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1.
Cell ; 185(14): 2591-2608.e30, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35803246

RESUMEN

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.


Asunto(s)
Neoplasias Encefálicas , Melanoma , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Linfocitos T CD8-positivos/patología , Ecosistema , Humanos , RNA-Seq
2.
Cancer ; 130(9): 1642-1649, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38180804

RESUMEN

INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single-agent cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD-1/PD-L1-blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD-1/PD-L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non-cross-resistant. METHODS: The current phase 2 trial treated patients with PD-1/PD-L1 blockade-resistant metastatic urothelial cancer with single-agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate. RESULTS: Twenty-six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune-related hepatitis. CONCLUSIONS: High dose CTLA-4 blockade in patients with PD-1/PD-L1-resistant metastatic urothelial cancer has modest activity and is associated with treatment-related toxicity similar to prior reports.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Carcinoma de Células Transicionales , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico
3.
Nature ; 553(7688): 347-350, 2018 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-29320474

RESUMEN

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.


Asunto(s)
Inmunoterapia , Melanoma/inmunología , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biopsia , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Puntos de Control del Ciclo Celular , Humanos , Melanoma/genética , Melanoma/metabolismo , Mutación/genética , Neurofibromina 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos
4.
Oncologist ; 26(3): e505-e507, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33225544

RESUMEN

BACKGROUND: The objective of this work was to characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: Patients from four medical centers were included if they presented with isolated brain metastases treated with local therapy and received adjuvant treatment with ICIs. RESULTS: Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n = 8) and/or stereotactic radiosurgery (SRS; n = 6), were included. Ipilimumab/nivolumab was the adjuvant ICI used in four patients, of whom one recurred (25%) and none died, compared with three of seven (43%) who recurred and two of seven (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial. CONCLUSION: Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI therapy, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.


Asunto(s)
Neoplasias Encefálicas , Radiocirugia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Terapia Combinada , Humanos , Inhibidores de Puntos de Control Inmunológico , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos
5.
Cancer ; 122(21): 3354-3362, 2016 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-27533633

RESUMEN

BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS: Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354-3362. © 2016 American Cancer Society.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , Neoplasias Hepáticas/secundario , Melanoma/patología , Membrana Mucosa/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Persona de Mediana Edad , Membrana Mucosa/efectos de los fármacos , Estadificación de Neoplasias , Nivolumab , Pronóstico , Receptor de Muerte Celular Programada 1/inmunología , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Tasa de Supervivencia
6.
Am J Dermatopathol ; 38(9): 687-9, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27541170

RESUMEN

False negative result remains an ongoing problem in direct gene sequencing of cancers. It is important to use the appropriate mutation detection method most appropriate to each circumstance and the available tissue. Here, we report a patient with melanoma of unknown primary with metastases to spleen and bone marrow, who was tested negative for Cobas BRAF V600E mutation, whose cancer progressed on antiprogrammed death 1 (PD1) receptor monoclonal antibody therapy. Subsequent VE1 immunohistochemistry was positive for BRAF V600E mutation, and the tumor responded dramatically to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/Mitogen-activated protein kinase inhibitor combination therapy. This demonstrates how alternative BRAF testing methodology could produce results that can influence treatment choice and the outcome.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Médula Ósea/secundario , Melanoma/genética , Melanoma/secundario , Neoplasias Primarias Desconocidas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Neoplasias de la Médula Ósea/genética , Análisis Mutacional de ADN/métodos , Reacciones Falso Negativas , Femenino , Humanos , Inmunohistoquímica , Proteínas Proto-Oncogénicas B-raf/análisis
7.
Ultrastruct Pathol ; 38(1): 13-25, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24134831

RESUMEN

Skeletal muscle from an encephalomyopathy was examined by morphological and biochemical modalities. Mitochondria displayed variability in size, numbers per myocyte, and morphology. Certain organelles had stacks of dense cristae, others contained variable numbers of crystalloids or several lipid droplets. In isolated skeletal muscle mitochondria, oxidative phosphorylation was reduced, but activities of the electron transport chain components were unaffected. This is the second case of adult onset encephalomyopathy with a phenotype overlapping MERRF and Kearns-Sayre syndrome associated with a heteroplasmic mtDNA 3255G > A mutation in the tRNA(UUR(LEU)). This study emphasizes the desirability of a multidisciplinary approach in the diagnosis of complex myopathies.


Asunto(s)
Encefalomiopatías Mitocondriales/patología , Encefalomiopatías Mitocondriales/fisiopatología , Músculo Esquelético/fisiopatología , Músculo Esquelético/ultraestructura , Humanos , Masculino , Persona de Mediana Edad
8.
JCEM Case Rep ; 2(7): luae136, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39049863

RESUMEN

22q11.2 deletion syndrome (22.q11.2 DS) is a genetic syndrome resulting from a microdeletion on chromosome 22. It has a diverse array of manifestations, and most cases are diagnosed early in childhood. We present the case of a 38-year-old female born in a developing country who presented to our clinic to establish care for a history of primary hypothyroidism. She was clinically and biochemically euthyroid on thyroid supplementation. She was also noted to have hypocalcemia in the setting of low PTH, for which the patient was previously prescribed calcitriol. Given a history of cleft palate, abnormal facial features, mild recurrent sinopulmonary infections, and her endocrine history (including short stature with height in the 6th percentile), genetic testing was obtained. She was diagnosed with a heterozygous whole gene deletion of the TBX1 gene. Additional genetic evaluation demonstrated a 2.6-Mb microdeleted segment of the 22a11.2 region encompassing 62 genes. The patient was referred to cardiology for evaluation of cardiac involvement given a history of tachyarrhythmia. This case highlights challenges in diagnosis and the implications of a delayed diagnosis of 22.q11.2 DS.

9.
JAMA Netw Open ; 6(8): e2327145, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37535354

RESUMEN

Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Main Outcomes and Measures: Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Results: Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. Conclusions and Relevance: In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.


Asunto(s)
Insuficiencia Suprarrenal , Antineoplásicos Inmunológicos , Enfermedades del Sistema Inmune , Melanoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Suprarrenal/inducido químicamente , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Cohortes , Estudios de Seguimiento , Enfermedades del Sistema Inmune/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Estudios Retrospectivos , Anciano
10.
Pigment Cell Melanoma Res ; 36(6): 542-556, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37804122

RESUMEN

Mucosal melanoma remains a rare cancer with high mortality and a paucity of therapeutic options. This is due in significant part to its low incidence leading to limited patient access to expert care and downstream clinical/basic science data for research interrogation. Clinical challenges such as delayed and at times inaccurate diagnoses, and lack of consensus tumor staging have added to the suboptimal outcomes for these patients. Clinical trials, while promising, have been difficult to activate and accrue. While individual institutions and investigators have attempted to seek solutions to such problems, international, national, and local partnership may provide the keys to more efficient and innovative paths forward. Furthermore, a mucosal melanoma coalition would provide a potential network for patients and caregivers to seek expert opinion and advice. The Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA) highlighted the current clinical challenges faced by patients, providers, and scientists, identified current and future clinical trial investigations in this rare disease space, and aimed to increase national and international collaboration among the mucosal melanoma community in an effort to improve patient outcomes. The included proceedings highlight the clinical challenges of mucosal melanoma, global clinical trial experience, basic science advances in mucosal melanoma, and future directions, including the creation of shared rare tumor registries and enhanced collaborations.


Asunto(s)
Melanoma , Humanos , New York , Melanoma/terapia , Melanoma/patología , Membrana Mucosa/patología , Terapia Combinada , Estadificación de Neoplasias
11.
Am J Med Genet C Semin Med Genet ; 157C(2): 83-9, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21500339

RESUMEN

Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n = 8), acute lymphoblastic leukemia (n = 8), low grade glioma (n = 6), and rhabdomyosarcoma (n = 6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.


Asunto(s)
Síndrome de Costello/genética , Predisposición Genética a la Enfermedad , Síndrome LEOPARD/genética , Neoplasias/epidemiología , Neoplasias/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/genética , Estudio de Asociación del Genoma Completo , Cardiopatías Congénitas/genética , Humanos , Mutación/genética , Transducción de Señal/genética
12.
J Immunother Cancer ; 9(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34599027

RESUMEN

BACKGROUND: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions. METHODS: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma. RESULTS: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy. CONCLUSIONS: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.


Asunto(s)
Biopsia/métodos , Inmunoterapia/métodos , Melanoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Femenino , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
13.
JAMA Oncol ; 7(5): 744-748, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33764387

RESUMEN

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.


Asunto(s)
Melanoma , Receptor de Muerte Celular Programada 1 , Estudios de Cohortes , Humanos , Incidencia , Masculino , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Estudios Retrospectivos
14.
J Immunother Cancer ; 9(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34599031

RESUMEN

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Melanoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Vacunas Combinadas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/farmacología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacunas Combinadas/farmacología , Adulto Joven
15.
J Immunother Cancer ; 7(1): 61, 2019 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-30832716

RESUMEN

Balancing the potential for durable remissions with autoimmune-like toxicities is a key clinical challenge in the use of immune checkpoint inhibitors (ICI). Certain toxicities are associated with an increased response rate; however, the molecular underpinnings of this association are poorly understood. Here, we report a patient with wide spread uveal melanoma who had an exceptional response to treatment with ipilimumab and nivolumab, but suffered severe immune-related sequelae, including central serous retinopathy with retinal detachment, tinnitus, and vitiligo resembling Vogt-Koyanagi-Harada disease, and refractory enteritis. TCR-sequencing of the primary tumor, a hepatic metastasis, duodenal biopsy and peripheral blood mononuclear cells, identified the identical T cell clone in all four tissues. This case provides preliminary evidence for cross-reactivity as a mechanism for the association between effect and toxicity of ICIs.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Ipilimumab/efectos adversos , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Enfermedades de la Retina/inducido químicamente , Neoplasias de la Úvea/tratamiento farmacológico , Síndrome Uveomeningoencefálico/inducido químicamente , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/inmunología , Neoplasias Óseas/secundario , Resultado Fatal , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Enfermedades de la Retina/inmunología , Linfocitos T/inmunología , Neoplasias de la Úvea/inmunología , Neoplasias de la Úvea/patología , Síndrome Uveomeningoencefálico/inmunología
16.
Oncoimmunology ; 8(1): e1524695, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30546965

RESUMEN

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

17.
J Immunother Cancer ; 5: 8, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28239462

RESUMEN

BACKGROUND: Immune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP). CASE PRESENTATIONS: A 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment. CONCLUSIONS: Thrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.


Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Ipilimumab/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Trombocitopenia/inducido químicamente , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Humanos , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Nivolumab , Rituximab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológico
18.
Comput Struct Biotechnol J ; 14: 211-22, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27358717

RESUMEN

Tumor heterogeneity is a major challenge and the root cause of resistance to treatment. Still, the standard diagnostic approach relies on the analysis of a single tumor sample from a local or metastatic site that is obtained at a given time point. Due to intratumoral heterogeneity and selection of subpopulations in diverse lesions this will provide only a limited characterization of the makeup of the disease. On the other hand, recent developments of nucleic acid sequence analysis allows to use minimally invasive serial blood samples to assess the mutational status and altered gene expression patterns for real time monitoring in individual patients. Here, we focus on cell-free circulating tumor-specific mutant DNA and RNA (including mRNA and non-coding RNA), as well as current limitations and challenges associated with circulating nucleic acids biomarkers.

20.
J Immunother Cancer ; 4: 60, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27777770

RESUMEN

BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced malignancies. Patients with baseline organ dysfunction are largely excluded from clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or effective in this setting. Further, these patients are often not candidates for other anti-cancer therapies, highlighting their need for active treatment options. METHODS: We performed a retrospective analysis of patients from multiple centers with advanced solid tumors and baseline organ dysfunction who received anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular ejection fraction ≤45 %), renal (creatinine ≥2 mg/dL or GFR ≤30 ml/min) or hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin ≥3x ULN). We assessed change in organ dysfunction, immune related adverse events (irAEs), response rate, progression free survival (PFS) and overall survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4). Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective response or stable disease) at data collection (48 %). Eleven patients had primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial responses (15 %), and one had a complete response (4 %). Overall, median PFS was 168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable irAEs and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Corazón/efectos de los fármacos , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Terapia Molecular Dirigida/efectos adversos , Receptor de Muerte Celular Programada 1/administración & dosificación , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Cardiotoxicidad , Femenino , Corazón/fisiopatología , Pruebas de Función Cardíaca , Humanos , Riñón/fisiopatología , Pruebas de Función Renal , Hígado/fisiopatología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/complicaciones , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Resultado del Tratamiento
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