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1.
Medicine (Baltimore) ; 99(43): e22510, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120740

RESUMO

INTRODUCTION: Chimeric antigen receptor T cells (CAR-T) targeting CD19 have shown great potential for treatment of B-cell malignancies. For those patients who can not achieve complete remission (CR) or suffer from relapse after CAR-T therapy, further therapeutic strategies still remain elusive. Whether existing CAR-T cells can revitalize in vivo and eradicate tumor cells is still unknown. PATIENT CONCERNS: We report a case of diffused large B-cell lymphoma patient who had achieved CR after CD19 targeted CAR-T therapy but relapsed after 5 months. DIAGNOSIS: Five months after CAR-T cell infusion, the patient was confirmed a relapse by follow-up PET/CT scan and a mass biopsy. Flow cytometry showed a dramatically decreased percentage of CAR-T cells in peripheral blood (PB). INTERVENTIONS: A second anti-CD19 CAR-T therapy was planned with deliberation. Firstly, the patient received lymphodepletion chemotherapy with fludarabine (25 mg/m, d1-d3) and cyclophosphamide (500 mg/m d2-d3). OUTCOMES: After fludarabine and cyclophosphamide (FC) lymphodepletion chemotherapy, pre-existing CAR-T cells were revitalized and the patient developed grade 2 cytokine release syndrome (CRS) contributing to the regression of relapsed B-cell lymphoma. CONCLUSIONS: This case suggested that FC chemotherapy could revitalize CAR-T cells contributing to the regression of relapsed B-cell lymphoma. Nevertheless, further researches are required in the future as this report described only a single case.


Assuntos
Ciclofosfamida/uso terapêutico , Depleção Linfocítica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão , Linfócitos T/imunologia , Vidarabina/análogos & derivados , Adulto , Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Vidarabina/uso terapêutico
2.
Lancet Haematol ; 7(11): e816-e826, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33091355

RESUMO

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. METHODS: We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. FINDINGS: From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I2=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I2=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I2=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I2=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I2=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. INTERPRETATION: The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. FUNDING: National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Síndrome da Liberação de Citocina/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/uso terapêutico , Indução de Remissão , Transplante Autólogo
3.
PLoS One ; 15(9): e0238493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886698

RESUMO

To better understand anti-malaria protective immune responses, we examined the cellular mechanisms that govern protective immunity in a murine Plasmodium yoelii 17X NL (PyNL) re-infection model. Initially, we confirmed that immune B cells generated during a primary PyNL infection were largely responsible for protection from a second PyNL infection. Using the previously identified memory B cell markers CD80, PD-L2, and CD73, we found an increase in the frequency of CD80-PD-L2-CD73+ B cells up to 55 days after a primary PyNL infection and at 4-6 days following a second PyNL infection. Moreover, injection of enriched immune CD19+CD73+ B cells into nonimmune mice were significantly more protective against a PyNL infection than CD73- B cells. Interestingly, a substantial fraction of these CD73+ B cells also expressed IgM and granzyme B, a biomolecule that has been increasingly associated with protective responses against malaria.


Assuntos
5'-Nucleotidase/metabolismo , Granzimas/metabolismo , Malária/prevenção & controle , 5'-Nucleotidase/imunologia , Animais , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Linfócitos B/imunologia , Feminino , Imunidade , Imunoglobulina M , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium yoelii/imunologia , Plasmodium yoelii/patogenicidade
4.
Ann Hematol ; 99(11): 2599-2609, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32935190

RESUMO

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.


Assuntos
Antígenos CD19/biossíntese , Células da Medula Óssea , Antígeno CD56/biossíntese , Mieloma Múltiplo , Proteínas de Neoplasias/biossíntese , Plasmócitos , Adulto , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/classificação , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasia Residual , Plasmócitos/metabolismo , Plasmócitos/patologia , Estudos Retrospectivos
5.
PLoS One ; 15(9): e0238819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976541

RESUMO

Adoptive cell transfer of Chimeric Antigen Receptor (CAR)-T cells showed promising results in patients with B cell malignancies. However, the detailed mechanism of CAR-T cell interaction with the target tumor cells is still not well understood. This work provides a systematic method for analyzing the activation and degranulation of second-generation CAR-T cells utilizing antigen-presenting cell surfaces. Antigen-presenting cell surfaces composed of circular micropatterns of CAR-specific anti-idiotype antibodies have been developed to mimic the interaction of CAR-T cells with target tumor cells using micro-contact printing. The levels of activation and degranulation of fixed non-transduced T cells (NT), CD19.CAR-T cells, and GD2.CAR-T cells on the antigen-presenting cell surfaces were quantified and compared by measuring the intensity of the CD3ζ chain phosphorylation and the Lysosome-Associated Membrane Protein 1 (LAMP-1), respectively. The size and morphology of the cells were also measured. The intracellular Ca2+ flux of NT and CAR-T cells upon engagement with the antigen-presenting cell surface was reported. Results suggest that NT and CD19.CAR-T cells have comparable activation levels, while NT have higher degranulation levels than CD19.CAR-T cells and GD2.CAR-T cells. The findings show that antigen-presenting cell surfaces allow a quantitative analysis of the molecules involved in synapse formation in different CAR-T cells in a systematic, reproducible manner.


Assuntos
Antígenos de Superfície/metabolismo , Linfoma de Células B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Transferência Adotiva/métodos , Células Apresentadoras de Antígenos/imunologia , Antígenos CD19/metabolismo , Linfócitos B/imunologia , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Linfócitos T/imunologia
6.
Lancet ; 396(10254): 839-852, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32888407

RESUMO

BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , Antígenos CD19/administração & dosagem , Antígenos CD19/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Síndrome da Liberação de Citocina/epidemiologia , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese/métodos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Doenças do Sistema Nervoso/epidemiologia , Neutropenia/epidemiologia , Recidiva , Segurança , Análise de Sobrevida , Trombocitopenia/epidemiologia , Resultado do Tratamento
7.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 953-957, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933625

RESUMO

OBJECTIVE: To study the clinical effect of recombinant human interferon α1b assisting acyclovir on immune function, inflammatory factors, and myocardial zymogram in children with infectious mononucleosis (IM). METHODS: A total of 182 children with IM who were admitted to the hospital from January to December, 2018, were divided into an observation group with 91 children and a control group with 91 children using a random number table. The children in the control group were treated with intravenous drip of acyclovir, and those in the observation group were treated with inhalation of recombinant human interferon α1b in addition to the treatment in the control group. The two groups were compared in terms of clinical symptoms, immune function, inflammatory response, myocardial zymogram, and adverse reactions. RESULTS: Compared with the control group, the observation group had significantly shorter time to body temperature recovery and disappearance of isthmopyra, cervical lymph node enlargement, hepatomegaly, and splenomegaly (P<0.05). After treatment, both groups had significant increases in CD4+, CD4+/CD8+, and CD19+, and the observation group had significantly higher levels of these markers than the control group (P<0.05). After treatment, both groups had significant reductions in the levels of CD8+, tumor necrosis factor-α, interlukin-6, creatine kinase, and creatine kinase-MB, and the treatment group had significantly lower levels of these markers than the control group (P<0.05). There was no significant difference in the incidence rate of adverse reactions between the two groups after treatment (P>0.05). CONCLUSIONS: For children with IM, recombinant human interferon α1b assisting acyclovir can effectively improve immune function, inhibit inflammatory reaction, reduce myocardial injury, and thus alleviate clinical symptoms.


Assuntos
Mononucleose Infecciosa , Antígenos CD19 , Hepatomegalia , Humanos , Estudos Prospectivos , Esplenomegalia
8.
Lancet Haematol ; 7(9): e690-e696, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32791043

RESUMO

People living with HIV are a global population with increased cancer risk but their access to modern immunotherapies for cancer treatment has been limited by socioeconomic factors and inadequate research to support safety and efficacy in this population. These immunotherapies include immune checkpoint inhibitors and advances in cellular immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy. Despite the field of cancer immunotherapy rapidly expanding with ongoing clinical trials, people with HIV are often excluded from such trials. In 2019, post-approval evaluation of anti-CD19 CAR T-cell therapy in people with HIV and aggressive B-cell lymphoma showed the feasibility of CAR T-cell therapy for cancer in this excluded group. Along with expanded treatment options for people with HIV is the ability to assess the effects of immunotherapy on the latent HIV reservoir, with certain immunotherapies showing the ability to alleviate this burden. This Series paper addresses the increased cancer burden in people with HIV, the increasing evidence for the safety and efficacy of immunotherapies in the context of HIV and cancer, and opportunities for novel applications of CAR-T therapy for the treatment of both haematological malignancies and HIV.


Assuntos
Infecções por HIV/patologia , Neoplasias Hematológicas/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/transplante , Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Infecções por HIV/complicações , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Humanos , Imunoterapia Adotiva , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/metabolismo
9.
Nat Commun ; 11(1): 3989, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778653

RESUMO

Upon stimulation, B cells assume heterogeneous cell fates, with only a fraction differentiating into antibody-secreting cells (ASC). Here we investigate B cell fate programming and heterogeneity during ASC differentiation using T cell-independent models. We find that maximal ASC induction requires at least eight cell divisions in vivo, with BLIMP-1 being required for differentiation at division eight. Single cell RNA-sequencing of activated B cells and construction of differentiation trajectories reveal an early cell fate bifurcation. The ASC-destined branch requires induction of IRF4, MYC-target genes, and oxidative phosphorylation, with the loss of CD62L expression serving as a potential early marker of ASC fate commitment. Meanwhile, the non-ASC branch expresses an inflammatory signature, and maintains B cell fate programming. Finally, ASC can be further subseted based on their differential responses to ER-stress, indicating multiple development branch points. Our data thus define the cell division kinetics of B cell differentiation in vivo, and identify the molecular trajectories of B cell fate and ASC formation.


Assuntos
Células Produtoras de Anticorpos/metabolismo , Linfócitos B/imunologia , Ativação Linfocitária/fisiologia , Animais , Antígenos CD19/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imunidade , Fatores Reguladores de Interferon/metabolismo , Selectina L , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Transcriptoma
10.
Ann Hematol ; 99(10): 2215-2229, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856140

RESUMO

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/economia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Análise Custo-Benefício , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Custos de Medicamentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Infusões Intravenosas , Injeções Subcutâneas , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Medicação , Qualidade de Vida , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral , Evasão Tumoral
11.
PLoS One ; 15(7): e0235449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716916

RESUMO

BACKGROUND: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. METHODS: We performed a cross sectional study on PB B cells in MS patients treated with interferon-ß (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). RESULTS: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-ß treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. CONCLUSION: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-ß and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/classificação , Antígenos CD/imunologia , Antígenos CD19 , Subpopulações de Linfócitos B/classificação , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Estudos Transversais , Fumarato de Dimetilo/administração & dosagem , Feminino , Cloridrato de Fingolimode/administração & dosagem , Citometria de Fluxo , Acetato de Glatiramer/administração & dosagem , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Interferon beta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Adulto Jovem
12.
Zhonghua Xue Ye Xue Za Zhi ; 41(6): 490-494, 2020 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-32654463

RESUMO

Objective: This study aimed to examine the safety and efficacy of CD19 chimeric antigen receptor T cell (CD19 CAR-T) therapy in relapsed/refractory Philadelphia chromosome-positive acute B-precursor lymphoblastic leukemia (R/R Ph(+) B-ALL) . Methods: The clinical data of 14 patients with R/R Ph(+) B-ALL treated with CD19 CAR-T cell therapy from November 2016 to April 2019 were retrospectively analyzed. Results: Among the 14 patients in this study, 7 were male and 7 were female, with a median age of 33 (7-66) years old. The efficacy was evaluated on the 28th day following CAR-T cells infusion; the overall response rate was 100.0% (14/14) , the complete response (CR) rate was 92.9% (13/14) , and the partial response (PR) rate was 7.1% (1/14) . After CAR-T cells infusion,12 cases (85.7%) developed cytokine release syndrome (CRS) : 1 case of grade 1 CRS, 4 cases of grade 2 CRS, 6 cases of grade 3 CRS, and 1 case of grade 4 CRS. Moreover, one case developed CAR T-cell-related encephalopathy syndrome (CRES) ; 14 cases had Ⅲ-Ⅳ hematological toxicity; and 13 CR cases had B cell dysplasia. These adverse reactions were all controllable. The median follow-up time was 441 (182-923) d. The median overall survival (OS) and progression-free survival (PFS) were 515 [95% confidence interval (CI) 287-743] days and 207 (95% CI 123-301) days, respectively. Conclusion: CD19 CAR-T cell therapy is safe and effective for R/R Ph(+) B-ALL treatment. However, the long-term efficacy needs to be further improved.


Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Idoso , Antígenos CD19 , Criança , Feminino , Humanos , Imunoterapia Adotiva , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T , Estudos Retrospectivos , Linfócitos T , Adulto Jovem
13.
Zhonghua Xue Ye Xue Za Zhi ; 41(6): 495-501, 2020 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-32654464

RESUMO

Objective: This study aimed to evaluate the maintenance therapy following an anti-CD19-CAR T-cell therapy for a B-cell acute lymphoblastic leukemia (ALL) patient who relapsed after allogeneic hematopoietic cell transplantation (allo-HSCT) and investigate the effect of donor stem cells and donor T lymphocyte infusion on the amplification of CD19 CAR-T cells. Methods: One refractory B-ALL patient relapsed after murine CD19 CAR-T cell therapy followed by a sibling allo-HSCT. He underwent a humanized CD19 CAR-T cell therapy followed by donor stem cell and donor T lymphocytes infusions as maintenance therapy in our hospital. The level of cytokines, the proportion of CD19 CAR-T cell, the level of CAR19 DNA expression in the peripheral blood, and the proportion of leukemia cells and donor chimerism in the bone marrow were detected. Correspondingly, T lymphocytes from the C57 spleen were separated to modify the CD19 CAR lentivirus and refused into C57 mice, and after 14 days, the B lymphocytes from C57 mice were separated and refused into the same C57 mice. The CD19 CAR T cells, B cells, and CD19 CAR gene counts in the peripheral blood were evaluated at different time points. Results: ①The patient achieved a complete response (CR) 14 days after a humanized CD19 CAR-T therapy with grade 1 cytokine release syndrome (CRS) and restored a donor chimerism to 99.76%. ② Following the remission from humanized CD19 CAR-T therapy, the patient received a maintenance therapy of donor stem cell infusion. Mild graft-versus-host disease (GVHD) manifested 24 days after infusion with an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. It fell with the remission of GVHD. The patient maintained CR and 99.69% donor chimerism during this period. ③ Throughout the subsequent donor T lymphocytes maintenance therapy, mild GVHD surfaced12 days after infusion without an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood. The patient maintained CR and 99.87% donor chimerism during this period. ④ In vivo experiments on C57 mice confirmed that the proportion of CD19 CAR-T cells and the level of CAR19 DNA expression were upregulated in mice following CAR-T cell infusion, accompanied by depletion of CD19(+) B lymphocyte. After infusion of CD19(+) B lymphocyte cells, an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood were observed again. Conclusions: The infusion of donor stem cells and donor T lymphocytes could be used as a maintenance treatment after CD19 CAR-T cell therapy for B-ALL patients who relapsed after allo-HSCT. Infusion of donor stem cells induced an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression with the occurrence of GVHD. It might lead to further elimination of minimal residual disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Antígenos CD19 , Linfócitos B , Doença Enxerto-Hospedeiro , Humanos , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos
14.
Nat Commun ; 11(1): 3412, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641742

RESUMO

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.


Assuntos
Linfócitos B Reguladores/metabolismo , Colesterol/metabolismo , Interleucina-10/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Animais , Antígenos CD19/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Técnicas de Cocultura , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Macrófagos/metabolismo , Síndrome Metabólica/metabolismo , Deficiência de Mevalonato Quinase/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Análise de Componente Principal , Transdução de Sinais , Células Th1/metabolismo , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Diabetes Res Clin Pract ; 167: 108341, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32707212

RESUMO

BACKGROUND: Host dysregulation of immune response was highly involved in the pathological process of Coronavirus disease 2019 (COVID-19), especially COVID-19 severe cases with DM. AIM: In this study we aimed at the dynamic change of peripheral lymphocyte and subsets during COVID-19 covery. METHODS: The peripheral lymphocyte and subsets of 95 confirmed cases with COVID-19 from baseline to four weeks were compared between critical illness and non-critical illness cases with or without DM. RESULTS: The dynamic characteristics of lymphocyte and subsets in COVID-19 patients was that it reduced significantly at one week, rapidly elevated to the peak at two weeks after onset, then gradually declined during recovery. The COVID-19 critical illness patients with DM had the lowest decline at one week and the slow lowest rise at two weeks after onset, while COVID-19 non-critical illness patients with DM had the rapid highest rise at two weeks after onset, both of them had similar lymphocyte and subsets at five weeks after onset and lower than those patients without DM. CONCLUSIONS: These findings provide a reference for clinicians that for COVID-19 patients with DM and the lowest decline of lymphocyte and subsets, immunomodulatory therapy as soon as possible might avoid or slow down disease progression; moreover for COVID-19 critical illness patients with or without DM and non-critical illness patients with DM, continuous immunomodulatory therapy in later stages of disease might speed up virus clearance, shorten hospital stay, improve disease prognosis in COVID-19 critical illness patients with DM.


Assuntos
Linfócitos B , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por Coronavirus/sangue , Complicações do Diabetes/sangue , Diabetes Mellitus/metabolismo , Células Matadoras Naturais , Pneumonia Viral/sangue , Subpopulações de Linfócitos T , Adulto , Idoso , Antígenos CD19 , Betacoronavirus , Complexo CD3 , Contagem de Linfócito CD4 , Antígeno CD56 , Comorbidade , Infecções por Coronavirus/complicações , Estado Terminal , Progressão da Doença , Feminino , Humanos , Tempo de Internação , Contagem de Linfócitos , Subpopulações de Linfócitos , Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(5): 390-397, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32696750

RESUMO

Objective To optimize the culture system of chimeric antigen receptor T (CAR-T) cells in vitro and lentivirus infection conditions. Methods Peripheral blood mononuclear cells (PBMCs) of healthy people and umbilical cord blood mononuclear cells (UCBMCs) of healthy pregnant women were isolated and purified by CD3 magnetic beads, and then they were cultured in different cell culture systems. There were eight cell culture systems containg different combinations of the following components: recombinant human interleukin 2 (rhIL-2), rhIL-12, rhIL-18, rhIL-7, rhIL-21, TWS119. Cell proliferation was detected by counting the cells at 0, 3, 5, 7, 10, 18 days after the cells were seeded into cell plates. Flow cytometry was used to detect the expression of programmed death 1 (PD-1), and ELISA was used to detect the expression of interferon-γ (IFN-γ). Cell culturing plates were coated with serial concentrations of recombinant human fibronectin fragment (RetroNectinr) (0, 20, 50 µg/mL), and antibodies against human CD3/CD28 (250, 500, 1 000 ng/mL). Then T cells cultured in the above plates were infected with negative control lentivirus at different multiplicity of infection (MOI=3, 5); 72 hours later, expression of green fluorescent protein (GFP) was observed under a fluorescence microscope to preliminarily determine virus infection efficiency. Flow cytometry was used to detect CD3/GFP positive rate to obtain lentivirus infection conditions. CD19 CAR lentivirus was packaged. Real-time quantitative PCR and Western blotting were performed to detect whether the CD19 CAR vector was successfully constructed. Finally, T cells were cultured in 1 µg/mL anti-human CD3/CD28 and 20 µg/mL RetroNectinr-coated culture plates, and rhIL-2, rhIL-12, rhIL-18 were added in the culture medium, then the cells were infected with CD19 CAR lentivirus at the optimized virus infection conditions. Results The cell culture system with the best proliferation ability was rhIL-2 combining with rhIL-18; the cell culture system with the strongest release of IFN-γ was rhIL-2 and rhIL-12 combined with rhIL-18. When the dose of antibodies against CD3/CD28 was 1 µg/mL, RetroNectinr was 20 µg/mL, and MOI was 3, the virus infection efficiency was optimal. The positive rate of CAR-T cells was 34% under the optimal condition. Conclusion The study achieved the optimal cell culture system of CD19 CAR-T cells in vitro and the conditions of lentivirus infection on primary T cells.


Assuntos
Lentivirus , Antígenos CD19 , Feminino , Humanos , Lentivirus/genética , Leucócitos Mononucleares , Gravidez , Receptores de Antígenos Quiméricos , Linfócitos T/imunologia
19.
Zhonghua Xue Ye Xue Za Zhi ; 41(4): 282-286, 2020 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-32447930

RESUMO

Objective: To analyze the influence of CD19 isoforms to the efficacy of CD19/CD3 Bispecific T-cell Engager (BiTE) antibody, and explore the resistance mechanism of BiTE immunotherapy. Methods: Semi-quantitative RT-PCR (qRT-PCR) was used to detect the expression of CD19 mRNA isoforms before and after BiTE treatment in a patient with CD19(+) B cell acute lymphoblastic leukemia (ALL) . CD19 isoforms were analyzed by Sanger sequencing. Flow cytometry and transcriptome sequencing were performed to analyze the expression of cell lineage specific molecules before and after BiTE treatment. Results: The expression of CD19 isoform with exon 2 deletion was identified at diagnosis. After relapsed and treatment of BiTE antibody, the patient did not achieve remission and CD19 antigen on leukemic cells turned negative detected by flow cytometry after BiTE treatment. However the expression ratio of CD19 isoform with exon 2 deletion was not increased. Flow cytometry phenotype and transcriptome sequencing confirmed that no linage switching developed, which suggested the expression of CD19 isoform caused by exon alternative splicing and lineage switching was not related to CD19 epitope loss in this patient. This patient achieved complete remission by sequential administration of self-developed CD22 CAR-T and CD19 CAR-T after disease progression. Conclusion: Targeting or combining an alternative antigen specific CAR-T may be a promising treatment option after losing CD19 expression in relapsed ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Antígenos CD19 , Linfócitos B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos , Linfócitos T
20.
J Cancer Res Clin Oncol ; 146(8): 2007-2016, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32449004

RESUMO

PURPOSE: Although adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells has shown durable clinical efficacy in patients with CD19+ B cell malignancies, the application of this approach to solid tumors is challenging. The goal of this proof-of-concept study was to investigate whether loading of CD19-CAR T cells (CART19) with anti-HER2 or anti-EGFR bispecific antibodies (BiAb) will target HER2+/EGFR+ CD19- targets and signal the intracellular domain of CAR without engaging antigen-specific CD19 ScFv of CAR T cells. METHODS: We used CART19 armed with anti-CD3 (OKT3) × anti-HER2 BiAb (HER2Bi) or anti-CD3 (OKT3) × anti-EGFR BiAb (EGFRBi) to evaluate the cytotoxicity directed at HER2 or EGFR expressing cancer cell lines compared with unarmed CART19 measured by short-term 51Cr release assay and long-term real-time cell analysis using xCelligence. We also determined the differences in exhaustion or effector phenotypes and cytokine profiles during the short- and long-term cytotoxicity assays. RESULTS: Specific cytotoxicity was exhibited by CART19 armed with HER2Bi or EGFRBi against multiple tumor cell lines. Armed CART19 and armed activated T cells (ATC) showed comparable specific cytotoxicity that ranged between 10 and 90% against breast, pancreatic, ovarian, prostate, and lung cancer cell lines at 10:1 E/T ratio. Serial killing (repeated killing) by HER2Bi-armed CART19 ranged between 80 and 100% at 10:1 E/T ratio against MCF-7 cells up to 19 days (up to 4th round of repeated killing) measured by a real-time cell analysis without CART19 becoming exhausted. CONCLUSIONS: HER2Bi- or EGFRBi-armed CART19 exhibited specific cytotoxicity against multiple HER2+/EGFR+/CD19- tumor targets in overnight and long-term serial killing assays. CART19 showed improved survival and were resistant to exhaustion after prolonged repeated exposure to tumor cells.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Neoplasias/terapia , Receptores ErbB/imunologia , Humanos , Ativação Linfocitária , Estudo de Prova de Conceito , Receptor ErbB-2/imunologia
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