The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.

BACKGROUND: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. METHODS: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. RESULTS: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). CONCLUSIONS: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Efficacy and tolerability of immunotherapy in advanced nasopharyngeal carcinoma with or without chemotherapy: a meta-analysis.

INTRODUCTION: Evidence of programmed death-1 inhibitors in nasopharyngeal carcinoma has been accumulated. However, previous clinical studies were basically small sample size. OBJECTIVE: This study aimed to summarize existing studies to comprehensively compare programmed death-1 inhibitors in nasopharyngeal carcinoma with or without chemotherapy. METHODS: Different databases were searched for full-text publications with a programmed death-1 inhibitor with or without chemotherapy. No study-to-study heterogeneity was detected, and fixed-effect models were applied to synthesize data. RESULTS: Seven studies were included. The mean progression-free survival duration of programmed death-1 inhibitors treatment was 4.66 months. The 6 month progression-free survival rate was 50%, however, the12 month progression-free survival rate fell to 27%. Comparing with programmed death-1 inhibitor monotherapy, the objective response rate was higher in combination therapy (pooled RR=2.90, 95% CI: 2.07-4.08). The partial response rate was higher in patients receiving programmed death-1 in association with chemotherapy (pooled RR=3.09, 95% CI: 2.15-4.46), In contrast, the progressive disease rate was lower in combination therapy group (pooled RR=0.06, 95% CI: 0.01-0.31). Stable disease condition was comparable (pooled RR=0.90, 95% CI: 0.50-1.64) with or without chemotherapy. Programmed death-1 single use or combined with chemotherapy did not influence the total adverse events occurrence (pooled RR=0.99, 95% CI: 0.93-1.05). However, combination therapy could increase the risk of serious adverse events such as anemia, thrombocytopenia, and neutropenia. CONCLUSION: The present study summarized the efficacy and safety of programmed death-1 inhibitors in nasopharyngeal carcinoma. Combination therapy showed higher anti-tumor activity except for higher risk of myelosuppression.

Efficacy and tolerability of immunotherapy in advanced nasopharyngeal carcinoma with or without chemotherapy: a meta-analysis / Eficácia e tolerabilidade da imunoterapia em carcinoma nasofaríngeo avançado, com ou sem quimioterapia: uma metanálise

Abstract Introduction Evidence of programmed death-1 inhibitors in nasopharyngeal carcinoma has been accumulated. However, previous clinical studies were basically small sample size. Objective This study aimed to summarize existing studies to comprehensively compare programmed death-1 inhibitors in nasopharyngeal carcinoma with or without chemotherapy. Methods Different databases were searched for full-text publications with a programmed death-1 inhibitor with or without chemotherapy. No study-to-study heterogeneity was detected, and fixed-effect models were applied to synthesize data. Results Seven studies were included. The mean progression-free survival duration of programmed death-1 inhibitors treatment was 4.66 months. The 6 month progression-free survival rate was 50%, however, the12 month progression-free survival rate fell to 27%. Comparing with programmed death-1 inhibitor monotherapy, the objective response rate was higher in combination therapy (pooled RR = 2.90, 95% CI: 2.07-4.08). The partial response rate was higher in patients receiving programmed death-1 in association with chemotherapy (pooled RR = 3.09, 95% CI: 2.15-4.46), In contrast, the progressive disease rate was lower in combination therapy group (pooled RR = 0.06, 95% CI: 0.01-0.31). Stable disease condition was comparable (pooled RR = 0.90, 95% CI: 0.50-1.64) with or without chemotherapy. Programmed death-1 single use or combined with chemotherapy did not influence the total adverse events occurrence (pooled RR = 0.99, 95% CI: 0.93-1.05). However, combination therapy could increase the risk of serious adverse events such as anemia, thrombocytopenia, and neutropenia. Conclusion The present study summarized the efficacy and safety of programmed death-1 inhibitors in nasopharyngeal carcinoma. Combination therapy showed higher anti-tumor activity except for higher risk of myelosuppression.

Resumo Introdução Há um acúmulo de evidências sobre os inibidores de morte celular programada‐1 no carcinoma nasofaríngeo. Porém, os estudos clínicos anteriores foram quase todos feitos com amostras de tamanho pequeno. Objetivo Resumir os estudos existentes para comparar de forma abrangente os inibidores de morte celular programada‐1 em carcinoma nasofaríngeo com ou sem quimioterapia. Método A pesquisa foi feita em diferentes bases de dados em busca de publicações de texto completo que usaram um inibidor de morte celular programada‐1 com ou sem quimioterapia. Nenhuma heterogeneidade entre os estudos foi detectada e modelos de efeito fixo foram aplicados para sintetizar os dados. Resultados Sete estudos foram incluídos. A duração média da sobrevida livre de progressão no tratamento com inibidores de morte celular programada‐1 foi de 4,66 meses. A taxa de sobrevida livre de progressão em seis meses foi de 50%; no entanto, a taxa de sobrevida livre de progressão em 12 meses caiu para 27%. Em comparação com a monoterapia com inibidor de morte celular programada‐1, a taxa de resposta objetiva (taxa de resposta combinada = 2,90, IC de 95%: 2,07-4,08). A taxa de resposta parcial foi maior em pacientes que receberam morte celular programada‐1 em combinação com quimioterapia (taxa de resposta combinada = 3,09, IC 95%: 2,15‐4,46). Ao contrário, a taxa de progressão da doença foi menor no grupo com terapia combinada (taxa de resposta combinada = 0,06, IC de 95%: 0,01-0,31). A condição de estabilidade da doença com ou sem quimioterapia foi comparável (taxa de resposta combinada = 0,90, IC de 95%: 0,50-1,64). O uso isolado de morte celular programada‐1 ou combinado com quimioterapia não influenciou a ocorrência de eventos adversos totais (taxa de resposta combinada = 0,99, IC de 95%: 0,93-1,05). No entanto, a terapia combinada pode aumentar o risco de eventos adversos graves, como anemia, trombocitopenia e neutropenia. Conclusão O presente estudo fez um resumo da eficácia e segurança dos inibidores de morte celular programada‐1 em carcinoma nasofaríngeo. A terapia combinada mostrou uma atividade antitumoral maior, excetuando‐se o risco maior de mielossupressão.

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases.

Programmed Cell Death 1 (PD-1) receptor and its ligands (PD-Ls) are essential to maintain peripheral immune tolerance and to avoid tissue damage. Consequently, altered gene or protein expression of this system of co-inhibitory molecules has been involved in the development of cancer and autoimmunity. Substantial progress has been achieved in the study of the PD-1/PD-Ls system in terms of regulatory mechanisms and therapy. However, the role of the PD-1/PD-Ls pathway in neuroinflammation has been less explored despite being a potential target of treatment for neurodegenerative diseases. Multiple Sclerosis (MS) is the most prevalent, chronic, inflammatory, and autoimmune disease of the central nervous system that leads to demyelination and axonal damage in young adults. Recent studies have highlighted the key role of the PD-1/PD-Ls pathway in inducing a neuroprotective response and restraining T cell activation and neurodegeneration in MS. In this review, we outline the molecular and cellular mechanisms regulating gene expression, protein synthesis and traffic of PD-1/PD-Ls as well as relevant processes that control PD-1/PD-Ls engagement in the immunological synapse between antigen-presenting cells and T cells. Also, we highlight the most recent findings regarding the role of the PD-1/PD-Ls pathway in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), including the contribution of PD-1 expressing follicular helper T (TFH) cells in the pathogenesis of these diseases. In addition, we compare and contrast results found in MS and EAE with evidence reported in other autoimmune diseases and their experimental models, and review PD-1/PD-Ls-targeting therapeutic approaches.

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas.

Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of de novo resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of de novo and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.

Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer.

PURPOSE: Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. METHODS: Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). RESULTS: The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). CONCLUSIONS: Tryptophan metabolites may have a potential for predicting the efficacy of ICIs. REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry 000026140.

The effect of PD-1 expression on tumor-associated macrophage in T cell lymphoma.

PURPOSE: Our study aimed to explore the programmed death 1 (PD-1) expression on tumor-associated macrophage (TAM) in T cell non-Hodgkin lymphoma (T-NHL) and its relationship with lymphoma prognosis. The effect of PD-1 expression on the function of macrophages was also studied. METHODS: Multispectral image quantitative analysis was applied for detecting PD-1 expression on macrophages in T cell lymphoma tissues. The Kaplan-Meier analysis was performed to evaluate the value of PD-1 expression of TAM in predicting the overall survival of T-NHL. PD-1 overexpression THP-1-derived macrophage was constructed and was cocultured with Jurkat cells to explore the effect of PD-1 on macrophage function. RESULTS: In 17 T cell lymphoma cases, the 1-year overall survival rate was significantly lower in patients with higher PD-1 expression on TAMs (0.25 vs 0.86, p < 0.05). After co-cultured with Jurkat cells, classically activated (M1)-related markers on PD-1 overexpressed macrophages were significantly lower than those on controls, while the expressions of alternatively activated (M2) related markers were similar. The PD-1 overexpressed macrophages showed inhibited phagocytosis (4.42% vs 40.7%, p < 0.001) and increased IL-10 secretion (144.48 pg/ml vs 32.32 pg/ml, p < 0.001). CONCLUSION: High PD-1 expression on TAMs in T-NHL may predict poor prognosis. The PD-1 overexpression of macrophages significantly inhibited polarization of M1 macrophages and phagocytosis, and more IL-10 was excreted. These changes may enhance the pro-tumor effects of tumor microenvironment.

The optimal immune checkpoint inhibitors combined with chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) plus chemotherapy (CT) have strikingly expanded the therapeutic landscape for advanced non-small cell lung cancer (NSCLC), but little is known about which is superior. We performed a meta-analysis that compared the efficacy and safety of PD-1 inhibitor + CT with PD-L1 inhibitor + CT. METHODS: PubMed, Embase, Web of Science, Cochrane Library, and major international scientific meetings were searched for relevant randomized controlled trials (RCTs), and the indirect analysis was performed for PD-1 + CT vs PD-L1 + CT. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (TRAEs). RESULTS: 8 phase III RCTs with 4253 patients comparing PD-1/PD-L1 + CT in NSCLC were included. The PD-1 + CT led to notably longer OS most in low/negative expression of PD-L1 for NSCLC patients compared with PD-L1 + CT. In terms of Grade 3-5 TRAEs, the results showed that PD-1 + CT and PD-L1 + CT exclusively increased the risk of adverse incidence than CT alone, especially for PD-L1 + CT (p < 0.00001). For subgroups including female, young patients, patients with nonsmoker, and EGFR/ALK wild-type, PD-1 + CT was associated with prolonged OS (p < 0.05). Meanwhile, for no liver metastasis of NSCLC patients, we found obviously OS advantage for patients treated with PD-1 + CT compared to PD-L1 + CT. CONCLUSIONS: ICIs + CT seemed to be more effective first-line regimen and PD-1 + CT could be recommended as the first-rank therapy for advanced NSCLC patients with low/negative expression of PD-L1. However, we should be particularly vigilant about the occurrence of the Grade 3-5 TRAEs.

Modulação da resposta imune em pacientes portadores de queilite actínica e carcinoma espinocelular de boca / Modulation of immune response in patients with actinic cheilitis and oral squamous cell carcinoma

Programmed death-1 (PD-1) é uma proteína de membrana que funciona como um importante regulador negativo da atividade de linfócitos ativa dos, participando, desta forma, do delicado balanço entre ativação e tolerância de células T. Dados recentes têm evidenciado que os mecanismos de tolerância periférica, mediados pela interação PD-1/PD- L1, também impedem uma resposta imune antitumoral eficaz, mesmo em condições nas quais os antígenos tumorais possam ser reconhecidos. Apesar de crescentes evidências demonstrarem o papel da via PD-1 no escape tumoral, pouco se sabe a respeito do seu significado em tumores da cavidade oral. Sabe-se menos ainda sobre a expressão desta molécula em lesões orais pré-neoplásicas. Baseado no exposto, o presente estudo analisou a expressão de PD-1 e seu ligante PD-L1 em lesões de queilite actínica e carcinoma espinocelular de boca através de citometria de fluxo e imunomarcação in situo Os resultados obtidos demonstraram que as células isoladas do sangue periférico e de lesões de queilite actínica e carcinoma espinocelular oral apresentam expressão aumentada de PD-1. A expressão de PD-L1 é mais restrita em queilite actínica, porém é intensa em carcinoma espinocelular oral.

Programmed death-1 (PD-l) is a transmembrane protein that acts as a negative regulator in effector T cells, modulating the delicate balance between effective antimicrobial immune defenses and immune-mediated tissue damage. However, recent evidences suggest that the PD-l: PD-L1 pathway can also block antitumor immune responses even when tumor antigens can be recognized. In spite of growing data indicating the involvement of PD-l in tumor escape, little is known about its role in tumors of oral cavity. In addition, the involvement of PD-l in pre-malignant lesions is an important issue to be clarified. In the present work we investigated the expression of PD-l and PD-L1 in blood and biopsies of patients with actinic cheilitis and oral squamous cell carcinoma by flow cytometry, immunofluorescence and immunohistochemistry. Our data showed that Iymphocytes obtained from peripheral blood and lesion sites exhibited high expression of PD-l in both groups studied Moreover, PD-L1 expression was intense in oral squamous cell carcinoma and moderate in actinic cheilitis.