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Importance: Serious illness conversations (SICs) that elicit patients' values, goals, and care preferences reduce anxiety and depression and improve quality of life, but occur infrequently for patients with cancer. Behavioral economic implementation strategies (nudges) directed at clinicians and/or patients may increase SIC completion. Objective: To test the independent and combined effects of clinician and patient nudges on SIC completion. Design, Setting, and Participants: A 2 × 2 factorial, cluster randomized trial was conducted from September 7, 2021, to March 11, 2022, at oncology clinics across 4 hospitals and 6 community sites within a large academic health system in Pennsylvania and New Jersey among 163 medical and gynecologic oncology clinicians and 4450 patients with cancer at high risk of mortality (≥10% risk of 180-day mortality). Interventions: Clinician clusters and patients were independently randomized to receive usual care vs nudges, resulting in 4 arms: (1) active control, operating for 2 years prior to trial start, consisting of clinician text message reminders to complete SICs for patients at high mortality risk; (2) clinician nudge only, consisting of active control plus weekly peer comparisons of clinician-level SIC completion rates; (3) patient nudge only, consisting of active control plus a preclinic electronic communication designed to prime patients for SICs; and (4) combined clinician and patient nudges. Main Outcomes and Measures: The primary outcome was a documented SIC in the electronic health record within 6 months of a participant's first clinic visit after randomization. Analysis was performed on an intent-to-treat basis at the patient level. Results: The study accrued 4450 patients (median age, 67 years [IQR, 59-75 years]; 2352 women [52.9%]) seen by 163 clinicians, randomized to active control (n = 1004), clinician nudge (n = 1179), patient nudge (n = 997), or combined nudges (n = 1270). Overall patient-level rates of 6-month SIC completion were 11.2% for the active control arm (112 of 1004), 11.5% for the clinician nudge arm (136 of 1179), 11.5% for the patient nudge arm (115 of 997), and 14.1% for the combined nudge arm (179 of 1270). Compared with active control, the combined nudges were associated with an increase in SIC rates (ratio of hazard ratios [rHR], 1.55 [95% CI, 1.00-2.40]; P = .049), whereas the clinician nudge (HR, 0.95 [95% CI, 0.64-1.41; P = .79) and patient nudge (HR, 0.99 [95% CI, 0.73-1.33]; P = .93) were not. Conclusions and Relevance: In this cluster randomized trial, nudges combining clinician peer comparisons with patient priming questionnaires were associated with a marginal increase in documented SICs compared with an active control. Combining clinician- and patient-directed nudges may help to promote SICs in routine cancer care. Trial Registration: ClinicalTrials.gov Identifier: NCT04867850.
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Neoplasias , Relações Médico-Paciente , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/psicologia , Neoplasias/terapia , Idoso , Comunicação , Adulto , Análise por Conglomerados , PennsylvaniaRESUMO
PURPOSE: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response. PATIENTS AND METHODS: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax. RESULTS: An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3-5.2) in the SM group (P = 0.017). CONCLUSIONS: Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS.
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Anticorpos Monoclonais Humanizados , Fluordesoxiglucose F18 , Melanoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/diagnóstico por imagem , Melanoma/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Fluordesoxiglucose F18/administração & dosagem , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do Tratamento , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Estudos Prospectivos , Prognóstico , Idoso de 80 Anos ou mais , Compostos RadiofarmacêuticosRESUMO
PURPOSE: Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR). RESULTS: Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. CONCLUSIONS: Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting. See related commentary by Wu and Luke, p. 9.
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Melanoma , Nivolumabe , Humanos , Nivolumabe/efeitos adversos , Melanoma/patologia , Anticorpos Monoclonais/efeitos adversos , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Macrophages play a pivotal role in tumor immunity. We report that reprogramming of macrophages to tumor-associated macrophages (TAMs) promotes the secretion of exosomes. Mechanistically, increased exosome secretion is driven by MADD, which is phosphorylated by Akt upon TAM induction and activates Rab27a. TAM exosomes carry high levels of programmed death-ligand 1 (PD-L1) and potently suppress the proliferation and function of CD8+ T cells. Analysis of patient melanoma tissues indicates that TAM exosomes contribute significantly to CD8+ T cell suppression. Single-cell RNA sequencing analysis showed that exosome-related genes are highly expressed in macrophages in melanoma; TAM-specific RAB27A expression inversely correlates with CD8+ T cell infiltration. In a murine melanoma model, lipid nanoparticle delivery of small interfering RNAs (siRNAs) targeting macrophage RAB27A led to better T cell activation and sensitized tumors to anti-programmed cell death protein 1 (PD-1) treatment. Our study demonstrates tumors use TAM exosomes to combat CD8 T cells and suggests targeting TAM exosomes as a potential strategy to improve immunotherapies.
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Exossomos , Melanoma , Humanos , Camundongos , Animais , Macrófagos Associados a Tumor/metabolismo , Linfócitos T CD8-Positivos , Regulação para Cima , Exossomos/metabolismo , RNA Interferente Pequeno/metabolismo , Melanoma/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Antígeno B7-H1/metabolismoRESUMO
PURPOSE: Routine collection of patient-generated health data (PGHD) may promote earlier recognition of symptomatic and functional decline. This trial assessed the impact of an intervention integrating remote PGHD collection with patient nudges on symptom and functional status understanding between patients with advanced cancer and their oncology team. METHODS: This three-arm randomized controlled trial was conducted from November 19, 2020, to December 17, 2021, at a large tertiary oncology practice. We enrolled patients with stage IV GI and lung cancers undergoing chemotherapy. Over 6 months, patients in two intervention arms received PROStep-weekly text message-based symptom surveys and passive activity monitoring using a wearable accelerometer. PGHD were summarized in dashboards given to patients' oncology team before appointments. One intervention arm received an additional text-based active choice prompt to discuss worsening symptoms or functional status with their clinician. Control patients did not receive PROStep. The coprimary outcomes patient perceptions of oncology team symptom and functional understanding at 6 months were measured on a 1-5 Likert scale (5 = high understanding). RESULTS: One hundred eight patients enrolled: 55% male, 81% White, and 77% had GI cancers. Patient-reported clinician understanding did not differ between control and intervention arms for symptoms (4.5 v 4.5; P = .87) or functional status (4.5 v 4.3; P = .31). In the intervention arms, combined patient adherence to weekly symptom reports and daily activity monitoring was 64% and 53%, respectively. Intervention patients in the PROStep versus PROStep + active choice arms reported low burden from wearing the accelerometer (mean burden [standard deviation], 2.7 [1.3] v 2.1 [1.3]; P = .15) and completing surveys (2.1 [1.2] v 1.9 [1.3]; P = .44). CONCLUSION: Patients receiving PROStep reported high understanding of symptoms and functional status from their oncology team, although this did not differ from controls.
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Estado Funcional , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Inquéritos e Questionários , Comunicação , Medidas de Resultados Relatados pelo PacienteRESUMO
Purpose: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results: Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance: Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
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Melanoma , Neoplasias de Mama Triplo Negativas , Humanos , Pessoa de Meia-Idade , RNA/metabolismo , Linfócitos T , Imunoterapia Adotiva/efeitos adversos , Melanoma/terapia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
BACKGROUND: Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy. METHODS: Here, we report two different methods for generating melanoma patient-derived organoids (MPDOs), one is embedded in collagen gel, and the other is inlaid in Matrigel. MPDOs in Matrigel are used for assessing the therapeutic effects of anti-PD-1 antibodies (αPD-1), autochthonous tumor infiltrating lymphocytes (TILs), and small molecule compounds. MPDOs in collagen gel are used for evaluating the chemotaxis and migratory capacity of TILs. FINDING: The MPDOs in collagen gel and Matrigel have similar morphology and immune cell composition to their parental melanoma tissues. MPDOs show inter- and intra-tumoral heterogeneity and contain diverse immune cells such as CD4+, CD8+ T, Treg, CD14+ monocytic, CD15+, and CD11b+ myeloid cells. The tumor microenvironment (TME) in MPDOs is highly immunosuppressive, and the lymphoid and myeloid lineages express similar levels of PD-1, PD-L1, and CTLA-4 as their parental melanoma tissues. Anti-PD-1 antibodies (αPD-1) reinvigorate CD8+ T cells and induce melanoma cell death in the MPDOs. TILs expanded by IL-2 and αPD-1 show significantly lower expression of TIM-3, better migratory capacity and infiltration of autochthonous MPDOs, and more effective killing of melanoma cells than TILs expanded by IL-2 alone or IL-2 with αCD3. A small molecule screen discovers that Navitoclax increases the cytotoxicity of TIL therapy. INTERPRETATION: MPDOs may be used to test immune checkpoint inhibitors and cellular and targeted therapies. FUNDING: This work was supported by the NIH grants CA114046, CA261608, CA258113, and the Tara Miller Melanoma Foundation.
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Linfócitos T CD8-Positivos , Melanoma , Humanos , Interleucina-2/metabolismo , Melanoma/tratamento farmacológico , Imunoterapia/métodos , Organoides/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Microambiente TumoralRESUMO
Importance: Serious illness conversations (SICs) between oncology clinicians and patients are associated with improved quality of life and may reduce aggressive end-of-life care. However, most patients with cancer die without a documented SIC. Objective: To test the impact of behavioral nudges to clinicians to prompt SICs on the SIC rate and end-of-life outcomes among patients at high risk of death within 180 days (high-risk patients) as identified by a machine learning algorithm. Design, Setting, and Participants: This prespecified 40-week analysis of a stepped-wedge randomized clinical trial conducted between June 17, 2019, and April 20, 2020 (including 16 weeks of intervention rollout and 24 weeks of follow-up), included 20â¯506 patients with cancer representing 41â¯021 encounters at 9 tertiary or community-based medical oncology clinics in a large academic health system. The current analyses were conducted from June 1, 2021, to May 31, 2022. Intervention: High-risk patients were identified using a validated electronic health record machine learning algorithm to predict 6-month mortality. The intervention consisted of (1) weekly emails to clinicians comparing their SIC rates for all patients against peers' rates, (2) weekly lists of high-risk patients, and (3) opt-out text messages to prompt SICs before encounters with high-risk patients. Main Outcomes and Measures: The primary outcome was SIC rates for all and high-risk patient encounters; secondary end-of-life outcomes among decedents included inpatient death, hospice enrollment and length of stay, and intensive care unit admission and systemic therapy close to death. Intention-to-treat analyses were adjusted for clinic and wedge fixed effects and clustered at the oncologist level. Results: The study included 20 506 patients (mean [SD] age, 60.0 [14.0] years) and 41 021 patient encounters: 22 259 (54%) encounters with female patients, 28 907 (70.5%) with non-Hispanic White patients, and 5520 (13.5%) with high-risk patients; 1417 patients (6.9%) died by the end of follow-up. There were no meaningful differences in demographic characteristics in the control and intervention periods. Among high-risk patient encounters, the unadjusted SIC rates were 3.4% (59 of 1754 encounters) in the control period and 13.5% (510 of 3765 encounters) in the intervention period. In adjusted analyses, the intervention was associated with increased SICs for all patients (adjusted odds ratio, 2.09 [95% CI, 1.53-2.87]; P < .001) and decreased end-of-life systemic therapy (7.5% [72 of 957 patients] vs 10.4% [24 of 231 patients]; adjusted odds ratio, 0.25 [95% CI, 0.11-0.57]; P = .001) relative to controls, but there was no effect on hospice enrollment or length of stay, inpatient death, or end-of-life ICU use. Conclusions and Relevance: In this randomized clinical trial, a machine learning-based behavioral intervention and behavioral nudges to clinicans led to an increase in SICs and reduction in end-of-life systemic therapy but no changes in other end-of-life outcomes among outpatients with cancer. These results suggest that machine learning and behavioral nudges can lead to long-lasting improvements in cancer care delivery. Trial Registration: ClinicalTrials.gov Identifier: NCT03984773.
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Neoplasias , Qualidade de Vida , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias/terapia , Comunicação , Aprendizado de Máquina , MorteRESUMO
Cancer immunotherapy often depends on recognition of peptide epitopes by cytotoxic T lymphocytes (CTLs). The tumor microenvironment (TME) is enriched for peroxynitrite (PNT), a potent oxidant produced by infiltrating myeloid cells and some tumor cells. We demonstrate that PNT alters the profile of MHC class I bound peptides presented on tumor cells. Only CTLs specific for PNT-resistant peptides have a strong antitumor effect in vivo, whereas CTLs specific for PNT-sensitive peptides are not effective. Therapeutic targeting of PNT in mice reduces resistance of tumor cells to CTLs. Melanoma patients with low PNT activity in their tumors demonstrate a better clinical response to immunotherapy than patients with high PNT activity. Our data suggest that intratumoral PNT activity should be considered for the design of neoantigen-based therapy and also may be an important immunotherapeutic target.
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Melanoma , Microambiente Tumoral , Animais , Antígenos de Neoplasias/metabolismo , Epitopos , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoterapia , Melanoma/metabolismo , Camundongos , Oxidantes/metabolismo , Peptídeos , Ácido Peroxinitroso/metabolismo , Linfócitos T CitotóxicosRESUMO
Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.
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Vacinas contra Influenza , Adulto , Humanos , Imunidade Humoral , Estações do Ano , Linfócitos T Auxiliares-Indutores , VacinaçãoRESUMO
The lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8+ T cells into tumors. In tissue samples from patients with melanoma, CD8+ T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1+ immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.
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Exossomos , Melanoma , Animais , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Exossomos/metabolismo , Humanos , Imunoterapia , Camundongos , Fosforilação , Receptor de Morte Celular Programada 1 , Microambiente TumoralRESUMO
BACKGROUND: Gamma delta (γδ) T lymphocytes are promising candidate for adoptive T cell therapy, however, their treatment efficacy is not satisfactory. Vδ2 T cells are unique to primates and few suitable models are available to assay their anti-tumour function. METHODS: We tested human γδ T cell activation, tumour infiltration, and tumour-killing in four three-dimensional (3D) models, including unicellular, bicellular and multicellular melanoma spheroids, and patient-derived melanoma organoids. We studied the effects of checkpoint inhibitors on γδ T cells and performed a small molecule screen using these platforms. RESULTS: γδ T cells rapidly responded to melanoma cells and infiltrated melanoma spheroids better than αß T cells in PBMCs. Cancer-associated fibroblasts (CAFs) in bicellular spheroids, stroma cells in multicellular melanoma spheroids and inhibitory immune cells in organoids significantly inhibited immune cell infiltrates including γδ T cells and lessened their cytotoxicity to tumour cells. Tumour-infiltrating γδ T cells showed exhausted immunophenotypes with high checkpoints expression (CTLA-4, PD-1 and PD-L1). Immune checkpoint inhibitors increased γδ T cell infiltration of 3D models and killing of melanoma cells in all four 3D models. Our small molecule screen assay and subsequent mechanistic studies demonstrated that epigenetic modifiers enhanced the chemotaxis and cytotoxicity of γδ T cells through upregulating MICA/B, inhibiting HDAC6/7 pathway and downregulating the levels of PD-L1 and PD-L2 in CAFs and tumour cells. These compounds increased CXCR4 and CD107a expression, IFN-γ production and decreased PD-1 expression of γδ T cells. CONCLUSIONS: Tumour-infiltrating γδ T cells show exhausted immunophenotypes and limited anti-tumour capacity in melanoma 3D models. Checkpoint inhibitors and epigenetic modifiers enhance anti-tumour functions of γδ T cells. These four 3D models provided valuable preclinical platforms to test γδ T cell functions for immunotherapy.
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Antígeno B7-H1 , Melanoma , Citotoxicidade Imunológica , Humanos , Imunoterapia/métodos , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.
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Colite , Melanoma , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Melanoma/terapia , Estudos Retrospectivos , Esteroides/uso terapêuticoRESUMO
BACKGROUND: While health systems have implemented multifaceted interventions to improve physician and patient communication in serious illnesses such as cancer, clinicians vary in their response to these initiatives. In this secondary analysis of a randomized trial, we identified phenotypes of oncology clinicians based on practice pattern and demographic data, then evaluated associations between such phenotypes and response to a machine learning (ML)-based intervention to prompt earlier advance care planning (ACP) for patients with cancer. METHODS AND FINDINGS: Between June and November 2019, we conducted a pragmatic randomized controlled trial testing the impact of text message prompts to 78 oncology clinicians at 9 oncology practices to perform ACP conversations among patients with cancer at high risk of 180-day mortality, identified using a ML prognostic algorithm. All practices began in the pre-intervention group, which received weekly emails about ACP performance only; practices were sequentially randomized to receive the intervention at 4-week intervals in a stepped-wedge design. We used latent profile analysis (LPA) to identify oncologist phenotypes based on 11 baseline demographic and practice pattern variables identified using EHR and internal administrative sources. Difference-in-differences analyses assessed associations between oncologist phenotype and the outcome of change in ACP conversation rate, before and during the intervention period. Primary analyses were adjusted for patients' sex, age, race, insurance status, marital status, and Charlson comorbidity index. The sample consisted of 2695 patients with a mean age of 64.9 years, of whom 72% were White, 20% were Black, and 52% were male. 78 oncology clinicians (42 oncologists, 36 advanced practice providers) were included. Three oncologist phenotypes were identified: Class 1 (n = 9) composed primarily of high-volume generalist oncologists, Class 2 (n = 5) comprised primarily of low-volume specialist oncologists; and 3) Class 3 (n = 28), composed primarily of high-volume specialist oncologists. Compared with class 1 and class 3, class 2 had lower mean clinic days per week (1.6 vs 2.5 [class 3] vs 4.4 [class 1]) a higher percentage of new patients per week (35% vs 21% vs 18%), higher baseline ACP rates (3.9% vs 1.6% vs 0.8%), and lower baseline rates of chemotherapy within 14 days of death (1.4% vs 6.5% vs 7.1%). Overall, ACP rates were 3.6% in the pre-intervention wedges and 15.2% in intervention wedges (11.6 percentage-point difference). Compared to class 3, oncologists in class 1 (adjusted percentage-point difference-in-differences 3.6, 95% CI 1.0 to 6.1, p = 0.006) and class 2 (adjusted percentage-point difference-in-differences 12.3, 95% confidence interval [CI] 4.3 to 20.3, p = 0.003) had greater response to the intervention. CONCLUSIONS: Patient volume and time availability may be associated with oncologists' response to interventions to increase ACP. Future interventions to prompt ACP should prioritize making time available for such conversations between oncologists and their patients.
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Planejamento Antecipado de Cuidados , Neoplasias , Oncologistas , Feminino , Humanos , Aprendizado de Máquina , Masculino , Neoplasias/terapia , FenótipoRESUMO
INTRODUCTION: Patients with advanced cancers often face significant symptoms from their cancer and adverse effects from cancer-associated therapy. Patient-generated health data (PGHD) are routinely collected information about symptoms and activity levels that patients either directly report or passively record using devices such as wearable accelerometers. The objective of this study was to test the impact of an intervention integrating remote collection of PGHD with clinician and patient nudges to inform communication between patients with advanced cancer and their oncology team regarding symptom burden and functional status. METHODS AND ANALYSIS: This single-centre prospective randomised controlled trial randomises patients with metastatic gastrointestinal or lung cancers into one of three arms: (A) usual care, (B) an intervention that integrates PGHD (including weekly text-based symptom surveys and passively recorded step counts) into a dashboard delivered to oncology clinicians at each visit and (C) the same intervention as arm B but with an additional text-based active choice intervention to patients to encourage discussing their symptoms with their oncology team. The study will enrol approximately 125 participants. The coprimary outcomes are patient perceptions of their oncology team's understanding of their symptoms and their functional status. Secondary outcomes are intervention utility and adherence. ETHICS AND DISSEMINATION: This study has been approved by the institutional review board at the University of Pennsylvania. Study results will be disseminated using methods that describe the results in ways that key stakeholders can best understand and implement. TRIAL REGISTRATION NUMBERS: NCT04616768 and 843 616.
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Neoplasias , Humanos , Oncologia , Neoplasias/terapia , Cuidados Paliativos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The clinical benefit of T cell immunotherapies remains limited by incomplete understanding of T cell differentiation and dysfunction. We generated an epigenetic and transcriptional atlas of T cell differentiation from healthy humans that included exhausted CD8 T cells and applied this resource in three ways. First, we identified modules of gene expression and chromatin accessibility, revealing molecular coordination of differentiation after activation and between central memory and effector memory. Second, we applied this healthy molecular framework to three settings-a neoadjuvant anti-PD1 melanoma trial, a basal cell carcinoma scATAC-seq dataset, and autoimmune disease-associated SNPs-yielding insights into disease-specific biology. Third, we predicted genome-wide cis-regulatory elements and validated this approach for key effector genes using CRISPR interference, providing functional annotation and demonstrating the ability to identify targets for non-coding cellular engineering. These studies define epigenetic and transcriptional regulation of human T cells and illustrate the utility of interrogating disease in the context of a healthy T cell atlas.
Assuntos
Epigenômica , Ativação Linfocitária , Linfócitos T CD8-Positivos , Diferenciação Celular/genética , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Humanos , Ativação Linfocitária/genéticaRESUMO
PURPOSE: Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T). PATIENTS AND METHODS: We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. RESULTS: Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. CONCLUSIONS: HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autofagia , Humanos , Hidroxicloroquina/uso terapêutico , Imidazóis , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêuticoRESUMO
Tumor-derived extracellular vesicles (TEVs) suppress the proliferation and cytotoxicity of CD8+ T cells, thereby contributing to tumor immune evasion. Here, we report that the adhesion molecule intercellular adhesion molecule 1 (ICAM-1) co-localizes with programmed death ligand 1 (PD-L1) on the exosomes; both ICAM-1 and PD-L1 are upregulated by interferon-γ. Exosomal ICAM-1 interacts with LFA-1, which is upregulated in activated T cells. Blocking ICAM-1 on TEVs reduces the interaction of TEVs with CD8+ T cells and attenuates PD-L1-mediated suppressive effects of TEVs. During this study, we have established an extracellular vesicle-target cell interaction detection through SorTagging (ETIDS) system to assess the interaction between a TEV ligand and its target cell receptor. Using this system, we demonstrate that the interaction of TEV PD-L1 with programmed cell death 1 (PD-1) on T cells is significantly reduced in the absence of ICAM-1. Our study demonstrates that ICAM-1-LFA-1-mediated adhesion between TEVs and T cells is a prerequisite for exosomal PD-L1-mediated immune suppression.
Assuntos
Exossomos/metabolismo , Terapia de Imunossupressão , Molécula 1 de Adesão Intercelular/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Adesão Celular/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Interferon gama/farmacologia , Melanoma/patologia , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/metabolismo , Ligação Proteica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: Oncologists may overestimate prognosis for patients with cancer, leading to delayed or missed conversations about patients' goals and subsequent low-quality end-of-life care. Machine learning algorithms may accurately predict mortality risk in cancer, but it is unclear how oncology clinicians would use such algorithms in practice. METHODS: The purpose of this qualitative study was to assess oncology clinicians' perceptions on the utility and barriers of machine learning prognostic algorithms to prompt advance care planning. Participants included medical oncology physicians and advanced practice providers (APPs) practicing in tertiary and community practices within a large academic healthcare system. Transcripts were coded and analyzed inductively using NVivo software. RESULTS: The study included 29 oncology clinicians (19 physicians, 10 APPs) across 6 practice sites (1 tertiary, 5 community) in the USA. Fourteen participants had previously had exposure to an automated machine learning-based prognostic algorithm as part of a pragmatic randomized trial. Clinicians believed that there was utility for algorithms in validating their own intuition about prognosis and prompting conversations about patient goals and preferences. However, this enthusiasm was tempered by concerns about algorithm accuracy, over-reliance on algorithm predictions, and the ethical implications around disclosure of an algorithm prediction. There was significant variation in tolerance for false positive vs. false negative predictions. CONCLUSION: While oncologists believe there are applications for advanced prognostic algorithms in routine care of patients with cancer, they are concerned about algorithm accuracy, confirmation and automation biases, and ethical issues of prognostic disclosure.