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BACKGROUND: Ureaplasma urealyticum is the most prevalent genital mycoplasma isolated from the urogenital tract of females, but there is no unified treatment plan. This study aimed to evaluate the efficacy of azithromycin in treating Ureaplasma urealyticum. METHODS: From the earliest to June 2022, published randomized controlled trials (RCTs) on azithromycin treatment of Ureaplasma urealyticum were retrieved by searching PubMed, Embase, Cochrane Library, and Web of Science. Two reviewers independently extracted the data. We utilized the Cochrane risk-of-bias assessment technique to assess the quality of included RCTs. The data were analyzed using the R language (version 4.0.4) software. RESULTS: Seven RCTs were finally included, involving 512 participants (240 in the experimental group, 272 in the control group). The experimental group was treated with azithromycin monotherapy, while the control group was treated with doxycycline or a placebo. Meta-analysis results suggested that azithromycin has a comparable therapeutic effect on Ureaplasma urealyticum in comparison to that of controls (risk ratio [RR] = 1.03, 95% confidence interval [CI] 0.94-1.12). Subgroup analysis showed that the dose and duration of azithromycin may don't affect its efficacy. CONCLUSION: Regarding the meta-analysis that we performed based on existing clinical studies, azithromycin is quite effective in treating Ureaplasma urealyticum.
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Azitromicina , Infecciones por Ureaplasma , Femenino , Humanos , Azitromicina/uso terapéutico , Azitromicina/farmacología , Ureaplasma urealyticum , Doxiciclina/uso terapéutico , Infecciones por Ureaplasma/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , UreaplasmaRESUMEN
Novel and efficient base-mediated N-alkylation and amidation of amidines with alcohols have been developed, which can be carried out in one-pot reaction conditions, which allows for the synthesis of a wide range of N-alkyl amines and free amides in good to excellent yields with high atom economy. In contrast to borrowing hydrogen/hydrogen autotransfer or oxidative-type N-alkylation reactions, in which alcohols are activated by transition-metal-catalyzed or oxidative aerobic dehydrogenation, the use of amidines provides an effective surrogate of amines. This circumvents the inherent necessity in N-alkylation of an oxidant or a catalyst to be stabilized by ligands.
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After the publication of this work [1].
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GRB2-associated-binding protein 1 (Gab1) belongs to Gab adaptor family, which integrates multiple signals in response to the epithelial growth factors. Recent genetic studies identified genetic variants of human Gab1 gene as potential risk factors of asthmatic inflammation. However, the functions of Gab1 in lungs remain largely unknown. Alveolar type-II cells (AT-IIs) are responsible for surfactant homeostasis and essentially regulate lung inflammation following various injuries (3). In this study, in vitro knockdown of Gab1 was shown to decrease the surfactant proteins (SPs) levels in AT-IIs. We further examined in vivo Gab1 functions through alveolar epithelium-specific Gab1 knockout mice (Gab1Δ/Δ). In vivo Gab1 deficiency leads to a decrease in SP synthesis and the appearance of disorganized lamellar bodies. Histological analysis of the lung sections in Gab1Δ/Δ mice shows no apparent pathological alterations or inflammation. However, Gab1Δ/Δ mice demonstrate inflammatory responses during the LPS-induced acute lung injury. Similarly, in mice challenged with bleomycin, fibrotic lesions were found to be aggravated in Gab1Δ/Δ These observations suggest that the abolishment of Gab1 in AT-IIs impairs SP homeostasis, predisposing mice to lung injuries. In addition, we observed that the production of surfactants in AT-IIs overexpressing Gab1 mutants, in which Shp2 phosphatase and PI3K kinase binding sites have been mutated (Gab1ΔShp2, Gab1ΔPI3K), has been considerably attenuated. Together, these findings provide the direct evidence about the roles of docking protein Gab1 in lungs, adding to our understanding of acute and interstitial lung diseases caused by the disruption of alveolar SP homeostasis.
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Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Homeostasis , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Fosfoproteínas/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Proteínas Adaptadoras Transductoras de Señales , Células Epiteliales Alveolares/ultraestructura , Animales , Bleomicina , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/deficiencia , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Transducción de SeñalRESUMEN
The alternative activation of M2 macrophages in the lungs has been implicated as a causative agent in pulmonary fibrosis; however, the mechanisms underlying M2 polarization are poorly characterized. In this study, we investigated the role of the ubiquitously expressed Src homology domain-containing tyrosine phosphatase Shp2 in this process. Shp2 inactivation augmented IL-4-mediated M2 polarization in vitro, suggesting that Shp2 regulates macrophage skewing and prevents a bias toward the M2 phenotype. Conditional removal of Shp2 in monocytes/macrophages with lysozyme M promoter-driven Cre recombinase caused an IL-4-mediated shift toward M2 polarization. Additionally, an increase in arginase activity was detected in Shp2(∆/∆) mice after i.p. injection of chitin, whereas Shp2-deficient macrophages showed enhanced M2 polarization and protection against schistosome egg-induced schistosomiasis. Furthermore, mutants were more sensitive than control mice to bleomycin-induced inflammation and pulmonary fibrosis. Shp2 was associated with IL-4Rα and inhibited JAK1/STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Rα, which enhanced IL-4-mediated JAK1/STAT6 activation that resulted in M2 skewing. Taken together, these findings define a role for Shp2 in alveolar macrophages and reveal that Shp2 is required to inhibit the progression of M2-associated pulmonary fibrosis.
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Activación de Macrófagos/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/inmunología , Fibrosis Pulmonar/inmunología , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/inmunología , Animales , Arginasa/biosíntesis , Bleomicina/efectos adversos , Bleomicina/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Quitina/farmacología , Inflamación/inducido químicamente , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Interleucina-4/inmunología , Interleucina-5/biosíntesis , Janus Quinasa 1/biosíntesis , Pulmón/inmunología , Pulmón/patología , Activación de Macrófagos/genética , Macrófagos Alveolares/inmunología , Ratones , Ratones Noqueados , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Fibrosis Pulmonar/inducido químicamente , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Superficie Celular/inmunología , Factor de Transcripción STAT6/biosíntesis , Esquistosomiasis Japónica/parasitología , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: Lung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients. METHODS: RT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors. RESULTS: Our study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly. CONCLUSIONS: Our data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción STAT3/genética , Translocación Genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Transformación Celular Neoplásica/genética , Humanos , Ratones , Proteínas Proto-Oncogénicas c-ret/genética , Factor de Transcripción STAT3/biosíntesis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Bronchial asthma is a chronic inflammatory disease of the airway mediated by a Th2 immune response. A great deal of data has demonstrated that regulatory T cells (Tregs) have the ability to suppress Th2 immune responses and the transcription factor fork-head box protein 3 (Foxp3) is indispensable for the development of CD4 + CD25 + Tregs. In this study, we hypothesized that enhanced local Foxp3 expression in lung tissue could suppress Th2-mediated allergic asthma. METHODS: Foxp3/PMX retroviruses containing the mouse Foxp3 gene were constructed and administered into asthmatic mice through intra-tracheal instillation before ovalbumin challenging. Foxp3 expression, airway hyper-responsiveness (AHR), bronchoalveolar lavage fluid (BALF) and tissue inflammatory cell and cytokine profiles were characterized. RESULTS: Foxp3 mRNA and protein were increased in the lung tissue of asthmatic mice. Enhanced expression of Foxp3 locally in the lung tissue reduced the airway AHR, inflammatory cell infiltration and mucus production. It also attenuated Th2 and Th17 immune responses as evidenced by reduced IL-4, IL-13 and IL-17 levels. CONCLUSIONS: This study demonstrates that enhanced Foxp3 expression in the airway by intra-tracheally instilled Foxp3/PMX retroviruses alleviates allergic airway inflammation by reducing the Th2 immune response.
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Asma/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Animales , Asma/metabolismo , Asma/prevención & control , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/biosíntesis , Inflamación/genética , Inflamación/metabolismo , Inflamación/prevención & control , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Tumor necrosis factor alpha induced protein 3 (TNFAIP3) is reportedly to have significant implications for autophagy regulation in various cancers. The current study aimed to decipher the role and mechanism of TNFAIP3 in diffuse large B-cell lymphoma (DLBCL) by modulating autophagy. METHODS: Information pertaining to the differential expression and prognostic role of TNFAIP3 in DLBCL was gleaned from the Gene Expression Omnibus (GEO) database. The TNFAIP3 expression levels in human DLBCL cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell counting kit-8 (CCK-8) and colony formation assays were employed to determine cell proliferation. Transwell assay and flow cytometry were applied to detect cell migration and apoptosis, respectively. Immunofluorescence and transmission electron microscope were used for the assessment of cell autophagy. The levels of apoptotic markers (caspase-3, cleaved-caspase-3, Bcl-2 Associated X (Bax), and B cell lymphoma-2 (Bcl-2)), autophagy indicators (the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I), Sequestosome (p62)), and pathway proteins (toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), Transcription Factor NF-Kappa-B P65 Subunit (p65), and phosphorylated-p65 (p-p65)) were assessed via Western blotting. Immunohistochemistry was employed to detect Ki67 expression in tumor tissues. RESULTS: TNFAIP3 expression in DLBCL samples was downregulated, correlating with poor prognosis. TNFAIP3 expression was also downregulated in DLBCL cells. It was found that TNFAIP3 impeded cell proliferation and migration, and enhanced apoptosis of OCI-LY3 cells. Intervention with autophagy inhibitor 3-methyladenine (3-MA) markedly reversed apoptosis of OCI-LY3 cells induced by TNFAIP3. Besides, TNFAIP3 induced autophagy via modulating the TLR4/MyD88/nuclear factor kappa B (NF-κB) signaling pathway. In vivo experiments showed that TNFAIP3 expression in DLBCL was downregulated, and upregulation of TNFAIP3 could inhibit tumor growth. CONCLUSION: TNFAIP3 inhibits DLBCL progression by inducing TLR4/MyD88/NF-κB pathway-mediated autophagy.
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Autofagia , Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Humanos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Autofagia/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , FN-kappa B/metabolismo , Línea Celular Tumoral , Animales , Regulación Neoplásica de la Expresión Génica , Ratones , Proliferación Celular , Apoptosis/genética , Masculino , Femenino , Progresión de la Enfermedad , Movimiento CelularRESUMEN
Chimeric antigen receptor T cells (CAR-T) therapy has achieved remarkable therapeutic success in treating a variety of hematopoietic malignancies. However, the high relapse rate and poor in vivo persistence, partially caused by CAR-T cell exhaustion, are still important barriers against CAR-T therapy. It remains largely elusive on the mechanisms of CAR-T exhaustion and how to attenuate exhaustion to achieve better therapeutic efficacy. In this study, we initially observed that CAR-T cells showed rapid differentiation and increased exhaustion after co-culture with tumor cells in vitro, and then performed single-cell ATAC-seq to depict the comprehensive and dynamic landscape of chromatin accessibility of CAR-T cells during tumor cell stimulation. Analyses of differential chromatin accessible regions and motif accessibility revealed that TFs were distinct in each cell type and reconstituted a coordinated regulatory network to drive CAR-T exhaustion. Furthermore, we performed scATAC-seq in patient-derived CAR-T cells and identified BATF and IRF4 as pivotal regulators in CAR-T cell exhaustion. Finally, knockdown of BATF or IRF4 enhanced the killing ability, inhibited exhaustion, and prolonged the persistence of CAR-T cells in vivo. Together, our study unraveled the epigenetic regulatory mechanisms of CAR-T exhaustion and provided new insights into CAR-T engineering to achieve better clinical treatment benefits.
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Cromatina , Receptores Quiméricos de Antígenos , Humanos , Cromatina/genética , Cromatina/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina , Recurrencia Local de Neoplasia/metabolismo , Inmunoterapia Adoptiva , Linfocitos TRESUMEN
Relapses of CD19-expressing leukemia in patients who achieved initial remission after CART cell treatment have been reported to correlate with poor CART cells persistence. Sustained tonic signaling or strong activation drives CART cell differentiation and exhaustion, which limit the therapeutic efficacy and persistence of CART cells. Here, we identified dasatinib as the optimal candidate to prevent or reverse both CD28/CART and 4-1BB/CART cell differentiation and exhaustion during ex vivo expansion, which profoundly enhanced the therapeutic efficacy and in vivo persistence. Moreover, strong activation-induced CART cells differentiation, exhaustion and apoptosis driven by CD3/CD28 stimulation or antigen exposure were dramatically prevented or reversed by dasatinib treatment. Mechanistically, dasatinib markedly reduced the phosphorylation of Src and Lck, and downregulated the expression of genes involved in CAR signaling pathways, which resulted in the optimization of cell differentiation, exhaustion and apoptosis-related gene expression. Our study proposes a promising pharmacological approach for optimizing CART cells manufacture, and provides an experimental basis for reinvigorating CART cells in clinical application.
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Dasatinib/farmacología , Inmunoterapia Adoptiva , Inhibidores de Proteínas Quinasas/farmacología , Linfocitos T/efectos de los fármacos , Antineoplásicos/farmacología , Antígenos CD28/inmunología , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular/efectos de los fármacos , Humanos , Inmunoterapia Adoptiva/métodos , Activación de Linfocitos/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
A rapid and efficient base mediated synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed using the annulation of nitriles with hydrazines, which can be expanded to a wide range of triazoles in good to excellent yields. Ammonia gas is liberated during the reaction, and halo and hetero functional groups as well as free hydroxyl and amino groups are tolerated in this transformation. A variety of alkyl and aryl-substituted nitriles can be functionalized with aromatic and aliphatic hydrazines employing this procedure. This finding provides a practical and useful strategy for the synthesis of various 15N-labeled 1,2,4-triazole derivatives, and two types of mGlu5 receptor pharmaceuticals can be easily assembled in a one-pot manner.
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A base-mediated cascade amidination/N-alkylation reaction of amines by alcohols has been developed. For the first time, nitriles have been identified as an efficient and benign water acceptor reagent in N-alkylation. Notably, the procedure tolerates a series of functional groups, such as methoxyl, halo, vinyl and hetero groups, providing a convenient method to construct different substituted diamino compounds, 15N labeled amine and could be scaled up to 1 mol scale offering 138.7 g of the desired product in good yield in one-pot. Mechanistic studies provided strong evidence for the amidination of amines with nitriles facilitated by t-BuOK.
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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 (25âmg/m, d1-d3) and cyclophosphamide (500âmg/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.
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Ciclofosfamida/uso terapéutico , Depleción Linfocítica , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Receptores Quiméricos de Antígenos/inmunología , Inducción de Remisión , Linfocitos T/inmunología , Vidarabina/análogos & derivados , Adulto , Antígenos CD19/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Síndrome de Liberación de Citoquinas/etiología , Humanos , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Vidarabina/uso terapéuticoRESUMEN
A practical and efficient base mediated synthesis of free 3-aminoindazoles has been developed from the reaction of nitriles with hydrazines, which successfully overcomes the difficulty of using aromatic hydrazines as substrates and allows for the synthesis of a wide range of N-aryl substituted free 3-aminoindazoles in moderate to excellent yields under mild conditions in one-pot. This finding provides a rapid and useful strategy for the synthesis of various functionalized 3-aminoindazole derivatives.
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A new porous organic polymer supported rhodium catalyst (Rh/POL-BINAPa&PPh3) has been developed for the hydroformylation of various alkynes to afford the corresponding α,ß-unsaturated aldehydes with high chem- and stereoselectivity, excellent catalytic activity and good reusability (10 cycles). The heterogeneous catalyst exhibited more catalytic activity than the comparable homogeneous Rh/BINAPa/PPh3 system.
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A new porous organic polymer has been prepared via copolymerization of divinyl-functionalized phosphoramidite ligand and tris(4-vinylphenyl)phosphine. The porous polymer was loaded with Rh(acac)CO2 to yield a supported Rh catalyst, which demonstrated good regioselectivity ( l/ b = 6.7-52.8) and high catalytic activity (TON up to 45.3 × 104) in hydroformylation of terminal and internal olefins. Remarkably, the heterogeneous catalyst can be reused at least 10 cycles without losing activity and selectivity in hydroformylation of 1-hexene.
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Hematopoietic stem cells (HSCs) produce all lineages of mature blood cells for the lifetime of an organism. In vertebrates, HSCs derive from the transition of the hemogenic endothelium (HE) in the floor of the embryonic dorsal aorta. Most recently, a series of proinflammatory factors, such as tumor necrosis factor-α, interferon-γ, and Toll-like receptor 4, have been confirmed to play a key role in HSC specification. However, the full complement of necessary signaling inputs remains unknown to date. Here, we show that interleukin-6R (IL6R) via IL6 is required and sufficient for HSC generation. We found that Notch activates IL6R by regulating its expression in the HE and in HSCs. The secretion of IL6 mainly originates from HSC-independent myeloid cells, but not from HSCs and their adjacent vascular endothelial cells. In addition, blocking IL6 signaling does not affect vascular development or the production of primitive erythrocytes. Taken together, our results uncover a previously obscure relationship between IL6 signaling and HSC production and provide new insights into HSC regeneration using proinflammatory factors in vitro.
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Diferenciación Celular/genética , Células Madre Hematopoyéticas/metabolismo , Interleucina-6/genética , Receptores de Interleucina-6/genética , Animales , Linaje de la Célula/genética , Eritrocitos/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Células Mieloides/metabolismo , Transducción de Señal/genética , Pez Cebra/genéticaRESUMEN
Chimeric antigen receptor (CAR) T-cell therapy has displayed potent anti-leukemia activity in acute lymphocytic leukemia (ALL), acting as a new ray of hope to refractory/relapsed patients. However, the influence of CAR-T therapy on host immune system has not been well elucidated. Thus, We applied high-throughput T cell receptor ß chain sequencing to track the dynamic change of T-cell repertoire induced by CAR-T therapy in B-cell ALL patients. Six Chinese patients achieving complete remission were under observation, whose blood samples, bone marrow samples and infused CAR-T samples were collected at serial time points before and after CAR-T therapy. We observed decreased TCR diversity and increased clonality of T-cell repertoire in both peripheral blood and bone marrow after CAR-T administration. The persistent T cell clones in blood and bone marrow expanded following leukemic cell destruction and were barely detected in CAR T-cell pool. For the first time, our results demonstrated CAR-T therapy could stimulate the clonal proliferation of CAR-negative T cells in patients. Considering other groups' animal results indicating that CAR-T therapy could facilitate the proliferation of tumor antigen-specific T cells and that the emergence of these T cell clones followed the destruction of leukemic cells, they are most likely tumor antigen-specific.
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Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos T/inmunología , China , Femenino , Humanos , MasculinoRESUMEN
Purpose: Patients with relapsed/refractory acute lymphocytic leukemia (R/R ALL) have a poor prognosis. Chimeric antigen receptor-modified T cells against CD19 (CART19) have displayed anti-leukemia activities. However, data from systemic trials in Chinese patients are limited.Experimental Design: T cells transduced with CD19-directed CAR lentiviral vectors were infused in patients with R/R ALL under fludarabine- and cyclophosphamide-based lymphodepletion. The postinfusion responses, toxicities, expansion, and persistence of CART19s in enrolled patients were observed and monitored.Results: We enrolled 15 patients with R/R ALL. The median transduction efficiency of CART19s was 33%. In vitro cytotoxicity assays were conducted and showed prominent antileukemia activities with CART19s. The patients received CART19s infusion at doses of 1.1 × 106/kg to 9.8 × 106/kg. Twelve patients achieved complete remission 1 month after CART19s infusion. CART19s expanded and persisted in peripheral blood and bone marrow. At 150 days, the overall survival rate and leukemia-free survival rate were 65.5% and 37.8%, respectively. The cumulative incidence of relapse and the nonrelapse mortality rate were 54.5% and 7.7%, respectively. Four patients underwent subsequent haploidentical hematopoietic stem cell transplantation. In this trial, 10 patients experienced cytokine release syndrome (CRS). Grade 3 CRS developed in 40% of patients and was associated with a higher disease burden on day -1 and a higher number of previous relapses.Conclusions: This trial demonstrated potent antileukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation. Clin Cancer Res; 23(13); 3297-306. ©2016 AACR.