RESUMEN
ABSTRACT: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor-associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Resistencia a Antineoplásicos , Proteínas Asociadas a Microtúbulos , Mieloma Múltiple , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Mieloma Múltiple/inmunología , Mieloma Múltiple/genética , Humanos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Bortezomib/farmacología , Bortezomib/uso terapéutico , Calreticulina/metabolismo , Calreticulina/genética , Muerte Celular Inmunogénica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Autofagia/efectos de los fármacosRESUMEN
Primary Sjogren syndrome (pSS) is the second most common autoimmune disorder worldwide, which, in the worst scenario, progresses to Non-Hodgkin Lymphoma (NHL). Despite extensive studies, there is still a lack of knowledge about developing pSS for NHL. This study focused on cells' signaling in pSS progression to the NHL type of diffuse large B-cell lymphoma (DLBCL). Using bulk RNA and single cell analysis, we found five novel pathologic-independent clusters in DLBCL based on cells' signaling. B-cell receptor (BCR) signaling was identified as the only enriched signal in DLBCL and pSS peripheral naive B-cells or salivary gland-infiltrated cells. The evaluation of the genes in association with BCR has revealed that targeting CD79A, CD79B, and LAMTOR4 as the shared genes can provide novel biomarkers for pSS progression into lymphoma.
Asunto(s)
Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Transducción de Señal , Receptores de Antígenos de Linfocitos B/genética , Factores de Intercambio de Guanina NucleótidoRESUMEN
The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , BiologíaRESUMEN
Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.
Asunto(s)
Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Humanos , Mieloma Múltiple/patología , Ferritinas/genética , Ferritinas/metabolismo , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Médula Ósea/metabolismo , Perfilación de la Expresión Génica , Microambiente Tumoral/genéticaRESUMEN
Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14-CD15+CD33+HLADR- cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC-related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Asunto(s)
Antígenos CD , Mieloma Múltiple , Células Supresoras de Origen Mieloide , Proteínas de Neoplasias , Antígenos CD/sangre , Antígenos CD/genética , Antígenos CD/inmunología , Femenino , Estudios de Seguimiento , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/patología , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Transcripción Genética/inmunologíaRESUMEN
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell-targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.
Asunto(s)
Hematopoyesis Clonal , Mieloma Múltiple/patología , Síndromes Mielodisplásicos/etiología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Femenino , Citometría de Flujo/métodos , Trasplante de Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Mutación , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Trasplante Autólogo , Microambiente TumoralRESUMEN
The treatment scenario for newly-diagnosed transplant-ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors and/or immunomodulatory drugs +/- the monoclonal antibody Daratumumab are used for first-line treatment, even if head-to-head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta-analysis of 27 phase 2/3 randomized trials including a total of 12,935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking-curve (SUCRA), a metric used to build a ranking chart. With a mean SUCRA of 83.8 and 80.08 respectively, VMP + Daratumumab (DrVMP) and Rd + Daratumumab (DrRd) reached the top of the chart. However, SUCRA is designed to work for single outcomes. To overcome this limitation, we undertook a dimensionality reduction approach through a principal component analysis, that unbiasedly grouped the 23 regimens into three different subgroups. On the bases of our results, we demonstrated that first line treatment for NEMM should be based on DrRd (most active, but continuous treatment), DrVMP (quite "fixed-time" treatment), or, alternatively, VRD and that, surprisingly, melphalan as well as Rd doublets still deserve a role in this setting.
Asunto(s)
Mieloma Múltiple , Humanos , Metaanálisis en Red , Mieloma Múltiple/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
In combination with lenalidomide and dexamethasone (KRd), Carfilzomib has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) on ASPIRE trial. Efficacy and safety of the triplet are still the object of investigation by many groups to confirm ASPIRE results in the setting of RRMM treated in real-life who don't meet trial restrictive inclusion criteria. Therefore, we report a retrospective multicenter analysis of 600 RRMM patients treated with KRd between December 2015 and December 2018. The median age was 64 years (range 33-85), and the median number of previous therapies was two (range 1-11). After a median of 11 KRd cycles, the overall response rate was 79.9%. The median progression-free survival (PFS) was 22 months, and the 2-year probability of PFS was 47.6%. Creatinine clearance<30 ml/min, >1 line of previous therapy, and high-risk FISH were all associated with a poor prognosis in multivariate analysis. The median overall survival (OS) was 34.8 months; the 2-year probability of OS was 63.5%. At multivariate analysis, creatinine clearance<30 ml/min, >1 line of previous therapy, and high-risk FISH were significantly associated with poor prognosis. After a median follow-up of 16 months (range 1-50), 259 withdrew from therapy. The main discontinuation reason was progressive disease (81.8%). Seventy-four patients (12.3%) discontinued therapy for toxicity. The most frequent side effects were hematological (anemia 49.3%, neutropenia 42.7%, thrombocytopenia 42.5%) and cardiovascular (hypertension 14.5%, heart failure 2.5%, arrhythmias 3.6%). Our study confirms the safety and efficacy of KRd in the real-life setting of RRMM patients and encourages its use in clinical practice.
Asunto(s)
Mieloma Múltiple , Humanos , Lenalidomida , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa , Estudios Retrospectivos , Dexametasona/efectos adversosRESUMEN
The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.
Asunto(s)
Mieloma Múltiple , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/efectos adversos , Estudios de Seguimiento , Humanos , Lenalidomida/uso terapéutico , Estudios Retrospectivos , Talidomida/efectos adversosRESUMEN
The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p < .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved < VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.
Asunto(s)
Mieloma Múltiple , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona , Humanos , Lenalidomida , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos , Estudios Retrospectivos , Terapia RecuperativaRESUMEN
BACKGROUND: The Sars-CoV-2 can cause severe pneumonia with multiorgan disease; thus, the identification of clinical and laboratory predictors of the progression towards severe and fatal forms of this illness is needed. Here, we retrospectively evaluated and integrated laboratory parameters of 45 elderly subjects from a long-term care facility with Sars-CoV-2 outbreak and spread, to identify potential common patterns of systemic response able to better stratify patients' clinical course and outcome. METHODS: Baseline white blood cells, granulocytes', lymphocytes', and platelets' counts, hemoglobin, total iron, ferritin, D-dimer, and interleukin-6 concentration were used to generate a principal component analysis. Statistical analysis was performed by using R statistical package version 4.0. RESULTS: We identified 3 laboratory patterns of response, renamed as low-risk, intermediate-risk, and high-risk, strongly associated with patients' survival (p < 0.01). D-dimer, iron status, lymphocyte/monocyte count represented the main markers discriminating high- and low-risk groups. Patients belonging to the high-risk group presented a significantly longer time to ferritin decrease (p: 0.047). Iron-to-ferritin-ratio (IFR) significantly segregated recovered and dead patients in the intermediate-risk group (p: 0.012). CONCLUSIONS: Our data suggest that a combination of few laboratory parameters, i.e. iron status, D-dimer and lymphocyte/monocyte count at admission and during the hospital stay, can predict clinical progression in COVID-19.
Asunto(s)
COVID-19/diagnóstico , COVID-19/terapia , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Hierro/sangre , Linfocitos/patología , Monocitos/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , COVID-19/sangre , COVID-19/mortalidad , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Recuento de Leucocitos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Pronóstico , Estudios Retrospectivos , SARS-CoV-2/fisiología , Resultado del TratamientoRESUMEN
Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Autoinmunidad , Antígenos HLA/inmunología , Miastenia Gravis/patología , Miositis/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anciano , Humanos , Masculino , Miastenia Gravis/inducido químicamente , Miastenia Gravis/inmunología , Miositis/inducido químicamente , Miositis/inmunología , PronósticoRESUMEN
Not available.
Asunto(s)
COVID-19/inmunología , Neoplasias Hematológicas/inmunología , SARS-CoV-2/inmunología , COVID-19/epidemiología , Neoplasias Hematológicas/epidemiología , HumanosAsunto(s)
Mieloma Múltiple , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/uso terapéutico , Humanos , Italia/epidemiología , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Terapia RecuperativaRESUMEN
AIM: A systematic review and meta-analysis from literature has been performed to assess the impact of targeted therapy in advanced pancreatic cancer. METHODS: By searching different literature databases and major cancer meetings proceedings, data from all randomized clinical trials designed to investigate molecular targeted agents in the treatment of advanced pancreatic cancer were collected. The time-frame between January 2007 and March 2015 was selected. Data on predefined end-points, including overall survival, progression-free survival in terms of Hazard Ratio and response-rate were extracted and analyzed by a random effects model. Pooled data analysis was performed according to the DerSimonian and Laird test. The occurrence of publication bias was investigated through Begg's test by visual inspection of funnel plots. RESULTS: Twenty-seven randomized clinical trials for a total of 8205 patients were selected and included in the final analysis. A significant benefit was demonstrated for anti-EGFR agents on overall survival (HR = 0.880; 95% confidence interval (CI) 0.797-0.972; p = 0.011). In the pooled analysis no benefit on overall survival (OS: pooled HR = 0.957; 95%CI 0.900-1.017; p = 0.153), or progression-free survival (PFS: pooled HR = 0.908; 95%CI 0.817-1.010; p = 0.075) for targeted-based therapies as compared to conventional treatments could be demonstrated. No advantage was reported in response-rate (OR for RR = 1.210; 95%CI 0.990-1.478; p = 0.063). Begg's funnel plot showed no evidence of publication bias. CONCLUSION: The use of molecular targeted agents does not translate into clinical benefit. Therefore, our work highlights the need to identify predictive factors for patient selection and rationally designed clinical trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pancreáticas/genética , Transducción de Señal/efectos de los fármacosAsunto(s)
Adenina/análogos & derivados , Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Índice de Severidad de la Enfermedad , Adenina/uso terapéutico , Anciano , Conjuntos de Datos como Asunto/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Análisis de SupervivenciaRESUMEN
Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG ≤ 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.
Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Neoplasias/terapia , Timidilato Sintasa/inmunología , Vacunas de Subunidad/administración & dosificación , Anciano , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Vacunas de Subunidad/inmunologíaRESUMEN
The analysis of deregulated microRNAs (miRNAs) is emerging as a novel approach to disclose the regulation of tumor suppressor or tumor promoting pathways in tumor cells. Targeting aberrantly expressed miRNAs is therefore a promising strategy for cancer treatment. By miRNA profiling of primary plasma cells from multiple myeloma (MM) patients, we previously reported increased miR-125a-5p levels associated to specific molecular subgroups. On these premises, we aimed at investigating the biological effects triggered by miR-125a-5p modulation in MM cells. Expression of p53 pathway-related genes was down-regulated in MM cells transfected with miR-125a-5p mimics. Luciferase reporter assays confirmed specific p53 targeting at 3'UTR level by miR-125a-5p mimics. Interestingly, bone marrow stromal cells (BMSCs) affected the miR-125a-5p/p53 axis, since adhesion of MM cells to BMSCs strongly up-regulated miR-125a-5p levels, while reduced p53 expression. Moreover, ectopic miR-125a-5p reduced, while miR-125-5p inhibitors promoted, the expression of tumor suppressor miR-192 and miR-194, transcriptionally regulated by p53. Lentiviral-mediated stable inhibition of miR-125a-5p expression in wild-type p53 MM cells dampened cell growth, increased apoptosis and reduced cell migration. Importantly, inhibition of in vitro MM cell proliferation and migration was also achieved by synthetic miR-125a-5p inhibitors and was potentiated by the co-expression of miR-192 or miR-194. Taken together, our data indicate that miR-125a-5p antagonism results in the activation of p53 pathway in MM cells, underlying the crucial role of this miRNA in the biopathology of MM and providing the molecular rationale for the combinatory use of miR-125a inhibitors and miR-192 or miR-194 mimics for MM treatment.
Asunto(s)
Redes Reguladoras de Genes , MicroARNs/genética , Mieloma Múltiple/genética , Proteína p53 Supresora de Tumor/genética , Regiones no Traducidas 3'/genética , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , MicroARNs/antagonistas & inhibidores , Mieloma Múltiple/patología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation in the bone marrow. Recent advancements in anti-CD38 monoclonal antibody therapies, such as daratumumab and isatuximab, have significantly improved MM patient survival. However, the lack of predictive factors of response to these therapies remains a challenge. Notably, anti-CD38 antibodies can interfere with laboratory tests, complicating response assessment. We conducted a retrospective study to evaluate the association between the appearance of positive IgGk (therapeutic antibody) on immunofixation/immunosubtraction (IF) and clinical parameters in 87 non-IgGk MM patients treated with anti-CD38 therapy. Positive IgGk IF was observed in 42 patients after a median of three treatment courses. Patients with positive IgGk IF had higher rates of complete/very good partial responses (p = 0.03) and improved progression-free survival (median not reached vs. 21.83 months, p < 0.01). High BMI (p = 0.03), higher hemoglobin (p = 0.02), lower CRP (p = 0.04), and lower monoclonal protein levels (p = 0.03) were associated with positive IgGk IF. Our findings suggest that monitoring therapeutic antibody appearance on IF may predict and optimize anti-CD38 therapy in MM. Potential explanations include the impact of patient factors (e.g. BMI) on drug pharmacokinetics, the relationship between antibody levels and immune response, and the influence of tumor biology. Further research is needed to elucidate the underlying mechanisms and clinical utility of this biomarker. Nonetheless, our results highlight the importance of considering therapeutic antibody detection when interpreting laboratory tests and managing MM patients receiving anti-CD38 therapies.
RESUMEN
Skeletal homeostasis relies upon a fine tuning of osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease (BD). Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation, and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related BD.