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1.
Science ; 372(6537)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795428

RESUMO

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.


Assuntos
Dasatinibe/farmacologia , Epigênese Genética , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenoma , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Memória Imunológica , Ativação Linfocitária , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Neoplasias Experimentais/terapia , Domínios Proteicos , Estabilidade Proteica , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais , Linfócitos T/metabolismo , Transcrição Genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Rinsho Ketsueki ; 62(3): 163-169, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33828008

RESUMO

To perform chimeric antigen receptor T (CAR-T) cell therapy in heavily pretreated patients with progressive disease and depleted lymphocytes, an optimized leukapheresis protocol must be established. To probe the effects of patient-related parameters on the collection efficiency of CD3+ cells, we retrospectively analyzed patients with relapsed/refractory diffuse large B-cell lymphoma who underwent leukapheresis for tisagenlecleucel at two centers. A total of 51 patients were analyzed, with a median age at apheresis of 59 years, and precollection hemoglobin levels, CD3+ cell counts, and platelet counts of 9.2 g/dl, 574/µl, and 15.8×104/µl, respectively. A median of 3.0×109 (0.7-8.4) CD3+ cells were harvested with 8.7 (4.0-15.7) l apheresis volume. The collection efficiency 2 (CE2) for CD3+ cells was 61.0% (21.0-127.3). One-day apheresis was sufficient to obtain the designated cell numbers in all cases. Lower hemoglobin levels, higher CD3+ cell counts, and higher platelet counts before apheresis were significantly associated with lower CE2 for CD3+ cells. These results suggest a need to increase the apheresis volume in anemic, lymphocyte- or platelet-rich patients due to an expected low CE2. Erythrocyte transfusions before or during apheresis may be a reasonable option for patients with anemia.


Assuntos
Leucaférese , Receptores de Antígenos Quiméricos , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Estudos Retrospectivos
3.
Anticancer Res ; 41(4): 1811-1819, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813386

RESUMO

BACKGROUND/AIM: Glioblastoma is the most common cancer among primary brain tumors, however, its prognosis and treatment advances are very poor. Here, we investigated whether c-Met, FOLR1, and AXL proteins are promising targets for chimeric antigen receptor (CAR) T-cell therapy, for they are known to be over-expressed in a variety of solid tumors. MATERIALS AND METHODS: CAR constructs were prepared and CAR KHYG-1 cells targeting c-Met, FOLR1, or AXL were made by lentiviral transduction. The activity of CAR KHYG-1 cells against cancer cells was measured by cytokine secretion and cell lysis assays. RESULTS: c-Met and AXL were over-expressed in most glioblastoma cell lines (11/13), but not in neuroblastoma cell lines (0/8). FOLR1 was over-expressed only in one among 16 glioblastoma cell lines. Our antigen-specific CAR KHYG-1 cells eradicated target positive glioblastoma cells selectively. CONCLUSION: Anti-c-Met and anti-AXL CAR NK or T cells could be effective in glioblastoma cells.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-met/imunologia , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Técnicas de Cocultura , Citocinas/metabolismo , Citotoxicidade Imunológica , Receptor 1 de Folato/imunologia , Receptor 1 de Folato/metabolismo , Glioblastoma/imunologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Células Jurkat , Células Matadoras Naturais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo
4.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804441

RESUMO

T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling.


Assuntos
Antígenos CD28/imunologia , Linfoma de Células T/imunologia , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Antígenos CD28/metabolismo , Proliferação de Células , Feminino , Humanos , Imunoterapia Adotiva , Linfoma de Células T/patologia , Linfoma de Células T/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos Quiméricos/genética , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Células Tumorais Cultivadas
5.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802203

RESUMO

Currently, bladder cancer (BC) represents a challenging problem in the field of Oncology. The high incidence, prevalence, and progression of BC have led to the exploration of new avenues in its management, in particular in advanced metastatic stages. The recent inclusion of immune checkpoint blockade inhibitors as a therapeutic option for BC represents an unprecedented advance in BC management. However, although some patients show durable responses, the fraction of patients showing benefit is still limited. Notwithstanding, cell-based therapies, initially developed for the management of hematological cancers by infusing immune or trained immune cells or after the engineering of chimeric antigen receptor (CAR) expressing cells, are promising tools to control, or even cure, solid tumors. In this review, we summarize recent cell-based immunotherapy studies, with a special focus on BC.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Humanos , Neoplasias da Bexiga Urinária/patologia
6.
Zhonghua Xue Ye Xue Za Zhi ; 42(2): 140-145, 2021 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-33858045

RESUMO

Objective: To investigate the characteristics and cytotoxicity in vitro of the residual leukemia cells in the culture system that caused the accidental transfer of CD19 chimeric antigen receptor (CAR) into leukemia cells during the preparation of autologous CD19 CAR-T cells of relapsed/refractory B-cell acute lymphoblastic leukemia. Methods: ①Peripheral blood mononuclear cells (PBMC) of 30 patients with relapsed/refractory B-cell acute lymphoblastic anemia (R/R B-ALL) who accepted CD19 CAR-T cell therapy and six healthy volunteers were collected. ②The residual leukemia cells were analyzed by flow cytometry in the system after the PBMCs of R/R B-ALL patients were sorted by CD3 magnetic beads. ③ CD3(+) T cells from patients and healthy volunteers were transfected with CD19 CAR and CD22 CAR lentivirus to prepare CD19 CAR-T and CD22 CAR-T cells. ④The Nalm-6 cell line was resuscitated and the Nalm-6 cells with CD19 CAR lentivirus were transfected to prepare CD19 CAR-Nalm-6 cells. The patient's primary ALL cells were transfected with CD19 CAR lentivirus at the same time. ⑤The transfection rates were analyzed by flow cytometer, the cell proliferation was analyzed by the CCK-8 method, and the cell-killing activities were detected by the lactate dehydrogenase method. Results: ① Among the 30 R/R B-ALL patients who received CD19 CAR-T cell therapy, two patients had 2.04% and 3.32% residual leukemia cells in CD3(+) T cells. After 4 days in culture, the residual leukemia cells disappeared and could not be detected by a flow cytometer with prolonged cultivation in vitro. ② The proliferation of CD19 CAR-Nalm-6 cells was higher than that of the Nalm-6 cells. ③ The killing activity of the CD19 CAR-T cells on Nalm-6 cells was higher than that of the CD19 CAR-Nalm6 cells at a target ratio of 1∶1 on 24, 48, 72 h, respectively. The cytotoxicity of CD22 CAR-T cells on CD19 CAR-Nalm-6 cells was significantly higher than that of CD19 CAR-T cells. ④ The cytotoxicity of CD22 CAR-T alone on CD19 CAR-Nalm-6 cells was higher than that of CD19 CAR-T combined with CD22 CAR-T at the same target ratio. Conclusion: The residual leukemia cells in the culture system in the preparation of CD19 CAR-T cells may lead to the introduction of CD19 CAR into leukemia cells and results in the failure of the CD19 CAR-T cell therapy. Detecting the residual leukemia cells in the culture system via flow cytometry before transfection with CD19 CAR lentivirus is needed. Thus, CD22 CAR-T cell therapy could be used as one of the salvage treatments.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Antígenos CD19 , Linfócitos B , Humanos , Imunoterapia Adotiva , Leucócitos Mononucleares , Linfócitos T
9.
BioDrugs ; 35(3): 281-302, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33826079

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.


Assuntos
Leucemia Mieloide Aguda , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia , Imunoterapia Adotiva , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos Quiméricos/genética , Microambiente Tumoral
10.
Methods Mol Biol ; 2265: 645-654, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704745

RESUMO

Expression of chimeric antigen receptors can redirect T cell specificity and allow for MHC-independent recognition of melanoma associated antigens. Retroviral transduction is used to express chimeric antigen receptor constructs in murine CD4+ and CD8+ T cells. Here we describe the production of retroviral supernatants and the activation, transduction, expansion, and selection of murine T cells expressing the chimeric-PD1 receptor. This protocol can be modified for any murine chimeric antigen receptor construct.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Imunoterapia Adotiva , Melanoma Experimental , Receptores de Antígenos Quiméricos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia
11.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670942

RESUMO

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia/métodos , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , /imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Feminino , Humanos , Imunoterapia Adotiva/métodos , Terapia de Alvo Molecular , Receptores de Antígenos Quiméricos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
12.
Anticancer Res ; 41(3): 1143-1156, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788705

RESUMO

Haematology has been at the forefront of cancer immunotherapy advancements. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is one of the earliest forms of cancer immunotherapy and continues to cure thousands of patients. Donor lymphocyte infusion (DLI) increases allo-HSCT efficacy and reduces graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T-cells have been approved for the treatment of distinct haematologic malignancies, producing durable response in otherwise untreatable patients. New target antigen identification and technological advances have enabled the structural and functional evolution of CARs, broadening their applications. Despite successes, adoptive T-cell (ATC) therapies are expensive, can cause severe adverse reactions and their use is restricted to few patients. This review considers the current status and future perspectives of allogeneic transplant and donor lymphocytes, as well as novel ATC therapies, such as CAR-T-cells in haematological malignancies by analysing their strengths, weaknesses, opportunities, and threats (SWOT). The biological rationale for anti-cancer mechanisms and development; current clinical data in specific haematological malignancies; efficacy, toxicity, response and resistance profiles; novel strategies to improve these characteristics; and potential targets to enhance or expand the application of these therapies are discussed.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Imunoterapia/métodos , Linfócitos T/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/uso terapêutico , Humanos , Imunoterapia Adotiva/efeitos adversos , Transfusão de Linfócitos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/imunologia , Doadores de Tecidos
13.
Cancer Invest ; 39(4): 285-296, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33646061

RESUMO

The switchable chimeric antigen receptors (CARs) have shown many advantages in CAR T-cell therapy. However, human primary T-cells are required to evaluate antigen-specific adaptors by IFN-γ assay or FACS analysis, which limits the throughput of adaptor screening. A sensitive and robust CD16-CAR Jurkat NFAT-eGFP reporter system has been developed to assess the therapeutic efficacy of antibody-targeted CAR-T-cell by effectively evaluating the T-cell activation by various tumor cells and the impact of immune checkpoint inhibitor antibodies. This reporter system facilitates the screening of targeted antibodies in a high throughput manner for the development of improved T-cell immunotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Cetuximab/farmacologia , Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Receptores de IgG/imunologia , Linfócitos T/transplante , Células A549 , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Células HCT116 , Ensaios de Triagem em Larga Escala , Humanos , Células Jurkat , Fatores de Transcrição NFATC/genética , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669431

RESUMO

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11-67% CR rates with 13-78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10-36% CR rates with 7-24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Leucemia Mieloide Aguda/metabolismo , Taxa de Sobrevida
15.
Ann Clin Transl Neurol ; 8(4): 968-979, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33780166

RESUMO

OBJECTIVE: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS: Narrative literature review. RESULTS: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.


Assuntos
Encefalopatias/fisiopatologia , Encéfalo/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos , Encefalopatias/epidemiologia , Encefalopatias/terapia , /terapia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunoterapia Adotiva/tendências
17.
J Affect Disord ; 286: 33-39, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33676261

RESUMO

BACKGROUND: We conducted a survey to investigate the prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: In total, 130 eligible patients completed the Self-Rating Anxiety Scale and Self-Rating Depression Scale at week 4 after CAR-T cell infusion. We collected sociodemographic information during the same period. We studied factors associated with anxiety and depressive symptoms using logistic regression analysis. RESULTS: The prevalence of anxiety and depressive symptoms at week 4 after infusion were 13.8% and 40.0%, respectively. A cutoff value of 50 or above indicates significantly anxiety and depressive symptoms. Binary logistic regression analysis showed that high school education and above (OR = 0.22, 95% CI = 0.06-0.78) and middle age (OR = 0.16, 95% CI = 0.03-0.90) were associated with lower risk of anxiety symptoms, and increased odds of depressive symptoms was associated with old age (OR = 11.39, 95% CI = 2.50-51.88), non-manual occupations before illness (OR = 3.72, 95% CI = 1.20-11.58), and higher healthcare expenditure (OR = 3.93, 95% CI = 1.50-10.33), while lower risk of depressive symptoms was associated with rural household location (OR = 0.25, 95% CI = 0.08-0.76) and being cared for by spouse (OR = 0.12, 95% CI = 0.02-0.63). CONCLUSIONS: Patients receiving CAR-T therapy with lower education background, old ages, urban household location, or who used to work as non-manual workers require more attention and psychological care. Support from a spouse and medical expense deductions from the government may help patients develop positive attitudes.


Assuntos
Neoplasias Hematológicas , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Ansiedade/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários , Linfócitos T
19.
Nat Commun ; 12(1): 1237, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623012

RESUMO

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.


Assuntos
Anticorpos Biespecíficos/imunologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/imunologia , Janus Quinase 2/metabolismo , Neoplasias/imunologia , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Citotoxicidade Imunológica , Humanos , Interferon gama/metabolismo , Camundongos , Transdução de Sinais , Transcriptoma/genética
20.
Science ; 371(6534): 1166-1171, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33632893

RESUMO

Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic "off-tumor" cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric antigen receptor (CAR)-T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive-feedback circuit that allows human cytotoxic T cells to discriminate targets on the basis of a sigmoidal antigen-density threshold. In this circuit, a low-affinity synthetic Notch receptor for HER2 controls the expression of a high-affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells-it increases both CAR expression and activation-leading to a sigmoidal response. T cells with this circuit show sharp discrimination between target cells expressing normal amounts of HER2 and cancer cells expressing 100 times as much HER2, both in vitro and in vivo.


Assuntos
Engenharia Celular , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva , Células K562 , Camundongos , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores Artificiais/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Esferoides Celulares , Ensaios Antitumorais Modelo de Xenoenxerto
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