic deficit and neuroradiological findings were common. Nonhemorrhagic stroke was rare and occurred in one child and another child had cortical blindness. Three children had no neurological deficit. Rapid progression of the disease carried grave prognosis. Opportunistic infections and tumors of the central nervous system were also uncommon among these children. Brain volume loss with dilatation of the lateral ventricle, bilateral symmetrical or asymmetrical calcification of the basal ganglia and periventricular involvement of the white matter were the commonest neuro-radiological findings observed in these children.Atrophy of the brain with dilatation of the lateral ventricles and calcification of the basal ganglia and peri-ventricular involvement of the white matter were the commonest neuro-radiological findings in children with HIV-1 encephalopathy. Similarly global delay or regression in development along with pyramidal tract signs and seizures were the commonest neurological findings. Behavioral problems were common in preschool and school aged children. Focal seizures were common in older children and preadolescents. Rapid progression of the disease carried grave prognosis.
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The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients.
Cell therapy
Cancer Therapy
Cancer Immunotherapy
CAR T-cell therapy
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Some patients with hematologic malignancies as acute lymphoblastic leukemia (ALL), can achieve complete remission (CR) after chimeric antigen receptor T cell (CAR-T) immunotherapy. However, many constraints still limit the wide application of CAR-T immunotherapy in patients with hematological malignancies and other cancers, especially in patients with solid tumors. The main challenges related to CAR-T immunotherapy include: relapse caused by immune escape of tumor antigens, cytokine release syndrome (CRS), poor survival time in vivo, low infiltration capacity and inactivation of CAR-T in solid tumors, etc.. This article summarizes effects and problems of CAR-T immunotherapy in clinical trials for hematological malignancies, and how to use comprehensive treatment and biotechnology strategies to solve the current problems, in order to improve safety and effectiveness of CAR-T immunotherapy, and expand clinical benefits of CAR-T immunotherapy for patients with different tumors.
Key words:
Immunotherapy, adoptive; Receptors, chimeric antigen; Hematologic neoplasms; Chimeric antigen receptor-T cell; Solid tumors; Chimeric antigen receptor T cells immunotherapy; Combined modality therapy
Cancer Immunotherapy
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