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Antibacterianos , Exantema , Linfoma Folicular , Piel , Síndrome de Stevens-Johnson , Anciano , Femenino , Humanos , Diagnóstico Diferencial , Exantema/etiología , Piel/patología , Dolor/etiología , Tomografía Computarizada por Rayos X , Exudados y Transudados/diagnóstico por imagen , Canal Anal/diagnóstico por imagen , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/tratamiento farmacológico , Síndrome de Stevens-Johnson/etiología , Combinación Amoxicilina-Clavulanato de Potasio/efectos adversos , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Doxiciclina/efectos adversos , Doxiciclina/uso terapéutico , Perineo , Abdomen , Negro o Afroamericano , Biopsia , Linfoma Folicular/complicaciones , Linfoma Folicular/diagnóstico , Linfadenopatía InmunoblásticaRESUMEN
Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT01947140).
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Aminopterina , Protocolos de Quimioterapia Combinada Antineoplásica , Depsipéptidos , Inhibidores de Histona Desacetilasas , Linfoma de Células T , Humanos , Aminopterina/análogos & derivados , Aminopterina/uso terapéutico , Aminopterina/administración & dosificación , Aminopterina/efectos adversos , Depsipéptidos/administración & dosificación , Depsipéptidos/efectos adversos , Depsipéptidos/uso terapéutico , Masculino , Persona de Mediana Edad , Femenino , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/administración & dosificación , Resultado del Tratamiento , Antagonistas del Ácido Fólico/uso terapéutico , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/administración & dosificación , Anciano de 80 o más AñosRESUMEN
PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.
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Lectinas Tipo C , Receptores Inmunológicos , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Ratones , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Lectinas Tipo C/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/antagonistas & inhibidores , Línea Celular Tumoral , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Linfoma de Células T/terapia , Linfoma de Células T/tratamiento farmacológico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacologíaRESUMEN
The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
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Linfoma de Células T Periférico , Linfoma de Células T , Ratones , Animales , Humanos , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Linfoma de Células T/genética , Genes Supresores de Tumor , Acetilcoenzima A/metabolismo , Glucólisis/genéticaRESUMEN
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.
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Núcleo Celular , Oncogenes , Humanos , Animales , Ratones , Activación Transcripcional , Proteínas Co-Represoras , Modelos Animales de Enfermedad , Proteína Potenciadora del Homólogo Zeste 2/genética , Factores de Transcripción , Proteínas Supresoras de TumorRESUMEN
Optimal treatment strategies for (relapsed and refractory [R/R]) peripheral T-cell lymphoma (PTCL) have not been well defined, and with the approval of several novel single agents (SA), the comparative efficacy of combination chemotherapy (CC) to single-agent strategies remains unclear. We conducted a meta-analysis to evaluate overall response rates (ORR) and toxicities of SA to CC. MEDLINE, Embase, Web of Science Core Collection, and Cochrane were systematically searched for phase I, phase II, and phase III trials investigating a defined SA or an anthracycline-, ifosfamide-, gemcitabine-, and platinum-based regimens. One hundred and fifty-one articles were included, encompassing single and combinations of 60 phase I trials involving 1075 patients, 95 phase II trials involving 3246, and 23 phase III trials involving 1888 patients. There was a high degree of heterogeneity in the trials. Using a random-effects model, the estimated ORR for SA in phase I trials were 40% (95% confidence interval [CI], 34.7%, 46.9%) relative to 41% for CC (95% CI, 27.4%, 56.1%; P = .97) and in phase II trials 34.4% (95% CI, 30.4%, 38.7%) for SA vs 55.3% (95% CI, 31%, 77.2%; P = .1) for CC. There were significant subgroup differences in ORR between histological subtypes of PTCL and drug classes. Our results highlight SA as an attractive outpatient option for R/R PTCL, and their incorporation in the development of upfront treatment paradigms merits urgent consideration. Our results underscore enrollment in clinical trials of SA as a critical strategy for R/R PTCL.
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Linfoma de Células T Periférico , Recurrencia Local de Neoplasia , Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Ifosfamida , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/patología , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt's (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.
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Síndrome de Inmunodeficiencia Adquirida , Enfermedad de Hodgkin , Linfoma Relacionado con SIDA , Linfoma de Células B Grandes Difuso , Linfoma de Células T Periférico , Enfermedad de Hodgkin/patología , Humanos , Linfoma Relacionado con SIDA/epidemiología , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/patología , Linfocitos T/patologíaRESUMEN
Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.
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Resistencia a Antineoplásicos , Factor de Transcripción Ikaros , Factores Inmunológicos/farmacología , Linfoma de Células T , Mieloma Múltiple , Ubiquitina-Proteína Ligasas , Humanos , Factor de Transcripción Ikaros/metabolismo , Lenalidomida/farmacología , Linfoma de Células T/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.
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Antineoplásicos/toxicidad , Cardiopatías/inducido químicamente , Miocitos Cardíacos/efectos de los fármacos , Pruebas de Toxicidad , American Heart Association , Animales , Cardiotoxicidad , Células Cultivadas , Modelos Animales de Enfermedad , Cardiopatías/genética , Cardiopatías/metabolismo , Cardiopatías/patología , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Medición de Riesgo , Estados UnidosRESUMEN
Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (MHC) class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I. Expression levels of surface CD47 and genes that modulate CD47 pyroglutamation did not correlate with the extent of phagocytosis induced by CD47 blockade in TCL lines. In vivo treatment of multiple human TCL patient-derived xenografts or an immunocompetent murine TCL model with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. Depletion of macrophages reduced efficacy in vivo, whereas depletion of neutrophils had no effect. F(ab')2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-Fcγ receptor interactions. In contrast, F(ab')2-only fragments increased phagocytosis by murine macrophages independent of SLAMF7-Mac-1 interaction. Full-length anti-CD47 mAbs also induced phagocytosis by Fcγ receptor-deficient murine macrophages. An immunoglobulin G1 anti-CD47 mAb induced phagocytosis and natural killer cell-mediated cytotoxicity of TCL cells that was augmented by cotreatment with mogamulizumab, an anti-CCR4 mAb, or a mAb blocking MHC class I. These studies help explain the disparate activity of monotherapy with agents that block CD47 in murine models compared with patients. They also have direct translational implications for the deployment of anti-CD47 mAbs alone or in combination.
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Antígenos de Diferenciación/inmunología , Antineoplásicos Inmunológicos/farmacología , Antígeno CD47/inmunología , Linfoma de Células T/tratamiento farmacológico , Receptores de IgG/inmunología , Receptores Inmunológicos/inmunología , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CD47/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Ratones , Receptores Fc/inmunologíaRESUMEN
Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/mortalidad , Sistema de Registros , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 (also termed PDCD1) expressing T cells and reducing AML-mediated expansion of myeloid-derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia-specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.
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Antineoplásicos Inmunológicos/farmacología , Azacitidina/análogos & derivados , Vacunas contra el Cáncer/inmunología , Leucemia Mieloide Aguda/tratamiento farmacológico , Microambiente Tumoral/inmunología , Animales , Antineoplásicos Inmunológicos/inmunología , Azacitidina/inmunología , Azacitidina/farmacología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Humanos , Inmunidad Celular/efectos de los fármacos , Leucemia Mieloide Aguda/inmunología , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Receptor de Muerte Celular Programada 1/metabolismo , Retroviridae/inmunología , Activación Viral/inmunologíaRESUMEN
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self-renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active ß-catenin levels and, in-turn, down-regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical outcomes in patients with AML. These findings emphasize the importance of MUC1-C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO-203 with Ara-C for the treatment of patients with AML.
RESUMEN
Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with 2 escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 National Institutes of Health Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline, 27 vs 14 mg; P = .01). Increased PD-1 expression on circulating CD4 (P = .009) and CD8 (P = .007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in National Institutes of Health cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pretreated patients, the results suggest abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase 2 trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.
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Abatacept/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Linfocitos T/efectos de los fármacos , Abatacept/administración & dosificación , Abatacept/efectos adversos , Adulto , Anciano , Enfermedad Crónica , Estudios de Cohortes , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Receptor de Muerte Celular Programada 1/análisis , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
Multiple myeloma (MM) is characterized by progressive immune dysregulation, loss of myeloma-specific immunity, and an immunosuppressive milieu that fosters disease growth and immune escape. Accordingly, cancer vaccines that reverse tumor-associated immune suppression represent a promising therapeutic avenue of investigation. We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted in the expansion of activated CD8 T cells expressing interferon-γ and perforin, with no significant change in the percentage of CD4 T cells producing interleukin-10. Further, coculture of patient's tumor cells with peripheral blood mononuclear cells and DCOne induced cytotoxic T-lymphocyte-mediated killing of autologous MM cells. These findings demonstrate that the allogeneic DCOne vaccine can induce T-cell activation and myeloma-specific immunity via cross presentation of antigens by native antigen-presenting cells.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Vesículas Extracelulares/inmunología , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/terapia , Vacunas contra el Cáncer , Diferenciación Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Reactividad Cruzada , Citotoxicidad Inmunológica , Células Dendríticas/trasplante , Humanos , Interferón gamma/metabolismo , Isoantígenos/inmunología , Activación de Linfocitos , Mieloma Múltiple/inmunología , Perforina/metabolismo , Microambiente TumoralRESUMEN
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL. Mol Cancer Ther; 16(10); 2304-14. ©2017 AACR.
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Azacitidina/análogos & derivados , Linfoma Cutáneo de Células T/tratamiento farmacológico , Mucina-1/genética , Estrés Oxidativo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Azacitidina/administración & dosificación , Línea Celular Tumoral , Decitabina , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/patología , Ratones , Mucina-1/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.