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1.
Blood ; 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39374535

RESUMEN

A robust prognostic and biological classification for newly diagnosed follicular lymphoma (FL) using molecular profiling remains challenging. FL tumors from patients treated in the RELEVANCE trial with rituximab-chemotherapy (R-chemo) or rituximab-lenalidomide (R2) were analyzed using RNA-sequencing, DNA-sequencing, immunohistochemistry (IHC) and/or fluorescence in situ hybridization. Unsupervised gene clustering identified two gene expression signatures (GS) enriched with normal memory (MEM) B-cells and germinal center (GC) B-cells signals, respectively. These two GS were combined into a 20-genes predictor (FL20) to classify patients into MEM-like (n=160) or GC-like (n=164) subtypes, which also displayed different mutational profiles. In the R-chemo arm, MEM-like patients had significantly shorter progression free survival (PFS) than GC-like patients (HR=2.13; p=0.0023), and this prognostic correlation remained significant in a multivariable model including FLIPI (p=0.005). In the R2 arm, both subtypes had comparable PFS, demonstrating a R2 benefit over R-chemo for MEM-like patients (HR=0.54; p=0.011). The prognostic value of FL20 was validated in an independent FL cohort with R-chemo treatment (GSE119214 (n=137)). An IHC algorithm (FLCM) using FOXP1, LMO2, CD22 and MUM1 antibodies was developed with significant prognostic correlation with FL20 in a training set of RELEVANCE (n=264) patients, which was then validated in a different set of patients (n=116). These data indicate that FL tumors can be classified into MEM-like and GC-like subtypes that are biologically distinct and clinically different in risk profile. The FLCM assay can be used in routine clinical practice to identify MEM-like FL patients who might benefit from therapies other than R-chemo, such as the R2 combination. ClinicalTrials.gov identifier: RELEVANCE: NCT01476787 and NCT01650701 INTRODUCTION.

2.
Nat Commun ; 15(1): 6790, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39117654

RESUMEN

Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Factor de Transcripción Ikaros , Lenalidomida , Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Factor de Transcripción 4 , Transcriptoma , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Lenalidomida/uso terapéutico , Lenalidomida/farmacología , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Linfocitos B/metabolismo , Linfocitos B/inmunología , Pronóstico , Animales , Línea Celular Tumoral , Perfilación de la Expresión Génica/métodos , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Variaciones en el Número de Copia de ADN
3.
Blood Cancer J ; 14(1): 100, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38902256

RESUMEN

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.


Asunto(s)
Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Femenino , Perfilación de la Expresión Génica , Persona de Mediana Edad , Transcriptoma , Mutación , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/genética , Biomarcadores de Tumor/genética , Anciano , Pronóstico , Microambiente Tumoral , Secuenciación del Exoma , Adulto , Proteínas de Unión al ADN/genética , Insuficiencia del Tratamiento
5.
Leuk Res ; 140: 107497, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38564986

RESUMEN

Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.


Asunto(s)
Isocitrato Deshidrogenasa , Leucemia Mieloide Aguda , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aminopiridinas/uso terapéutico , Resistencia a Antineoplásicos/genética , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Triazinas/uso terapéutico
6.
Haematologica ; 109(4): 1082-1094, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-37941406

RESUMEN

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.


Asunto(s)
Azacitidina , Leucemia Mieloide Aguda , Animales , Ratones , Humanos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Antígenos CD34/metabolismo , Leucemia Mieloide Aguda/genética , Peroxidasa , Células Madre/metabolismo
7.
Bioinformatics ; 39(39 Suppl 1): i131-i139, 2023 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-37387130

RESUMEN

MOTIVATION: Recent advances in spatial proteomics technologies have enabled the profiling of dozens of proteins in thousands of single cells in situ. This has created the opportunity to move beyond quantifying the composition of cell types in tissue, and instead probe the spatial relationships between cells. However, most current methods for clustering data from these assays only consider the expression values of cells and ignore the spatial context. Furthermore, existing approaches do not account for prior information about the expected cell populations in a sample. RESULTS: To address these shortcomings, we developed SpatialSort, a spatially aware Bayesian clustering approach that allows for the incorporation of prior biological knowledge. Our method is able to account for the affinities of cells of different types to neighbour in space, and by incorporating prior information about expected cell populations, it is able to simultaneously improve clustering accuracy and perform automated annotation of clusters. Using synthetic and real data, we show that by using spatial and prior information SpatialSort improves clustering accuracy. We also demonstrate how SpatialSort can perform label transfer between spatial and nonspatial modalities through the analysis of a real world diffuse large B-cell lymphoma dataset. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at: https://github.com/Roth-Lab/SpatialSort.


Asunto(s)
Linfoma de Células B Grandes Difuso , Proteómica , Humanos , Teorema de Bayes , Bioensayo , Análisis por Conglomerados
8.
medRxiv ; 2023 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-37333387

RESUMEN

PURPOSE: 60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. PATIENTS AND METHODS: Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure. RESULTS: Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31] P < .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09] P < .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. CONCLUSION: This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.

9.
J Clin Invest ; 133(13)2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37219943

RESUMEN

Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.


Asunto(s)
Linfoma de Células B Grandes Difuso , Linfocitos T , Humanos , Ratones , Animales , Linfoma de Células B Grandes Difuso/patología , Fibroblastos/metabolismo , Ganglios Linfáticos , Microambiente Tumoral
10.
Br J Haematol ; 201(6): 1129-1143, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36990798

RESUMEN

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.


Asunto(s)
Médula Ósea , Leucemia Mieloide Aguda , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos/uso terapéutico , Antígenos CD34 , Azacitidina/farmacología , Azacitidina/uso terapéutico , Microambiente Tumoral
11.
EJHaem ; 3(1): 139-153, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35846221

RESUMEN

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

12.
Clin Cancer Res ; 28(15): 3367-3377, 2022 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-35583604

RESUMEN

PURPOSE: Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide and avadomide. Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated, and subsequently degraded. In diffuse large B-cell lymphoma (DLBCL) cells, Aiolos and Ikaros are direct transcriptional repressors of interferon-stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy to enhance cell autonomous activities of CRBN modulators (CELMoD). EXPERIMENTAL DESIGN: We conducted paired RNA sequencing with histone modification and Aiolos/Ikaros chromatin immunoprecipitation sequencing to identify genes regulated by these transcription factors and to elucidate correlations to drug sensitivity. We confirmed Aiolos/Ikaros mediated transcriptional complex formation in DLBCL patient samples including those treated with avadomide. RESULTS: In DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase, which modify the chromatin landscape of these promoters. A rational combination approach of avadomide with a specific histone deacetylase inhibitor leads to a significant increase in ISG transcription compared with either single agent, and synergistic antiproliferative activity in DLBCL cell lines. CONCLUSIONS: Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros-mediated transcriptional repression and unique therapeutic combination strategies.


Asunto(s)
Inhibidores de Histona Desacetilasas , Linfoma de Células B Grandes Difuso , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Factores Inmunológicos/uso terapéutico , Lenalidomida/farmacología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Ubiquitina-Proteína Ligasas/genética
13.
J Matern Fetal Neonatal Med ; 35(25): 7207-7209, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34219599

RESUMEN

Point of care ultrasound (POCUS) is an emerging method for assessing umbilical venous catheter (UVC) position. We implemented a training module for neonatal providers geared toward POCUS proficiency in assessing UVC position in our neonatal intensive care unit. Over 14 months, the percentage of providers qualified to use POCUS for UVC placement increased from 0 to 33%. The median time to achieve proficiency was 5 months (interquartile range: 3-14 months). Additionally, we discovered that a minimum of two views were required to correctly assess catheter tip location. The two views in which it was easiest to correctly identify the catheter tip were the subcostal and parasternal short view using the cardiac ultrasound windows, and the phased array ultrasound probe.


Asunto(s)
Unidades de Cuidado Intensivo Neonatal , Sistemas de Atención de Punto , Recién Nacido , Humanos , Ultrasonografía/métodos , Venas Umbilicales/diagnóstico por imagen , Catéteres
14.
Clin Cancer Res ; 27(24): 6696-6708, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34667029

RESUMEN

PURPOSE: This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF-secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR). PATIENTS AND METHODS: Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months. RESULTS: Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27-DNAM1-CD8+ T cells and antigen-presenting cells was associated with disease progression. CONCLUSIONS: MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.


Asunto(s)
Vacunas contra el Cáncer , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD8-positivos , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Lenalidomida , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico
15.
Adv Immunol ; 150: 43-103, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34176559

RESUMEN

Follicular lymphoma (FL) is an indolent yet challenging disease. Despite a generally favorable response to immunochemotherapy regimens, a fraction of patients does not respond or relapses early with unfavorable prognosis. For the vast majority of those who initially respond, relapses will repeatedly occur with increasing refractoriness to available treatments. Addressing the clinical challenges in FL warrants deep understanding of the nature of treatment-resistant FL cells seeding relapses, and of the biological basis of early disease progression. Great progress has been made in the last decade in the description and interrogation of the (epi)genomic landscape of FL cells, of their major dependency to the tumor microenvironment (TME), and of the stepwise lymphomagenesis process, from healthy to subclinical disease and to overt FL. A new picture is emerging, in which an ever-evolving tumor-TME duo sparks a complex and multilayered clonal and functional heterogeneity, blurring the discovery of prognostic biomarkers, patient stratification and reliable designs of risk-adapted treatments. Novel technological approaches allowing to decipher both tumor and TME heterogeneity at the single-cell level are beginning to unravel unsuspected cell dynamics and plasticity of FL cells. The upcoming drawing of a comprehensive functional picture of FL within its ecosystem holds great promise to address the unmet medical needs of this complex lymphoma.


Asunto(s)
Linfoma Folicular , Ecosistema , Humanos , Inmunoterapia , Linfoma Folicular/terapia , Pronóstico , Microambiente Tumoral
16.
Leukemia ; 35(2): 522-533, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32139889

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1, SPEN, and MYD88 [L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes. However, patients with these high-risk mutations had more favorable outcomes when the immunomodulatory agent lenalidomide was added to RCHOP (R2CHOP). We are the first to report the genomic validation of a high-risk phenotype with a preferential response towards R2CHOP therapy in non-GCB DLBCL patients. These conclusions could be translated to a clinical setting to identify the ~38% of non-GCB patients that could be considered high-risk, and would benefit from alternative therapies to standard RCHOP based on personalized genomic data.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lenalidomida/administración & dosificación , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Estudios Retrospectivos , Rituximab/administración & dosificación , Tasa de Supervivencia , Vincristina/administración & dosificación , Adulto Joven
17.
Blood ; 137(2): 216-231, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33024998

RESUMEN

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/farmacología , Leucemia Linfocítica Crónica de Células B/inmunología , Activación de Linfocitos/efectos de los fármacos , Piperidonas/farmacología , Quinazolinonas/farmacología , Linfocitos T/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Humanos , Inmunoterapia/métodos , Interferones/inmunología , Ratones , Transducción de Señal/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Blood ; 135(13): 996-1007, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-31977002

RESUMEN

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.


Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Piperidonas/uso terapéutico , Quinazolinonas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunofenotipificación , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Piperidonas/administración & dosificación , Piperidonas/efectos adversos , Piperidonas/farmacocinética , Pronóstico , Quinazolinonas/administración & dosificación , Quinazolinonas/efectos adversos , Quinazolinonas/farmacocinética , Recurrencia , Retratamiento , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento
19.
Blood ; 135(13): 1008-1018, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-31977005

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding 2 biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies replicated the subgroups, with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and the need for a patient-selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients exhibited an enrichment in response rate and progression-free survival of 44% and 6.2 months vs 19% and 1.6 months for classifier-negative patients (hazard ratio, 0.49; 95% confidence interval, 0.280-0.86; P = .0096). The classifier was not prognostic for rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and nontumor composition and has potential utility to enrich for clinical response to immunomodulatory agents, including avadomide.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Biología Computacional/métodos , Femenino , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Transcriptoma
20.
Br J Haematol ; 185(2): 240-253, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30767211

RESUMEN

Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism. While single-agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T- and NK-cell counts, while R-chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R-chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL - moving from combination immunochemotherapy to chemotherapy-free immunotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Lenalidomida/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Rituximab/administración & dosificación , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/efectos de los fármacos , Ciclofosfamida/uso terapéutico , Citocinas/biosíntesis , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Humanos , Sinapsis Inmunológicas/efectos de los fármacos , Sinapsis Inmunológicas/inmunología , Inmunoterapia/métodos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Lenalidomida/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Linfoma Folicular/inmunología , Neutrófilos/efectos de los fármacos , Prednisona/uso terapéutico , Rituximab/inmunología , Rituximab/uso terapéutico , Células Tumorales Cultivadas , Vincristina/uso terapéutico
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