Monitoreo de las insuficiencias orgánicas en pacientes graves con hemopatías malignas por el uso de las células CAR-T / Monitoring of organ failures in critically ill patients with blood malignancies by the use of CAR - T cell

Introducción: La inmunoterapia con células T modificadas con receptor quimérico antígeno específico es un tratamiento prometedor para hemopatías malignas. Sin embargo, la activación dirigida de la respuesta inmunitaria desata en ciertos casos complicaciones específicas graves y mortales. Objetivos: Describir el monitoreo de las complicaciones por el uso de las células T con receptor antígeno quimérico en pacientes graves con hemopatías malignas. Métodos: Se realizó una investigación bibliográfico documental acerca del tema. Se consultaron las bases de datos de SciELO y PubMed de los últimos cinco años. Conclusiones: Se describieron las complicaciones derivadas de la terapia con células inmunoefectoras, que aumentan el desarrollo de insuficiencias orgánicas, a través del síndrome de liberación de citoquinas y el síndrome de toxicidad neurológica. El tratamiento se basó en establecer medidas de monitorización y soporte, tratamiento con anticonvulsivantes, corticosteroides e ingreso en los servicios de medicina intensiva de forma precoz. Se disminuyó el riesgo en la aparición de complicaciones y muerte con un adecuado monitoreo de las insuficiencias orgánicas derivadas de la inmunoterapia de células T con receptor antígeno quimérico.

Introduction: Immunotherapy with T-cells modified with antigen-specific chimeric receptor is a promising treatment for malignant hemopathies. However, the targeted activation of the immune response in certain cases unleashes specific severe and fatal complications. Objectives: To describe the monitoring of complications from the use of CAR T-cells in critically ill patients with blood malignancies. Methods: A bibliographical-documentary research on the subject was carried out. The SciELO and Pubmed databases of the last five years were consulted. Conclusions: Complications derived from the therapy with immunoeffector cells are described, which increase the development of organ failures, through the cytokine release syndrome and the neurological toxicity syndrome. Treatment is based on monitoring and support measures, treatment with anticonvulsants, corticosteroids, and early admission to intensive care. With adequate monitoring of organ failure derived from chimeric antigen receptor T-cell immunotherapy, a decreased risk of complications and death in these patients was carried out.

CAR-T cell therapy for multiple myeloma: a practical toolkit for treatment in Brazil

ABSTRACT Introduction Chimeric antigen receptor T (CAR-T) cell therapy is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) that is a multi-step process involving various stakeholders. Appropriate education on the practical logistics is therefore paramount to ensure treatment success. Methods A group of key opinion leaders met to explore the key elements of setting up and running a CAR-T center in Brazil. For each step in the CAR-T cell therapy process, the experts agreed on basic requirements, gave their key recommendations from practical experience, and considered any remaining unanswered questions. Results This paper presents best-practice recommendations and advice on how to overcome common challenges for each step in the CAR-T cell therapy process, with a focus on the current situation in Brazil. Key themes throughout the process are collaboration within the multidisciplinary team and with the referring physician, along with communication and education for patients and their caregivers. Conclusion We believe that the expert insights presented in this paper, in particular on optimal patient selection and timing of CAR-T cell therapy, will deepen understanding of the CAR-T process and aid implementation of this novel therapy for patients with RRMM in Brazil.

Advance in chimeric antigen receptor-T cell immunotherapy for multiple myeloma / 中国生物制品学杂志

@#In recent years,considerable progress has been made in the treatment of multiple myeloma(MM).However,despite the current improved prognosis of this malignancy,it always ends in relapse and therefore new therapeutic approaches are urgently needed to overcome it.The chimeric antigen receptor(CAR)-T cells targeting B cell maturation antigen(BCMA),cluster of differentiation 19(CD19),cluster of differentiation 38(CD38) and kappa light chains have been evaluated,and have achieved remarkable results in clinical trials.However,even when MM is treated with CAR-T cell therapy,most patients eventually relapse,which is the greatest limitation of this therapy.This paperreviewedthe research progress,limitations and optimization of CAR-T cell immunotherapy in the treatment of MM.

Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients / 医学前沿

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade ⩾ 3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.

Immune reconstitution in patients with allogeneic hematopoietic stem cell transplantation after CAR-T immunotherapy / 中华检验医学杂志

Objective:To study the performance of immune reconstitution in patients with chimeric antigen receptor (CAR)-T cell immunotherapy bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:A total of 61 patients with acute B lymphocytic leukemia (B-ALL) who received CAR-T cell bridging allo-HSCT in Beijing Lu Daopei Hospital from August 2018 to December 2021 were enrolled, and the clinical medical records of the above patients were retrospectively analyzed. The average age was 14 (7, 30) years old, including 39 males and 22 females. 32 patients were treated with CAR-T cell immunotherapy(CAR-T Group) and 29 didn't with CAR-T cell immunotherapy(non-CAR-T group). The follow-up period was 561 (235,784) days. Multicolor flow cytometry was used to detect the peripheral blood lymphocyte subsets, i.e. total lymphocytes, T lymphocytes, helper T cells, cytotoxic T cells, B lymphocytes, NK cells, and Treg cell counts before transplantation and 1, 2, 3, 6, 8, 10, and 12 months after transplantation, to evaluate the immune reconstitution performance post allo-HSCT.Results:Serum globulin before transplantation: The IgA level in the CAR-T group was 0.18 (0.06, 0.49) g/L, which was lower than that of 1.03 (0.63, 1.56) g/L in the non-CAR-T group ( U=103.5, P<0.001). The IgG level in the CAR-T group was 5.54 (4.04, 7.09) g/L, lower than that of 6.78 (5.27, 9.26) g/L in the non-CAR-T group, ( U=1 298.5, P=0.017), and the IgM level in the CAR-T group was 0.18 (0.05, 0.30) g/L, lower than that of 0.40 (0.26, 0.71) g/L in the non-CAR-T group ( U=166.0, P<0.001). In the CAR-T group before transplantation, the absolute count of total lymphocyte in peripheral blood was 833.00 (335.00, 1 727.50) /μl, lower than that of 1 052.00 (545.75, 1 812.50) /μl in the non-CAR-T group ( U=404.0, P<0.001). The absolute count of T lymphocyte in the CAR-T group before transplantation was 686.00 (233.00, 1 307.00)/μl, lower than that of 860.00 (391.00, 1 419.75) /μl in the non-CAR-T group ( U=406.0, P<0.001). The absolute count of helper T lymphocytes in the CAR-T group was 146.00 (40.50, 327.50) /μl, lower than that of 162.50 (66.00, 384.75) /μl in the non-CAR-T group ( U=494.0, P=0.002). The absolute count of cytotoxic T lymphocytes in the CAR-T group was 343.00 (56.50, 924.00) /μl, lower than that of 478.00 (143.50, 992.25) /μl in the non-CAR-T group ( U=483.5, P=0.001). The absolute count of B lymphocytes in CAR-T group was 22.00 (6.00, 186.00) /μl, lower than that of 33.00 (8.00, 220.00) /μl in the non-CAR-T group ( U=498.0, P=0.002). And when two groups of patients were monitored after transplantation, there was no statistical difference in absolute cell counts of each immune cell subpopulation( P>0.05). Comparing the clinical features of the two groups, the pre-transplant history of the CAR-T group was 981.00 (368.50, 1 514.75) d, longer than that of 323.00 (167.50, 450.50) d in the non-CAR-T group ( U=263.0, P=0.004). The dose of rabbit anti-human thymic immunoglobulin (ATG) in the pretreatment protocol of patients in the CAR-T group was 5.00 (5.00, 7.50) mg/Kg, lower than that of 7.00 (5.00, 7.50) mg/kg in the non-CAR-T group ( U=288.5, P=0.018). The infusion dose of CD34 +cells in the CAR-T group was 5.91 (4.23, 6.02) ×10 6/kg, higher than that of 4.51 (4.00, 5.93)×10 6/kg in the non-CAR-T group ( U=291.0, P=0.012). The duration of the application of cyclosporine after transplantation in the CAR-T group was 167.00 (119.25, 299.50) d, which was shorter than that of 197.00 (102.50, 450.50) d in the non-CAR-T group ( U=421.0, P=0.001). Conclusions:For patients in CAR-T group with low immune function before transplantation, it may be possible to make them comparable to non-CAR-T group in immune reconstitution state by reducing the dose of pretreatment ATG, increasing the counts of CD34 + cells infusion in the graft, and discontinuing cyclosporine as soon as possible after transplantation.

Research Progress of Multi-target CAR-T Cell Therapy for Cancer / 肿瘤防治研究

Chimeric antigen receptor T cell (CAR-T) is a kind of adoptive cell immunotherapy, in which T cells are genetically modified to exert targeted killing effect on tumors. CAR-T cell therapy has shown remarkable antitumor efficacy for the treatment of tumors, especially for hematological malignancies, but is less effective in solid tumors. Single-target CAR-T is prone to off-target effect during application, and there is a risk of relapse or more refractory treatment. The development of double-target or multi-target CAR-T is expected to extend the antigen coverage of target cells, effectively avoids antigen escape and prevents tumor recurrence, and prolongs the survival time of patients. This article reviews the advances of multi-target chimeric antigen receptor T cell, and discusses the prospect of its development.

Research progress of EGFRvIII targeted immunotherapy in the treatment of glioblastoma / 药学学报

Glioblastoma (GBM) is the most common primary brain tumor, which is prone to recurrence and metastasis with poor prognosis. In recent years, immunotherapy has prolonged the survival of patients with GBM, providing a new option for the treatment of GBM. Target selection is very important for immunotherapy. Epidermal growth factor receptor variant III (EGFRvIII) is highly expressed on the surface of GBM cells in some patients, and EGFRvIII was not expressed in normal tissues. EGFRvIII are pivotal for the occurrence and progression of GBM, various targeted therapy including immunotherapy is promising to improve the efficacy of GBM. Currently, there are various approaches to target EGFRvIII, including humanized monoclonal antibodies, adoptive cell therapies and therapeutic vaccines. In this review, we focus on the preclinical and clinical findings of targeting EGFRvIII for GBM.

Advances in research on visualization of living cell drugs in vivo / 中国药科大学学报

@#The development of living cell drugs and their successful application in clinical treatments require full clarification of the fate of cells after transplantation, which is critical to the safety and efficacy of living cell drugs.In order to solve this problem, cell imaging technology has come into our sight, and the use of visualization technology for non-invasive tracing of living cell drugs could reveal the distribution, homing and activity of living cell drugs in the body, which helps to determine the best number of transplanted cells, optimize the administration scheme, improve the transplantation efficiency, enhance the targeting of transplanted cells, and reduce the potential off-target accumulation risk.This paper summarizes the research advances of non-invasive visual tracing in vivo for living cell drugs from the perspectives of radionuclide imaging, magnetic resonance imaging, magnetic particle imaging, computed tomography imaging, fluorescence imaging and multimodal imaging.The aim is to obtain the biological behavior of living cell drugs in vivo with the application of appropriate contrast agent and tracing technology, and provide a more reasonable scientific basis for the research and development of living cell drugs and their transplantation therapy.

Terapia com células CAR-T: reprogramação celular para o combate de neoplasias malignas / CAR-T cell therapy: cell reprogramming to combat malignant neoplasms

As células CAR-T são linfócitos geneticamente modificados para reconhecerem um espectro amplo de antígenos de superfície celulares. Além disso, atacam células tumorais malignas, que expressam esses antígenos, por meio da ativação da coestimulação citoplasmática, secreção de citocinas, citólise de células tumorais e proliferação de células T. O objetivo desse estudo é abordar a imunoterapia com células CAR-T, a fim de explicar seu conceito, processo de fabricação e papel no tratamento de neoplasias hematológicas e tumores sólidos. Foi realizada uma revisão através do portal PubMed, utilizando como descritores: "car-t cell therapy" e "neoplasms", determinados com base nos "Descritores em Ciências da Saúde". Foram obtidos, inicialmente, 10 artigos, os quais foram lidos integralmente para a confecção dessa revisão. Além disso, foram adicionados 3 ensaios clínicos atualizados sobre o tema. Na terapia com células CAR-T, as células T são coletadas do paciente, geneticamente modificadas para incluir receptores de antígeno específicos e, posteriormente, expandidas em laboratórios e transfundidas de volta para o paciente. Assim, esses receptores podem reconhecer células tumorais que expressam um antígeno associado a um tumor. A terapia com células CAR-T é mais conhecida por seu papel no tratamento de malignidades hematológicas de células B, sendo a proteína CD19 o alvo antigênico mais bem estudado até o momento. Entretanto, estudos estão sendo feitos para verificar a eficácia desse tratamento, também, em tumores sólidos. Portanto, apesar de inicialmente ser indicada apenas para um grupo seleto de pessoas, essa terapia tem demonstrado grande potencial para atuar em um espectro maior de pacientes.

The CAR-T cells are lymphocytes genetically modified to recognize a broader spectrum of cell surface antigens. In addition, they attack malignant tumor cells, which express these antigens, by activating cytoplasmic co-stimulation, cytokine secretion, tumor cell cytolysis and T cell proliferation. The aim of this study is to address immunotherapy with CAR-T cells, in order to explain its concept, manufacturing process and role in the treatment of hematological neoplasms and solid tumors. This is a literature review conducted through the PubMed portal, that uses the terms "car-t cell therapy" and "neoplasms" as descriptors, determined based on the DeCS (Descritores em Ciências da Saúde). To prepare this review, initially 10 articles were found and read in full. In addition, 3 updated clinical trials on the subject were added. For CAR-T cell therapy, T cells are collected from the patient, genetically modified to include specific antigen receptors, and later expanded in laboratories and transfused back to the patient. Thus, these receptors can recognize tumor cells that express a tumor-associated antigen. CAR-T cell therapy is best known for its role in the treatment of B cell hematological malignancies, with the CD19 protein being the most studied antigenic target to date. However, studies are being conducted to verify the effectiveness of this treatment, also, in solid tumors. Therefore, despite being formulated only for a selected group of patients, this therapy has great potential to act on a broader spectrum of patients.

Validation and preliminary application of VSV-G qPCR assay for detection replication competent lentivirus / 中华微生物学和免疫学杂志

Objective:To establish VSV-G qPCR assay for detection of replication competent lentivirus(RCL) and verify its application.Methods:A real-time fluorescent quantitative PCR for VSV-G envelope gene was developed. Several parameters including specificity, linear, amplification efficiency, precision, trueness, dynamic range, limit of detection, limit of quantification and robustness were verified. Preliminary application on CAR-T cells, end of production cells and the harvest of lentivirus vector was performed by using the method developed.Results:The real-time fluorescent quantitative PCR assay for VSV-G was specific for the detection VSV-G without specific amplification on 293T, PBMC and C8166 cells. The linear range of the assay was 1×10 2 copies/test-1×10 9 copies/test with a R2 value more than 0.998 and amplification efficiency between 93% and 98%. The precision (relative standard deviation) of the assay was less than 12% and the trueness (the rate of recovery) of the assay was between 85% and 106%. The limit of detection (LOD) and limit of quantification (LOQ) of the assay was 5 copies/test and 40 copies/test. In addition, the robustness of the assay was also well. All the results of validation illustrated that the assay could meet the detection requirements. All of the 54 samples including CAR-T cells, lentivirus vector and end of product cells after amplification and passage on C8166 cells were negative of RCL by using the established assay. Conclusions:The real-time fluorescent quantitative PCR for VSV-G were established successfully. All of the validation results illustrated that the assay could meet the detection requirements. The application of the assay was conducive to further enhance the safety of the lentivirus vector related products.

Advances of multi-targeted chimeric antigen receptor T cells in malignant tumors / 中国肿瘤临床

China has the highest incidence of malignant tumors and associated mortality worldwide; efforts are underway to reduce their recurrence rate and fatality. However, single-target chimeric antigen receptor (CAR) T cells used in the treatment of malignant tumors are prone to antigen target loss, tumor recurrence, and other limitations. Presently, multi-target CAR-T cells that can identify and target two or more tumor-related antigens have been developed in China and in the rest of the world; these cells can be used to effectively avoid antigen escape and prevent tumor recurrence. In this review, we have focused on the progress in multi-target CAR-T strategies currently being developed and tested for the treatment of malignant tumors. We have also discussed the advantages of multi-targeted CAR-T cell therapies and measures to overcome limitations, such as tumor recurrence after single-targeted CAR-T-cell treatment; we have also analyzed the therapeutic effects of multi-targeted CAR-T-cell treatments combined with other regimen. The use of multi-target CAR-T cells as a new therapeutic option to improve anticancer efficacy and reduce cancer progression, has also been proposed.

Preclinical study of suicide gene as a safety switch to control CAR-T cell cytotoxicity / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate whether AP1903, a small-molecule chemical inducer, can terminate the cytotoxicity of CD19CAR-T cells over-expressing iCasp9 suicide gene in vivo and in vitro. Methods: CD19CAR-T cells over-expressing iCasp9 (iCasp9-CD19CAR-T) were constructed and co-incubated with AP1903. Then, the cell phenotype and apoptosis were detected by Flow cytometry, and the iCasp9/CID suicide gene system was verified on K562 and T cells, respectively. The cytotoxicity of iCasp9-CD19CAR-T cells was detected in vivo (survival rate of NCG mice bearing Raji cell transplanted xenograft) and in vitro (cell killing function was detected by Flow cytometry) under the administration of AP1903. Results: Compared with CD19CAR-T cells, iCasp9-CD19CAR-T cells showed in significant difference in proliferation, phenotype and cytotoxicity both in vitro and in vivo (all P>0.05). At 2 h after AP1903 administration, the apoptosis rates of K562 and T cells co-expressing iCasp9 and CD19CAR were (33.8±0.9)% and (27.95±0.35)%, respectively; and at 24 h after AP1903 administration, the apoptosis rates reached 100% in both cell lines. The in vitro cytotoxicity of iCasp9-CD19CAR-T cells induced by AP1903 was significantly lower than that without AP1903 treatment (P<0.01); the 60-day survival rate of mice bearing Raji cell transplanted tumor treated with AP1903-induced iCasp9-CD19CAR-T cells was also significantly lower than those treated with iCasp9-CD19CAR-T cells alone (P<0.01). Conclusion: AP1903 can effectively terminate the cytotoxicity of CD19CAR-T cells over-expressing iCasp9 suicide gene in vitro and in vivo.

Research progress on CAR T-cell neurologic toxicity / 中国输血杂志

Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Currently, two CAR T-cell products have been approved for clinical use by the U. S. FDA. A barrier to widespread use of CAR T-cell therapy is post-infusion toxicity, including primarily cytokine release syndrome and neurologic toxicity, in which neurotoxicity is the main factor for incidence rate and mortality rate.As there is still a lack of pathophysiological research on this symptom, this review describes existing neurologic toxicity and insights into the pathophysiology of this syndrome, which provides new opportunities for targeted therapeutic interventions to modulate CAR T-cell therapy toxicities.

Chimeric Antigen Receptor T Cell Therapy: A Novel Modality for Immune Modulation / 전남의대학술지

Cancer remains a leading cause of death, despite multimodal treatment approaches. Even in patients with a healthy immune response, cancer cells can escape the immune system during tumorigenesis. Cancer cells incapacitate the normal cell-mediated immune system by expressing immune modulation ligands such as programmed death (PD) ligand 1, the B7 molecule, or secreting activators of immune modulators. Chimeric antigen receptor (CAR) T cells were originally designed to target cancer cells. Engineered approaches allow CAR T cells, which possess a simplified yet specific receptor, to be easily activated in limited situations. CAR T cell treatment is a derivative of the antigen-antibody reaction and can be applied to various diseases. In this review, the current successes of CAR T cells in cancer treatment and the therapeutic potential of CAR T cells are discussed.

A general view of CD33⁺ leukemic stem cells and CAR-T cells as interesting targets in acute myeloblatsic leukemia therapy

Acute myeloblastic leukemia (AML) is the most frequent acute leukemia in adulthood with very poor overall survival rates. In the past few decades, significant progresses had led to the findings of new therapeutic approaches and the better understanding of the molecular complexity of this hematologic malignancy. Leukemic stem cells (LSCs) play a key role in the initiation, progression, regression, and drug resistance of different types of leukemia. The cellular and molecular characteristics of LSCs and their mechanism in the development of leukemia had not yet been specified. Therefore, determining their cellular and molecular characteristics and creating new approaches for targeted therapy of LSCs is crucial for the future of leukemia research. For this reason, the recognition of surface maker targets on the cell surface of LSCs has attracted much attention. CD33 has been detected on blasts in most AML patients, making them an interesting target for AML therapy. Genetic engineering of T cells with chimeric antigen receptor (CAR-T cell therapy) is a novel therapeutic strategy. It extends the range of antigens available for use in adoptive T-cell immunotherapy. This review will focus on CAR-T cell approaches as well as monoclonal antibody (mAB)-based therapy, the two antibody-based therapies utilized in AML treatment.

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma / 医学前沿

The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

Precision medicine in acute lymphoblastic leukemia / 医学前沿

The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid > 50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

New strategies for the treatment of neurotoxic side effects in CAR-T cell therapy / 中国肿瘤生物治疗杂志

@# Chimeric antigen receptor modified T (CAR-T) cell therapy is one of the important methods of tumor immunotherapy. The targeting, killing, proliferation and persistence of CAR-T cells are significantly enhanced than that of conventional T cells.After continuous improvement and evolution, CAR-T cell treatment has achieved excellent progress in hematological tumors and has received extensive attention. However, neurotoxicity arising from the treatment, also known as CAR-T cell relevant encephalopathy syndrome (CRES), has affected its clinical application. Exploring the pathogenesis of CRES and high-risk factors, and finding appropriate strategies is therefore critical for the prevention and treatment of CRES. Here, we take CD19-CAR-T cell treatment as example to review the symptoms and pathogenesis of CRES, discuss high-risk factors as well as coping strategies, in an effort to provide a reference for clinical treatment.

Development and evaluation considerations of viral vector production for CAR-T cell products / 中国肿瘤生物治疗杂志

@#Due to the spectacular therapy results in hematologic tumors, chimeric antigen receptor T (CAR-T) cell therapy has been the research hot-spot in the field of cell-immunotherapy. Viral vectors, as the critical raw material in CAR-T cell manufacturing, are closely related to the safety, efficacy and quality control of CAR-T cell products, in the aspects of the structure design of CAR gene, refinement of production process, quality control and setting of characterization and specification etc. Based on the research progress in lentiviral and γ-retroviral vectors development and the evaluation experiences, this paper discusses some common problems that need to be focused on in the preparation of viral vectors, expecting to provide references for the development and the authorization applications of domestic related products in the future.

Optimizing CAR structure to improve safety and efficiency of CAR-T cell therapy / 中国肿瘤生物治疗杂志

@# CAR-T cell therapy has developed rapidly in recent years, and has achieved amazing results in the treatment of some malignant tumors of the blood system, but little progress has been made in the treatment of solid tumors. At present, the main problems to be solved in CAR-T cell therapy are: (1) enhancing the killing activity of CAR-T cells; (2) relieving the immunosuppressive state of tumors; (3) bringing CAR-T cells into solid tumors; (4) enhancing the safety of CAR-T cell therapy. By optimizing the structure of CAR, a series of defects in the CAR-T cell therapy can be overcome, and the curative effect of CAR-T can be enhanced and the complications can be alleviated. In this paper, some optimization and improvement measures and methods on the structure design of CAR in recent years are elaborated, and the effectiveness and safety of the CAR-T cell therapy are explored.