RESUMEN
Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post-CAR-T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND-2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR-B38M CAR-T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression-free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)-based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR-T (including LCAR-B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR-T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR-B38M CAR-T cells produced moderate efficacy, with better outcomes for PI-based salvage regimens.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Mieloma Múltiple , Terapia Recuperativa , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Terapia Recuperativa/métodos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Anciano , Adulto , Resultado del TratamientoRESUMEN
Previous studies have shown that Protocadherins (PCDHs) enhance tumor proliferation, invasion, and metastasis; yet their role in pancreatic cancer (PC) progression and the tumor immune microenvironment remains unclear. This study aims to elucidate the role of PCDH1 in different cancer types, with a particular focus on its impact on immune suppression in PC. Utilizing data from TCGA, GTEx, and Gent2 databases, we assessed the expression of PCDH1 across various cancer types. The prognostic value of PCDH1 was demonstrated through Cox regression, Kaplan-Meier analysis, and ROC curve, while its relationship with gene mutations, tumor mutational burden (TMB), immune cell infiltration, and other clinical factors was investigated using Spearman correlation. Furthermore, the effect of PCDH1 on PC malignancy was experimentally validated by a series of in vitro and in vivo assays. Our results show a significant upregulation of PCDH1 in various tumor types, which is associated with poor prognosis, suggesting its potential application as an independent prognostic biomarker. Notably, in PC, PCDH1 exhibited significant associations with gene mutations, TMB, and immune cell infiltration. Clinical validations revealed a correlation between high PCDH1 expression and poor prognosis, coupled with a low level of CD8+ T cell infiltration. Furthermore, both in vitro and in vivo experiments confirmed the role of PCDH1 in promoting PC cell proliferation and migration while inhibiting CD8+ T cell recruitment through its modulation of CCL5-CCR5 axis. In conclusion, PCDH1 regulates the proliferation and migration of PC cells as well as CD8+ T cell infiltration in PC. PCDH1 may serve as a prognostic biomarker in multiple tumor types.
RESUMEN
OBJECTIVES: Young adults with acute myeloid leukemia (AML) often fail to achieve permanent complete remission (CR) and frequently relapse, indicating an urgent need to explore effective salvage therapies. Recent advances in AML treatment have been attributed to the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax (VEN) with hypomethylating agents (HMAs); however, the use of this combination in young adults with relapsed or refractory (R/R) AML has not been reported. METHODS: We retrospectively examined 31 young patients with R/R AML treated with VEN plus an HMA. We evaluated the demographic data, cytogenetic characteristics, AML types, response rates, and transplantation-related data for the patients in our cohort. RESULTS: The combination of VEN + HMA yielded a CR rate of 48.4%. The most prominent hematologic adverse event was neutropenia, which occurred in all patients, with 90.3% of cases being grade ≥3. Non-hematologic toxicities were relatively mild and infrequent, with an incidence of 45.2%. More than half of the patients with sustained CR had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT), of whom two died of transplant-related complications. CONCLUSION: Our results showed that the combination of VEN + HMA appeared to be a highly effective and well-tolerated salvage therapy option for young patients with R/R AML, enabling more young patients to proceed to potentially curative allo-HSCT. However, additional, well-designed studies with larger numbers of patients are required to confirm the advantages of VEN + HMA in this population.
Asunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Adulto Joven , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Leucemia Mieloide Aguda/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Chimeric antigen receptor (CAR)-reprogrammed T cell therapy is a novel and powerful treatment against hematological malignancies. Cytokine release syndrome (CRS) and other potentially life-threatening toxicities are known side effects which need appropriate management and supportive care. Coagulopathy is a common and severe CAR-T-related adverse event, while a comprehensive profile of coagulopathy in patients with multiple myeloma (MM) undergoing CAR-T cell therapy has not been reported. Therefore, we performed a comprehensive analysis of coagulopathy in 51 patients with r/r MM given anti-B cell maturation antigen CAR-T cell therapy. We found that 49% of patients had coagulation disorders, and 29% of patients experienced disseminated intravascular coagulation (DIC). Severe CRS, abnormal liver function and higher tumor burden were risk factors for the CAR-T-related coagulopathy. We found that the serum IL-6 level and alanine aminotransferase level were potential indicators for CAR-T-related DIC. Furthermore, we found that coagulation disorders occurred within 1 month after CAR-T cell infusion, mainly between days 10 and 13, which was 2-5 days later than the beginning of CRS and simultaneous with the beginning of abnormal liver function and the peak of CRS. In addition, although patients with coagulation dysfunction had a trend for better outcomes and prognosis, no statistical significance was found. In conclusion, our research provided a comprehensive understanding of CAR-T-related coagulopathy in MM. Upon timely and standardized treatment, coagulopathy was manageable in most cases.
Asunto(s)
Trastornos de la Coagulación Sanguínea , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Estudios Retrospectivos , Antígeno de Maduración de Linfocitos B/uso terapéutico , Trastornos de la Coagulación Sanguínea/terapia , Trastornos de la Coagulación Sanguínea/complicaciones , Síndrome de Liberación de Citoquinas/etiologíaRESUMEN
BACKGROUND: Multiple myeloma remains incurable despite treatment advancements over the last 20 years. LCAR-B38M Cells in Treating Relapsed/Refractory Multiple Myeloma was a phase 1, first-in-human, investigator-initiated study in relapsed/refractory multiple myeloma conducted at four sites in China. The study used LCAR-B38M chimeric antigen receptor-T cells expressing two B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity, and a CD3ζ signaling domain with a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. This chimeric antigen receptor construct is identical to ciltacabtagene autoleucel. In the LEGEND-2 study (n = 57, Xi'an site), overall response rate was 88%; median (95% CI) progression-free survival and overall survival were 19.9 (9.6-31.0) and 36.1 (26.4-not evaluable) months, respectively; and median follow-up was 25 months. This case study reports on a patient with relapsed/refractory multiple myeloma (λ light chain type) who was treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study (Xi'an site); he had received five prior lines of treatment and had extensive extramedullary lesions. CASE PRESENTATION: The patient, a 56-year-old Asian male, received cyclophosphamide (500 mg daily × 3 days) as lymphodepletion therapy and a total dose of 0.5 × 106 chimeric antigen receptor + T cells/kg split into three infusions (days 1, 24, and 84 from June to August 2016). He experienced grade 2 cytokine release syndrome after the first infusion; all symptoms resolved with treatment. No cytokine release syndrome occurred following the second and third infusions. His λ light chain levels decreased and normalized 20 days after the first infusion, and extramedullary lesions were healed as of January 2018. He has sustained remission for 5 years and received no other multiple myeloma treatments after LCAR-B38M chimeric antigen receptor T cell infusion. As of 30 October 2020, the patient is still progression-free and has maintained minimal residual disease-negative (10-4) complete response status for 52 months. CONCLUSIONS: This case provides support that treatment with LCAR-B38M chimeric antigen receptor T cells can result in long-term disease remission of 5 or more years without disease progression in a heavily pretreated patient with extensive extramedullary disease and no other treatment options.
Asunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Masculino , Humanos , Persona de Mediana Edad , Receptores Quiméricos de Antígenos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Antígeno de Maduración de Linfocitos B , Linfocitos T/patología , Progresión de la EnfermedadRESUMEN
BACKGROUND: LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. METHODS: LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. RESULTS: As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. CONCLUSIONS: The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.
Asunto(s)
Linfoma Folicular , Mieloma Múltiple , Neoplasias Primarias Secundarias , Antígeno de Maduración de Linfocitos B , China/epidemiología , Ciclofosfamida/uso terapéutico , Síndrome de Liberación de Citoquinas , Estudios de Seguimiento , Humanos , Mieloma Múltiple/tratamiento farmacológicoRESUMEN
Our previous research has shown that monocytic leukemia-associated antigen-34 (MLAA-34) was a novel antiapoptotic molecule with unique expression in acute monocytic leukemia (M5), making it an ideal target for T-cell-based immunotherapy. Here, we sought to identify HLA-A*0201-restricted cytotoxic T-lymphocyte (CTL) epitope of MLAA-34 by reverse immunology. In all, 10 HLA-A*0201 restricted epitopes of MLAA-34 were predicted by bioinformatics. MLAA-34324-332, MLAA-34293-301, and MLAA-34236-244 showed the strongest HLA-A*0201-binding affinity. The percentages of HLA-A*0201-MLAA-34236-244 tetramer+ CD8+ T cells in MLAA-34236-244-induced CTLs were raised apparently. Enzyme-linked immunospot showed that MLAA-34236-244 and MLAA-34324-332-specific CTLs produced a higher amount of interferon-γ. MLAA-34236-244-induced CTLs presented a stronger cytotoxic effect on THP-1 cells (HLA-A*0201+MLAA-34+) at various effector to target ratios. MLAA-34236-244 peptide vaccine could inhibit the tumor growth and improve mean survival time of leukemia-bearing human peripheral blood lymphocyte reconstituting severe combined immunodeficient mice. Mice immunized with MLAA-34236-244 vaccine had increased percentages of MLAA-34236-244 tetramer+ CD8+ T cells in the spleen after each round of immunization. High-purity CD8+ and CD4+ T cells were sorted by Dynabeads as effector cells. The killing activity of CD8+ T cells was higher than that of CD4+ T cells. CTLs derived from the MLAA-34 peptide vaccine group were significantly higher than other therapeutic groups and showed specific cytotoxicity to THP-1 cells. Increased interferon-γ and interleukin (IL)-2 and decreased IL-10 and IL-4 were seen in the MLAA-34236-244 peptide vaccine group. MLAA-34236-244 peptide (ILDRHNFAI) is an effective HLA-A*0201-restricted CTL epitope and that it may serve as a promising strategy in designing antigen-specific immunotherapy against MLAA-34-positive acute monocytic leukemia.
Asunto(s)
Antígenos de Neoplasias/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Epítopos de Linfocito T/inmunología , Antígeno HLA-A2/inmunología , Leucemia Monocítica Aguda/inmunología , Linfocitos T Citotóxicos/inmunología , Células A549 , Animales , Antineoplásicos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Células Dendríticas/inmunología , Humanos , Inmunoterapia/métodos , Células MCF-7 , Ratones , Ratones SCID , Péptidos/inmunología , Células THP-1/inmunología , Células U937RESUMEN
Multiple myeloma (MM) is a disease in which abnormal plasma cells proliferate and secrete monoclonal immunoglobulin in the bone marrow. The main characteristic of plasma cells is the expression of the cell surface antigen syndecan-1 (CD138). However, the expression of CD138 is limited to terminally differentiated plasma cells during B cell development. A small subpopulation (2~5%) of human MM cells that lack CD138 expression has been shown to possess enormous proliferation potential in vitro experiment and in animal models, and they also can differentiate into CD138+ plasma cells. Thus, this small subset of MM cells was regarded as myeloma cancer stem cell (MCSC). However, its characteristics associated with the pathogenesis of MM remain unclear. In this study, we analyzed the gene expression data of CD138 cell lines downloaded from Gene Expression Omnibus (GEO) database. Limma package in RStudio was used to identify differentially expressed genes (DEGs). Genes enrichment and protein-protein interaction (PPI) network analysis were performed on DAVID and STRING databases. Furthermore, overall survival (OS) analysis in MM patient was utilized to screen out the hub-genes closely associate with the MM pathogenesis process. Hub-genes expression validation and receiver operating characteristic curve (ROC) analysis was performed in different stages of plasma cell disorder diseases. Finally, we verified these findings in MM patient samples. Through integrated bioinformatics analysis of MM CD138- and CD138+ cell lines, we found that CDC7, CDK1, and CHK1 are highly expressed in CD138- MM cells. These genes are crucial in the G2/M phase of the cell cycle pathway, which is closely related to the malignant proliferation in various tumor cells. Of note, we found that patients with high expression of CDC7, CDK1, and CHK1 had shorter overall survival time. The expression of CHK1 was significantly increased in MM cells compared with normal plasma cell (NPC) and MGUS. More importantly, we further clarified that the expression of CHK1 in release/refraction MM (R/R MM) has obviously increased compared with new diagnosed MM (ND MM).
Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Sindecano-1/metabolismo , Adulto , Anciano , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mapas de Interacción de Proteínas , Sensibilidad y EspecificidadRESUMEN
Numerous studies confirmed that aberrant microRNA (miRNA) expression contributes to cancer development and progression. We carried out this study to explore the expression profile of miRNAs in intermediate risk acute myeloid leukemia (AML) and locate certain miRNAs as biomarkers. We profiled differentially expressed miRNAs by performing miRNA sequencing analysis in the patients' samples. Bioinformatic analysis showed the most significantly expressed genes mostly involved in cellular component organization, cell differentiation, and cell development. Reverse-transcription polymerase chain reaction validated the expression of miR-582-5p in different groups of AML samples. It was confirmed that miR-582-5p was downregulated in newly diagnosed AML and relapse/refractory AML compared with CR AML or controls. Among intermediate risk AML patients with normal cytogenetics, a lower level of miR-582-5p is correlated with an unfavorable outcome, and a shorter overall survival. Gain- and loss-of-function experiments revealed that miR-582-5p could inhibit proliferation, suppress migration, and invasion ability and induce apoptosis of leukemia cells. Furthermore, overexpression of miR-582-5p can increase sensitivity of cells to Ara-C. In conclusion, miR-582-5p can serve as an antioncogenic biomarker in intermediate risk AML with normal cytogenetics for risk classification and outcome prediction. These results showed a novel role for miR-582-5p in predicting the prognosis and promoting the tumor growth of AML.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Médula Ósea , Leucemia Mieloide Aguda , MicroARNs/metabolismo , Adulto , Apoptosis , Médula Ósea/metabolismo , Médula Ósea/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.
Asunto(s)
Antineoplásicos/farmacología , Bortezomib , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Nucleósidos de Purina/farmacología , Apoptosis/efectos de los fármacos , Bortezomib/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , HumanosRESUMEN
BACKGROUND: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. METHODS: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Aï¬liated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. RESULTS: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical signiï¬cance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). CONCLUSION: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/sangre , Proteínas de Neoplasias/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Semaforinas/sangre , Adulto , Anciano , Anemia Ferropénica/sangre , Anemia Ferropénica/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Pronóstico , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Inducción de Remisión , Semaforinas/biosíntesis , Semaforinas/genéticaRESUMEN
Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Dexametasona/uso terapéutico , Inmunoterapia Adoptiva/efectos adversos , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Adolescente , Síndrome de Liberación de Citoquinas/etiología , Citocinas/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Calidad de Vida , Adulto JovenRESUMEN
BACKGROUND: The bone marrow microenvironment provides an optimal substrate for multiple myeloma (MM) initiation and progression. The soluble component of MM niche is dynamic with the disease states of MM. We formerly employed proteomic profiling to construct a MM model. Four peptides constituting the model were selected by supervised neural network algorithm (SNN). METHODS: 62 Newly diagnosed (ND) MM and 64 healthy controls (HCs) were picked up for validating the distinguishing capability of the SNN model. Nano-liquid chromatography-electrospray ionization-tandem mass spectrometry was used for peptide identification. MM in different disease states and HCs were choosed for peptides relative intensities comparison. Western blot and ELISA were employed to validate the variability. RESULTS: The sensitivity and specificity of the independent testing data set for blind validation were 93.55% and 92.19%. The relative intensities of three out of the four peptides were increased in ND and refractory and relapse patients but decreased to that level of HCs in complete remission and very good partial remission patients. Relative intensity of the remaining peptide was negatively associated with MM remission. The peptides sequencing results showed that they were derived from dihydropyrimidinase-like 2, fibrinogen alpha chain, platelet factor 4 and alpha-fetoprotein. CONCLUSIONS: The potential value of the four peptides in monitoring MM treatment response was arised from their close correlation with MM disease states.
RESUMEN
OBJECTIVE: Frequent loss of expression of platelet factor 4 (PF4) in multiple myeloma (MM) was revealed in several previous researches. The predictive analysis of serum PF4 level in newly diagnosed MM has not been well elucidated. This study is to assess if serum PF4 could be a prognostic factor in predicting treatment response and survival of MM treated with thalidomide and VAD regimens. METHODS: Sera of 122 MM were gained pre- and post-treatment of chemotherapy and oral thalidomide. Serological PF4 measurements were performed by ELISA. Kaplan-Meier method was employed for survival analysis. Log rank test was used significance analysis. Multivariate analysis of overall survival used Cox-regression. RESULTS: Our data showed that the median serum PF4 concentration was negatively associated with MM response and a significant correlation between serum PF4 level and unfavorable clinical features (ß2-microglobulin, ISS stage, del17p and creatinine). MM with lower serum PF4 concentration at diagnosis were prone to gain complete remission and very good partial remission after two courses of chemotherapy. Besides del17p, ß2-microglobulin, treatment response, the low serum PF4 concentration was an independent variable associated with a poor overall survival by univariate analysis and multivariate analysis. CONCLUSIONS: We speculate serum PF4 is a promising response and prognostic factor in newly diagnosed MM treated with thalidomide and VAD regimens.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/sangre , Mieloma Múltiple , Proteínas de Neoplasias/sangre , Factor Plaquetario 4/sangre , Talidomida/administración & dosificación , Adulto , Anciano , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). METHODS: This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. RESULTS: At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. CONCLUSIONS: LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
Asunto(s)
Antígeno de Maduración de Linfocitos B/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Receptores Quiméricos de Antígenos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Inducción de Remisión , Adulto JovenRESUMEN
AIMS: Multiple myeloma (MM) is an incurable hematological cancer with a higher rate of relapse. Alterations in the function of long non-coding RNAs (lncRNAs) promote the progression and metastasis of cancer. We carry out this study to explore the expression profile of differently expressed lncRNAs in newly diagnosed MM. MAIN METHODS: The Bone marrows we analyzed were obtained from five MM and five IDA patients (serving as controls). Arraystar Human LncRNA Array V4.0 was used to profile expression of lncRNAs and mRNAs. Gene ontology (GO) and pathway analysis were utilized to understand the biological roles of differently expressed genes, while Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for constructing the lncRNA-mRNA co-expression network. Quantitative polymerase chain reaction (qRT-PCR) was performed to confirm the expressions of dysregulated lncRNAs. KEY FINDINGS: Bioinformatic analysis of the lncRNA expression identified >3000 dysregulated lncRNAs (differenceâ¯≥â¯2-fold) in MM samples. GO and pathway analysis revealed that ECM-receptor and cell cycle pathway-related genes were significantly associated with MM. Four dysregulated lncRNAs were confirmed by qRT-PCR. Among them, the expression of ST3GAL6-AS1, LAMA5-AS1and RP11-175D17.3wereassociated with stage and risk status of MM. On the basis of GEO public database analysis, LAMA5-AS1 was related with an overall survival rate of MM patients. SIGNIFICANCE: These results reveal the feasible functions of lncRNAs in pathogenesis of MM. Further studies are required to explore whether these lncRNAs could serve as candidate therapeutic targets and new molecular biomarkers for MM.
Asunto(s)
Mieloma Múltiple/genética , ARN Largo no Codificante/biosíntesis , Adulto , Anciano , Células de la Médula Ósea/efectos de los fármacos , Biología Computacional , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , ARN Largo no Codificante/efectos de los fármacos , ARN Largo no Codificante/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Tasa de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION AND OBJECTIVE: To improve the complete remission (CR) rate of newly diagnosed acute myeloid leukemia (AML) patients and alleviate the severe side effects of double induction chemotherapy, we combined a standard regimen with granulocyte colony-stimulating factor (G-CSF) priming chemotherapy to compose a new double induction regimen for AML patients who failed to achieve CR after the first course. PATIENTS AND METHODS: Ninety-seven patients with AML who did not achieve CR after the first course of standard chemotherapy were enrolled. Among them, 45 patients received G-CSF priming combined with low-dose chemotherapy during days 20-22 of the first course of chemotherapy, serving as priming group, 52 patients were administered standard chemotherapy again, serving as control group. RESULTS: Between the two groups there were no differences in the French-American-British (FAB) classification, risk status, the first course of chemotherapy, blood cell count or blasts percentage of bone marrow before the second course. But the CR rate was significantly higher and the adverse effect was much lower in the priming group than the control group. Cox multivariate regression analysis showed that WBC level before the second course and the selection of the second chemotherapy regimen were two independent factors for long survival of patients. DISCUSSION: These results elucidate that standard chemotherapy followed by G-CSF priming new double induction chemotherapy is an effective method for AML patients to improve CR rate and reduce adverse effects.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa , Resultado del Tratamiento , Adulto JovenRESUMEN
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt that are involved in tumorigenesis and play a key role in cancer progression. To determine whether lncRNAs are involved in acute myeloid leukemia (AML), we analyzed the expression profile of lncRNAs and mRNAs in AML. Five pairs of AML patients and iron deficiency anemia (IDA) controls were screened by microarray. Through coexpression analysis, differently expressed transcripts were divided into modules, and lncRNAs were functionally annotated. We further analyzed the clinical significance of crucial lncRNAs from modules in public data. Finally, the expression of three lncRNAs, RP11-222K16.2, AC092580.4, and RP11-305O.6, were validated in newly diagnosed AML, AML relapse, and IDA patient groups by quantitative RT-PCR, which may be associated with AML patients' overall survival. Further analysis showed that RP11-222K16.2 might affect the differentiation of natural killer cells, and promote the immunized evasion of AML by regulating Eomesodermin expression. Analysis of this study revealed that dysregulated lncRNAs and mRNAs in AML vs IDA controls could affect the immune system and hematopoietic cell differentiation. The biological functions of those lncRNAs need to be further validated.
Asunto(s)
Anemia Ferropénica/genética , Leucemia Mieloide Aguda/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Largo no Codificante/genética , Estudios de Casos y Controles , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Pronóstico , Mapas de Interacción de Proteínas , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To screen serum peptide associated with renal impairment in patients with multiple myeloma(MM) and search early biomarker of MM renal impairment. METHODS: The weak cation exchange magnetic bead combined with matrix assisted laser desorption/ionization time of flight mass spectrometry was used to compare and analyze serum peptidome of MM with or without renal impairment. RESULTS: There were 18 peptide peaks with statistical significance in the molecular weight range from 700 to 10 000 Da(P<0.05), among them 7 peptides were upregulated and 11 were downregulated. The Quick Classifier diagnostic model composed of 3 peptides, which can strongly distinguish MM patients with or without renal impairment by means of Embedded Software. Its sensitivity and specificity were 97.14% and 94.12%, respectively. Peptides with molecular weight of 3908.85 Da and 3216.06 Da were significantly upregulated in MM patients with renal impairment, while the peptide with molecular weight of 2990.08 Da was significantly downregulated in MM patients with renal impairment. CONCLUSION: Peptides associated with MM renal impairment obtained by serum peptidome technology can provide a new clue for early assessment and diagnosis of clinical MM renal impairment.
Asunto(s)
Biomarcadores/análisis , Enfermedades Renales/etiología , Mieloma Múltiple/complicaciones , Péptidos/análisis , Humanos , Enfermedades Renales/diagnóstico , Mieloma Múltiple/diagnóstico , Proteómica , Sensibilidad y Especificidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
As sensitization of leukemia cells with granulocyte colony-stimulating factor (G-CSF) can enhance the cytotoxicity of chemotherapy in myeloid malignancies, a pilot study was conducted in order to evaluate the effect of G-CSF priming combined with low-dose chemotherapy in patients with higher risk myelodysplastic syndrome (MDS). The regimen, G-HA, consisted of cytarabine (Ara-C) 7.5mg/m(2)/12h by subcutaneous injection, days 1-14, homoharringtonine (HHT) 1.5mg/m(2)/day by intravenous continuous infusion, days 1-14, and G-CSF 150mg/m(2)/day by subcutaneous injection, days 0-14. 56 patients were enrolled, 34 patients (61%, 95% confidence interval: 51.44-70.56%) achieved complete remission (CR). Median duration of neutropenia was 7days (ranging from 2 to 16days). Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (5%), liver function abnormality (5%), and heart function abnormality (2%). No central nervous system toxicity was found. Mortality within the first 4 weeks was 4%. The G-HA regimen is effective in remission induction for higher risk MDS patients and well tolerated due to the acceptable toxicity in maintenance therapy in the patients who cannot undergo Hematopoietic cell transplantation (HCT).