Research progress in targeted therapies of chronic lymphocytic leukemia / 上海交通大学学报（医学版）

Chronic lymphocytic leukemia(CLL)is one of small B-cell lymphomas and leukemias,characterized as a clonal disease of mature B cells.The disease is remarkably heterogeneous,with the majority of patients having an indolent course,yet they are currently incurable.Abnormal signaling pathways are indispensable in the pathogenesis of CLL.In CLL,the common abnormalities of signaling pathways include B-cell receptor(BCR)signaling,apoptosis,nuclear factor kappa B(NF-κB)signaling and Notch signaling.According to the target in signaling pathways,a series of targeted drugs,such as Bruton's tyrosine kinase(BTK)inhibitors(ibrutinib,zanubrutinib),phosphorylate phosphoinositide 3-kinase(PI3K)inhibitor(duvelisib)and B-cell leukemia/lymphoma 2(BCL2)inhibitor(venetoclax),which have significantly changed the prognosis of patients in clinic.Other targeted drugs,such as fenebrutinib,nemtabrutinib and umbralisib,as well as chimeric antigen receptor T-cell(CAR-T)therapy developed in the field of immuno-oncology and T cell engineering,are currently under trial,with more personalized treatment modalities being explored,which may become potential drug targets in the future.In this paper,relevant literature of CLL was reviewed,and recent research progress in molecular pathogenesis and targeted therapies of chronic lymphocytic leukemia was reviewed.

Research progress of chimeric antigen receptor T cell and T cell antigen coupler modified T cell technology / 中国生物制品学杂志

@#At present,malignant tumor has become one of the public problems that seriously threaten human health. In addition to surgery,radiotherapy,chemotherapy,targeted therapy and other methods,with the development of molecular biology,immunotherapy has also developed rapidly,becoming an emerging method of cancer treatment. The most commonly used immune cells in clinical treatment are DC,NK,CIK,CTL and chimeric antigen receptor T cell(CAR-T). Among them,CAR-T technology is the initial technology for global research,while due to its off-target,neurotoxicity,transfection vector defects and other problems,it also has certain limitations in clinical application. T cell antigen coupler modified T cell(TAC-T)technology is a new technology developed on the basis of CAR-T,which uses natural T cell receptor(TCR)to modify T cells and retarget the antigen of cancer cells. In this paper,the research status of CAR-T technology and the research progress of TAC-T technology are reviewed in order to provide reference for further study on the mechanism of TAC-T technology and its safety of clinical application.

Relationship of cytokines to adverse reaction of chimeric antigen receptor T cell immunotherapy and targeted drug intervention / 中国生物制品学杂志

@#Chimeric antigen receptor T cell(CAR-T)immunotherapy is the most potential adoptive immunotherapy for malignant tumors,which needs no antigen presenting cells(APC)and is not limited by major histocompatibiliy complex(MHC). CAR-T immunotherapy not only recognizes and kills tumor cells directly,but also forms memory T cells and establishs long-term anti-tumor mechanism,of which the effect in leukemia,multiple myeloma and other non-solid tumors as well as the great potential in solid tumors have been widely verified. However,a variety of adverse reactions such as cytokine release syndrome(CRS),neurotoxicity(NT)and miss target effect are produced during CAR-T immunotherapy,of which the occurrence of CRS and NT may be related to the abnormal level of cytokines. Remarkable increase of cytokine level is a major characteristics of CRS. However,the increase of cytokines is neither the root cause nor the only result of CAR-T adverse reaction. CAR-T immunotherapy has a high incidence of adverse reaction which may even endanger the life of patients. Cytokine targeted drugs such as Anakinra and Tocilizumab may decrease the incidence of adverse reaction and improve the prognosis of patients. This paper reviews the correlation of cytokines with CRS and NT in CAR-T immunotherapy and the effect of cytokine targeting drugs,so as to provide a reference for the basic research,quality control and clinical application of CAR-T immunotherapy.

Recent research on chimeric antigen receptor T cells in children with refractory/relapsed acute lymphoblastic leukemia / 中国当代儿科杂志

At present, the treatment of refractory/relapsed acute lymphoblastic leukemia is still in a difficult situation, and even if the intensity of chemotherapy is increased or it is combined with hematopoietic stem cell transplantation, some children may have a poor prognosis and a short survival time. Chimeric antigen receptor T-cell (CAR-T) immunotherapy uses genetically engineered T cells and does not rely on the human leukocyte antigen pathway to recognize tumor-specific antigens, and then CAR-T cells bind to target antigen cells to trigger immune response, thereby exerting a sustained anti-leukemia effect. As the most rapidly developed tumor immunotherapy, major breakthroughs have been made for CAR-T cells in the treatment of various hematological tumors, but there still lacks a comprehensive system for the research, development, and production of CAR-T cells and standardized diagnosis and treatment protocols in China. This article reviews the recent research on CAR-T cells in children with refractory/relapsed acute lymphoblastic leukemia.

Recent Progress of Nano-drug Combined with Chimeric Antigen Receptor T Cell Therapy in the Treatment of Soild Tumors / 中国肺癌杂志

Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematological malignancies. However, CAR-T therapy for solid tumors is still limited due to the unique solid-tumor microenvironment and heterogeneous target antigen expression, which leads to an urgent need of combining other therapies. At present, nano delivery system has become one of the most promising directions for the development of anti-tumor drugs. Based on the background of CAR-T and tumor treatment, we focus on the research progress of nanomedicine combined with CAR-T therapy, and systematically review the strategies and examples in recent years in the aspects of in vivo delivery of mRNA, regulation of tumor microenvironment, combination with photothermal therapy. And we also look forward to the future direction of this filed.
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Research progress of CAR-T immunotherapy in solid tumors combined with new strategies / 中国药科大学学报

@#In recent years, the chimeric antigen receptor T-cell (CAR-T) therapy has achieved breakthrough progress in the treatment of hematologic malignancies. However, when it comes to solid tumors, numerous challenges persist.These include limited CAR-T cell infiltration, susceptibility to T cell exhaustion, off-target effects, and more.Thus, novel therapeutic strategies are imperative to enhance the efficacy of CAR-T therapy for solid tumors. In comparison to standalone CAR-T approaches, the combination of CAR-T with other tumor treatment modalities has demonstrated remarkable effectiveness in both preclinical and clinical research.This review article summarizes the advancements in combining CAR-T with various solid tumor treatments: antibody drugs, oncolytic viruses, tumor vaccines, and nanomedicines.The objective is to furnish a theoretical foundation and novel perspectives for the development of innovative CAR-T combination strategies tailored for solid tumor therapy.

Treatment progress of relapsed/refractory follicular lymphoma / 白血病·淋巴瘤

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. The outcome of relapsed/refractory FL patients after multi-therapy is poor. The 64th American Society of Hematology annual meeting in 2022 announced the latest updates on relapsed/refractory FL, including targeted therapy, bio-specific antibodies and chimeric antigen receptor T-cell. This review provides an overview of these updates.

Progress of chimeric antigen receptor T-cell in treatment of multiple myeloma / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy targeting B-cell maturation antigen (BCMA) has shown significant efficacy in relapsed/refractory multiple myeloma. With the rapid development of CAR-T therapies, CAR-T therapies targeting BCMA continue to be optimized, and new products such as new targets, dual-targets and universal CAR-T are arriving successively. Data from several relevant clinical studies were updated at the 64th American Society of Hematology Annual Meeting.

Progress of minimal residual disease monitoring in adult acute lymphoblastic leukemia / 白血病·淋巴瘤

Acute lymphoblastic leukemia (ALL) is a malignancy originating from B-/T-lineage lymphoid progenitor cells. With the continuous development of new drugs as well as therapeutic regimens, adult ALL patients have improved complete remission rates and overall survival rates, but the survival rate of patients after relapse remains low. The positive minimal residual disease after complete remission is an important reason for relapse. Although minimal residual disease monitoring has been found to be important in predicting patients prognosis in recent years, the uniform stratified treatment protocols have not yet been developed in the clinical practice of adult ALL. This article reviews the prognostic significance of minimal residual disease monitoring at different time points, as well as the progress of removal methods of minimal residual disease.

Progress of ibrutinib combined with CD19 chimeric antigen receptor T-cell in treatment of chronic lymphocytic leukemia / 白血病·淋巴瘤

Chronic lymphocytic leukemia (CLL) is a clonal malignant disease of B lymphocytes (T lymphocytes are rare) and usually occurs in elderly people. CLL has a highly variable clinical course, with a median survival of 35 to 63 months. In the era of immunochemotherapy, the survival of CLL patients has improved significantly, but most patients still have primary drug resistance and relapse after the treatment. The emergence of Bruton tyrosine kinase inhibitor has completely changed the treatment mode of CLL, making the treatment of CLL into the era of targeted therapy. Ibrutinib combined with CD19 chimeric antigen receptor T-cell has good efficacy and can improve the prognosis of patients.

Progress of companion diagnostics in chimeric antigen receptor T-cell therapy / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved good efficacy in treatment of hematological malignancies. As a precise and individualized treatment method, CAR-T is gradually moving towards commercialization. In addition to the introduction of corresponding policies and guiding principles, the related detection protocols should also be updated and improved to maximize its effect and achieve precise individualization. This article introduces and expands the concept of "companion diagnostics" that first appeared in targeted drugs, and introduces the significances of various detection technologies and biomarkers for patient screening, safety monitoring and evaluation of efficacy and CAR-T function in the whole process of CAR-T treatment.

Research progress of cytokine release syndrome related to CAR-T immunotherapy / 国际肿瘤学杂志

Chimeric antigen receptor T-cell (CAR-T) immunotherapy is one of the new models of tumor targeted therapy. However, the presence of cytokine release syndrome (CRS) after CAR-T infusion is a key obstacle limiting its therapeutic effects. Macrophage activation and pyrosis of target tumor cells can trigger the release of interleukin-6 and other inflammatory factors, and excessive inflammatory factors can lead to excessive activation of endothelial cells, which is a key molecular mechanism for the escalation of CRS and the occurrence of serious adverse events. Intervention in multiple stages of cytokine production and structural optimization of chimeric antigen receptor molecules are effective strategies to reduce CRS.

The value of ouantitative parameters of magnetic resonance imaging in predicting the efficacy of chimeric antigen receptor T-cell therapy for children and adolescents with mature aggressive B-cell non-Hodgkin lymphoma / 中华实用儿科临床杂志

Objective:To investigate the value of quantitative parameters of magnetic resonance imaging (MRI) in predicting the efficacy of chimeric antigen receptor T-cell (CAR-T) therapy for children and adolescents with mature aggressive B-cell non-Hodgkin lymphoma (NHL).Methods:It was a retrospective multicenter study.Clinical data of 44 children and adolescents diagnosed with mature aggressive B-cell NHL between January 2016 and January 2023 in Henan Cancer Hospital, Beijing Gaobo Boren Hospital, and the First Affiliated Hospital of Xinxiang Medical University were retrospectively analyzed.Patients were divided into complete response (CR) group and non-CR group based on the international criteria for the diagnosis of pediatric NHL.Quantitative parameters of MRI, including T2 signal intensity, the minimal apparent diffusion coefficient (ADCmin), maximal ADC (ADCmax), and the mean ADC (ADCmean) were measured before and within 2 weeks after CAR-T infusion.The correlation between the above parameters and the achievement of CR was analyzed.The intraclass correlation coefficient (ICC) was used to assess the inter-observer agreement among observers in measuring quantitative parameters of MRI.Differences between groups were analyzed using the independent sample t-test.Factors influencing CR were identified through the binary Logistic regression analysis, and a prediction model was established.Model performance was evaluated by plotting receiver operating characteristic (ROC) curves. Results:Significant differences were observed between the CR group and non-CR group in T2 signal intensity before CAR-T infusion (267±152 vs.364±160, P=0.048), and ADCmin (0.94±0.38 vs.0.53±0.28, P<0.05), ADCmax (1.73±0.69 vs.0.84±0.43, P<0.05), ADCmean (1.28±0.48 vs.0.67±0.33, P<0.05), and T2 signal intensity within 2 weeks after CAR-T infusion (198±139 vs.345±168, P=0.004). A univariate prediction model was created by introducing the above quantitative parameters.The area under the curve (AUC), specificity, sensitivity, and accuracy of T2 signal intensity before CAR-T infusion in predicting the efficacy on children and adolescents with mature aggressive B-cell NHL were 0.800, 84.0%, 57.9%, and 72.7%, respectively.The AUC, specificity, sensitivity, and accuracy of ADCmax within 2 weeks of CAR-T infusion were 0.958, 88.0%, 78.9%, and 84.1%, respectively.The AUC, specificity, sensitivity, and accuracy of T2 signal intensity within 2 weeks of CAR-T infusion were 0.869, 84.0%, 68.4%, and 77.3%, respectively. Conclusions:Quantitative parameters of MRI, including ADC values and T2 signal intensity, are of great significance in the early prediction of CAR-T therapy efficacy on children and adolescents with mature aggressive B-cell NHL.Among these parameters, ADCmax presents the strongest predictive performance and serves as a valuable indicator for predicting a complete response with CAR-T treatment.

Clinical study of cytokine models to predict organ functional impairment after treatment with chimeric antigen receptor T cells in children with B-lineage lymphocytic leukemia / 中国小儿急救医学

Objective:To explore the predictive value of peripheral blood cytokine models on organ functional impairment after chimeric antigen receptor T(CAR-T) cell therapy in children with B-lineage lymphocytic leukemia.Methods:The clinical data of 44 children with acute B-lineage lymphoblastic leukemia who received CAR-T cell therapy at Children′s Hospital of Soochow University from September 2018 to October 2020 were retrospectively analyzed.Peripheral blood cytokines, including interleukin(IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon(IFN)-γ and IL-17A, were measured daily for 14 days after receiving CAR-T cell therapy.The trend of peripheral blood cytokine levels was analyzed at the endpoint of organ function recovery or death within 14 days after CAR-T cell treatment.Receiver operating characteristic curve was used to establish a mathematical prediction model to predict the occurrence of organ damage in the children.Results:Of the 44 children, 31 cases were boys and 13 cases were girls, with a median age of 7.96 (5.19, 11.48)years.Cytokine release syndrome(CRS) response occurred in 95.5% (42/44) children, with 88.1% (37/42) had a grade 1-3 CRS response, and 16.7% (7/42) had a severe grade 4-5 CRS response.Using IL-6>3 892.95 pg/mL as cut-off value, the area under the curve(AUC) for predicting acute respiratory failure was 0.818, with a sensitivity of 0.8 and a specificity of 0.735, while combining IFN-γ>414.4 pg/mL, IL-6>3 892.95 pg/mL and IL-2>27.05 pg/mL were the three cut-off values, with an AUC of 0.741, sensitivity of 0.6 and specificity of 0.912 for predicting acute respiratory failure. Using IFN-γ>1 699.5 pg/mL as cut-off value, the AUC for predicting shock was 0.908, with a sensitivity of 0.722 and a specificity of 1.With IL-6>4 607.3 pg/mL as cut-off value, the AUC for predicting liver injury was 0.964, with a sensitivity of 1 and a specificity of 0.906, while combining both IL-6>4 607.3 pg/mL and IFN-γ>1 446.2 pg/mL as cut-off values, the AUC for predicting liver injury was 0.977, with a sensitivity of 1 and a specificity of 0.906.Combining both IL-6>6 972.2 pg/mL and IFN-γ>3 981.5 pg/mL predicted a positive predictive value of 62.5% and a negative predictive value of 94.4% for grade 4-5 CRS response, with an AUC of 0.846, a predictive sensitivity of 0.714 and a specificity of 0.838, and all children had a combination of two or more organ function injuries.Conclusion:The combination of IL-6 and IFN-γ can effectively predict the incidence of liver injury and cytokine release syndrome.The combination of peripheral blood cytokines IFN-γ, IL-6 and IL-2 can be used to predict the incidence of acute respiratory failure after the treatment of CAR-T cells in children with acute B-lineage lymphoblastic leukaemia.IFN-γ single index can be used to predict the incidence of shock.The combination of IL-6 and IFN-γ can be used to predict the incidence of liver injury and the severity of CRS.

Advances in synergistic treatment of radiotherapy and chimeric antigen receptor T cell therapy for refractory / relapsed diffuse large B-cell lymphoma / 中华放射肿瘤学杂志

Chimeric antigen receptor T (CAR-T) cell therapy is one of the most significant advances in cancer treatment in the last few decades, revolutionizing the treatment paradigm for patients with refractory / recurrent diffuse large B-cell lymphoma (R/R DLBCL) and effectively improving the survival rate of these patients. However, due to the high incidence of grade III-IV side effects of CAR-T cell therapy and the fact that some patients did not obtain remission after CAR-T cell therapy or developed rapid disease progression within a short period of time, researchers are attempting to explore combined therapies, such as chemotherapy, radiotherapy and immunotherapy, to reduce the incidence of side effects and prolong the duration of persistent remission in patients. Among these options, radiotherapy in combination with CAR-T cell therapy have been proven to improve clinical prognosis. In this article, the theoretical basis of synergistic treatment of radiotherapy and CAR-T cell therapy in patients with R/R DLBCL, the safety and efficacy of radiotherapy, the sequence of radiotherapy and CAR-T cell therapy, and the dose of the target area of radiotherapy were reviewed, aiming to provide more evidence for the application and optimization of radiotherapy combined with CAR-T cell therapy for R/R DLBCL.

Study on the relationship between serum cytokines levels after chimeric antigen receptor (CAR)-T cell immunotherapy and the prognosis of bridged allogeneic hematopoietic stem cell transplantation in acute B lymphoblastic leukemia patients / 中华检验医学杂志

Objective:To investigate the relationship between the levels of serum cytokines and chemokines and the prognosis of patients with acute B-ALL after receiving chimeric antigen receptor (CAR)-T cell immunotherapy and acute graft-versus-host disease (aGVHD) in patients after bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:According to the case-control principle, Forty-two patients with B-ALL who received CD19-CAR-T cell immunotherapy bridged to allo-HSCT at Heibei Yanda Ludaopei Hospital from September 18, 2019 to May 9, 2022 were enrolled. Mann-Whitney U test was used to compare the changes of aGVHD-related cytokines and chemokine levels between CAR-T cell immunotherapy and bridging transplantation in different patients at the same time. Their plasma levels of cytokines and chemokines related to aGVHD were monitored at the day before CAR-T therapy and after CAR-T treatment at day 4, 7,14,21,28. The receiver operating characteristic curve was drawn to evaluate the predictive value of cytokines and chemokines in predicting the occurrence and the death of aGVHD patients. Kaplan-Meier method and Log-rank tests were used for Overall survival (OS) analysis. Results:Twenty-four of total 42 patients had aGVHD, of which 11 patients died and 31 patients survived. There was no significant difference in cytokines and chemokines between the aGVHD group and the non-aGVHD group on the day before CAR-T cell treatment. According to statistical analysis, the serum Elafin levels of aGVHD group was higher than that of non-aGVHD group at the 21st day [4 482 (2 811, 6 061) ng/L vs 2 466 (1 948, 3 375) ng/L, Z=3.145, P=0.001] and the 28st day [4 391 (2 808, 5594) ng/L vs 2 463 (1 658, 2 830) ng/L, Z=2.038, P=0.048] separately. At the 14th day, serum cytokines and chemokines levels between the two group were as follows,MIP-1 α [21.02 (12.36, 30.35) ng/L vs 5.56 (3.64, 10.79) ng/L], sCD25 [422.47 (257.99, 1 233.78) IU/ml vs 216.11 (133.75,457.39) IU/ml], Elafin [4 101 (2 393, 5 006) ng/L vs 2 155 (1 781, 3 033) ng/L], IL-6 [119.08 (23.97, 183.43) ng/L vs 8.39 (2.91, 17.42) ng/L] and IL-8 [13.56 (12.50, 24.52) ng/L vs 2.83 (1.73,6.87) ng/L] were at higher levels ( Z=2.653, P=0.007; Z=2.176, P=0. 030; Z=2.058, P=0.041; Z=3.329, P<0.001; Z=3.162, P=0.001). The KM survival curve showed that the cumulative survival rates of patients with higher serum levels of MIP-1α, sCD25, Elafin, IL-6 and IL-8 were lower than those with low levels at day 14, and the difference was statistically significant (χ 2=12.353, 4.890, 6.551, 10.563, 20.755, P<0.05). Conclusion:The outcomes of patients treated with CAR-T cell therapy bridged to allo-HSCT was correlated with serum MIP-1α, sCD25, Elafin, IL-6 and IL-8 levels after receiving CAR-T therapy. High concentrations of MIP-1α, sCD25, Elafin, IL-6 and IL-8 suggest poor prognosis and can be used as biomarkers to suggest appropriate clinical selection of therapy.

Targets of chimeric antigen receptor T-cell in breast cancer and the application progress / 肿瘤研究与临床

Breast cancer is the most common malignant tumor in women. It is particularly important to seek targeted therapy other than surgery, chemoradiotherapy, endocrine therapy. With the continuous exploration of tumor immunotherapy, more and more therapeutic targets have been discovered. This paper reviews therapeutic targets of chimeric antigen receptor T-cell (CAR-T) and the application in breast cancer.

Prevention and treatment of virus infection in chimeric antigen receptor T cell therapy / 白血病·淋巴瘤

The widespread application of chimeric antigen receptor T (CAR-T) cell immunotherapy in clinical practice presents the challenges for management and prevention of virus infection during the therapy. The paper reviews the risk factors of virus infection for patients during CAR-T cell immunotherapy, summarizes virus infection after treatment and proposes the strategies for infection prevention and treatment.

Auto-HSCT bridging to CAR-T for follicular lymphoma transformed to B-lymphoblastic leukemia/lymphoma: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To investigate the effect of autologous hematopoietic stem cell transplantation (auto-HSCT) bridging to chimeric antigen receptor T cell (CAR-T) immunotherapy for follicular lymphoma (FL) transformed to B-lymphoblastic leukemia/lymphoma (B-LBL).Methods:The diagnosis and treatment of 1 patient with FL transformed to B-LBL admitted to the First Hospital of Soochow University in August 2020 were retrospectively analyzed and the literature was reviewed.Results:The male patient was 65 years old, and was diagnosed as FL (stage Ⅳ group A, FL international prognostic index -1 score 3 points, high-risk group) in August 2020. And then he was given 6 courses of RB (rituximab combined with bendamustine) regimen, with complete remission (CR) at mid-term and end-stage PET-CT, followed by regular maintenance therapy with rituximab every 2 months, and disease progressed after 4 courses of maintenance therapy. According to the results of histopathology and bone marrow aspiration in December 2021, he was diagnosed B-LBL involving the bone marrow. Partial remission was achieved after induction therapy with zanubnulindb combined with hyper CVAD (cyclophosphamide + doxorubicin + vindesine + dexamethasone) regimen, followed by auto-HSCT bridging to CAR-T treatment targeting CD19 and CD22, which proceeded smoothly with cytokine release syndrome grade 0, immune effector cell-associated neurotoxicity syndrome grade 0. The patient successfully underwent hematopoietic reconstruction and orally taken ibrutinib after discharge. PET-CT indicated CR 2 months after transplantation and he was still in disease-free survival state.Conclusions:The prognosis of FL transformed to B-LBL is poor, and auto-HSCT bridging to CAR-T can improve the prognosis and prolong the survival time of patients who cannot undergo allogeneic hematopoietic stem cell transplantation.

Progress of CD99 as a potential therapeutic target for leukemia / 白血病·淋巴瘤

CD99 gene encodes a transmembrane protein and participates in cell differentiation, adhesion, migration and protein transport. The expression of CD99 is generally low in most normal tissues and cells, and CD99 is differentially expressed in bone marrow and the surface of lymphatic hematopoietic cells. This article reviews the research progress of CD99 in hematological diseases, explores the role of CD99 in myeloid and lymphocytic leukemia, and the significance of CD99 as a therapeutic target for hematological malignancies.