Biomarcatori di risposta in pazienti affetti da neoplasia del polmone metastatico in trattamento con immunoterapia

RAZIONALE Nonostante gli entusiasmanti risultati dell’impiego dell’immunoterapia nel trattamento delle neoplasie solide, solo il 30-40% dei pazienti presentato un beneficio a lungo termine mentre il restante 60-70% presenta progressione dopo i primi mesi di trattamento. La ricerca di biomarcatori in grado di selezionare i pazienti responsivi dai pazienti non responsivi rappresenta oggi la vera sfida dell’immuno-oncologia. In questo scenario si inserisce questo lavoro che ha l’obiettivo di investigare il ruolo prognostico/predittivo di alcuni biomarcatori. In particolare valuteremo il ruolo del pathway di IDO, il possibile ruolo del microbioma e il ruolo del fattore reumatoide. MATERIALI E METODI Sono stati arruolati pazienti affetti NSCLC in stadio IV seguiti presso Azienda Ospedaliera Sant’Andrea di Roma, Facoltà di Medicina e Psicologia Sapienza Università di Roma, da giugno 2016 a luglio 2017 Il trattamento con Nivolumab è stato somministrato a una dose standard di 3 mg / kg ogni 2 settimane fino a progressione di malattia o sviluppo di tossicità inaccettabile ANALISI CHINURENINE Abbiamo valutato i livelli sierici di trp, kyn e acido chinolinico con una cromatografia liquida modificata-metodo spettrometria di massa tandem (LC-MS / MS), ANALISI MICROBIOMA : Ogni campione di feci è stato raccolto e processato. Il DNA genomico è stato isolato dall'intero set di campioni, utilizzando il kit QIAamp DNA Stool Mini (Qiagen, Germania). La regione V1-V3 del locus RNA ribosomiale 16S (rRNA) è stata amplificata per la successiva fase di pirosequenziamento su un sequenziatore genoma 454-Junior (Roche 454 Life Sciences, Branford, USA). ANALISI DEL FATTORE REUMATOIDE In una coorte di pazienti, abbiamo determinato i livelli sierici di pre-trattamento di FR (kit ELISA in fase solida, valori superiori a 16 U / ml sono stati considerati positivi). RISULTATI ANALISI DELLE CHIMURENINE : La PFS era significativamente più lunga nei pazienti che presentavano valori inferiori di kyn / trp rispetto a pazienti con valori più elevati di kyn / trp (PFS mediana non raggiunta a 3 mesi; HR: 0,2; IC 95%: 0,06-0,62; p = 0,001). ANALISI MICROBIOMA : La meta-tassonomia del microbiota è stata descritta per i pazienti con NSCLC rispetto ai CTRL e ad ogni periodo di trattamento con Nivolumab. Nei pazienti affetti da NSCLC Rikenellaceae, Prevotella, Streptococco, Lactobacillus (p <0,05), Bacteroides plebeius, Oscillospira, Enterobacteriaceae (p <0,05) sono risultati aumentati rispetto ai CTRL. I non responder avevano Ruminococcus bromii, Dialister, Sutterella più abbondante dei pazienti responder alla terapia (p <0,05). Un po 'aumentato nei responder è apparso Akkermansia muciniphila, Bifidobacterium longum e Faecalibacterium prausnitzii (p <0,05). Propionibacterium acnes, Veillonella, Staphylococcus aureus, Peptostreptococcus apparivano significativamente sovraespressi, mentre il Clostridium perfringens era significativamente ridotto al C1 rispetto al punto temporale C3 del trattamento ANALISI DEL FATTORE REUMATOIDE : La progressione precoce della malattia è risultata significativamente più frequente nei pazienti con RF positiva (5/7, 71,4%) rispetto a quelli negativi (8/28, 28,6%, p <0,0001) CONCLUSIONE Il nostro studio suggerisce che i pazienti con elevato rapporto kyn/trp , un elevato livello plasmatico di FR sono caratterizzati da una prognosi estremamente infausta e da una resistenza primaria agli anti PD-1. Il nostro studio suggerisce inoltre che diversi profili di microbioma siano associati a rischio diverso di sviluppare cancro del polmone, ma anche come siano associati a differente risposta all’immunoterapia. I nostri dati si inseriscono nello scenario della medicina di precisione ed in particolare della immuno-oncologia di precisione in cui la ricerca del biomarcatore di risposta o resistenza è cruciale nel selezionare il paziente e ottimizzare le risorse ed i trattamenti disponibili

The microbiota impact. bacteria shaping immunity, disease and response to therapy

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A Smart Home Network for Proactive Users

According to the European Strategy Energy Technology (SET) Plan, the resident-user engagement into thenational energy strategy is pivotal, as reported by the Challenge 1st: “Active consumer is at the centre of the energy system”. The Italian Ministry of Economic Development and ENEA have entered into a Program Agreement for the execution of the research and development lines of General Interest for the NationalElectricity System. In particular, as part of the “Development of an integrated model of the Urban Smart District” project. An experimental demonstration of a Smart Home network is being carried out in the Centocelle district of Rome and called “Smart Home Centocelle”. The project was developed in an informal settlement, which shares a common background with likewise urban settings, such as a lack of public transportation convenience or enjoyable public spaces and average quality housing, whereas people who adhered to the project have a medium-high education level and proved to be sensitive to alternative and more sustainable energy sources. Our research has examined the deployment progress made so far, gathering and analysing all the information to assess how the project applications could affect various quality-of-life dimensions: safety, health, environmental quality and personal comfort perception, social connectedness and the cost of living, above all

The role of stereotactic body radiation therapy in oligometastatic colorectal cancer

Rationale: Regorafenib is the new standard third-line therapy in metastatic colorectal cancer (mCRC). However, the reported 1-year overall survival rate does not exceed 25%. Patient concerns: A 55-year-old man affected by mCRC, treated with regorafenib combined with stereotactic body radiotherapy (SBRT), showing a durable response. Interventions: After 6 months of regorafenib, a PET/CT scan revealed a focal uptake in a solid lung nodule which was treated with SBRT, whereas continuing regorafenib administration. Fourteen months later, the patient had further progression in a parasternal lymph node, but treatment with regorafenib was continued. The regorafenib-associated side effects, such us the hand-foot syndrome, were favorable managed by reducing the dose from 160 to 120 mg/day. Outcomes: Patient-reported outcome was characterized by a progression-free survival of approximately 3 years. Lessons: in presence of oligometastatic progression, a local SBRT while retaining the same systemic therapy may be a better multidisciplinary approach. Moreover, disease progression is no longer an absolute contraindication for continuing the regorafenib treatment

Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment. METHODS: Pre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann-Whitney test. RESULTS: Twenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (< 3 months) to nivolumab treatment. The median value of kyn/trp ratio was 0.06 µg/ml and the median value of quinolinic acid was 68.45 ng/ml. A significant correlation between early progression and higher kyn/trp ratio and quinolinic acid concentration was observed (p = 0.017 and p = 0.005, respectively). Patients presenting lower values of kyn/trp ratio and quinolinic acid levels showed longer PFS (median PFS not reached versus 3 months; HR: 0.3; p = 0.018) and OS (median OS not reached vs 3 months; HR: 0.18; p = 0.0005). CONCLUSION: IDO activity, expressed as kyn/trp ratio, is associated with response to immunotherapy; in particular, higher kyn/trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in those patients with high level of kyn/trp ratio

Agnostic evaluation of ipilimumab and nivolumab association: a metanalysis

Background: Ipilimumab and Nivolumab, targeting the molecules CTLA-4, PD-1, respectively,have shown efficacy against several types of cancer. Despite these results, only a small percentage of patients maintains a long-lasting effect. Even Ipilimumab, in combination with nivolumab, has demonstrated a significant clinical benefit in multiple tumor types. However, no trial has been designed with the primary endpoint to compare the efficacy of nivolumab plus ipilimumab combined, compared to nivolumab alone. Hence, the added value of ipilimumab in the combination has not clearly been established yet. The aim of this study was to demonstrate the superiority of the combination strategy compared to the single agent therapy. Materials and methods: We performed a meta-analysis of Phase I-II-III Clinical Trials, published from 2010 up to 2020, in which the combination of ipilimumab plus nivolumab was compared to nivolumab alone. We extracted ORR, OS and PFS HR on the basis of treatment from the subgroup analysis of each trial. Results: A total of 7 trials were included in the present meta-analysis. Overall, 1313 patients were treated with the nivolumab plus ipilimumab combination compared to 1110 patients treated with nivolumabalone. All trials reported the Objective response rate(ORR), no heterogeneity was found among studies and the pooled Odds Ratio was highly in favor of the nivolumab plus ipilimumab combination with respect to nivolumab alone (1.683; 95% CI: 1.407-2.012; P &lt; 0.0001). Three studies were considered for Progression free survival (PFS) analysis, and the pooled Hazard Ratio favored the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.807; 95% CI: 0.719-0.907; P &lt; 0.0001). The Overall survival(OS) endpoint was considered only in 2 trials, and the pooled HR favored, also in this case, the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.87; 95% CI: 0.763-0.997; P = 0.045)

Drug resistance of BRAF-mutant melanoma: Review of up-to-date mechanisms of action and promising targeted agents

Abstract Melanoma onset and progression are associated with a high variety of activating mutations in the MAPK-pathway, most frequently involving BRAF (35–45%) and NRAS (15–25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed

Risk of SARS-CoV-2 infection and disease in metastatic triple-negative breast cancer patients treated with immune checkpoint inhibitors

Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease with particularly poor outcomes [1]. Over the past few years, relevant gains in knowledge concerning the molecular landscape of this disease have allowed to considerably broaden the available therapeutic armamentarium. Poly ADP-ribose polymerase-1 inhibitors, epigenetic agents, anti-androgens, tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) may all optimally exemplify the targeted therapeutic weapons recently gained in the fight against mTNBC [2]. Targeting of immune checkpoints through their respective monoclonal antibodies translates into effective antitumor responses not only in widely recognized ‘immunogenic’ tumor types, for example, melanoma and renal cell carcinoma, but also in other solid tumors including breast cancer [3]. PD-1 is an immune checkpoint expressed on the surface of B cells, T cells and natural killer T cells, with a critical role in modulating self tolerance, immune homeostasis and inflammation. When activated by PD-L1 or -L2, PD-1 mediates downregulation of T-cell activity, causes T-cell lysis and reduces cytokine production significantl

Degradation rate of 5-fluorouracil in metastatic colorectal cancer. A new predictive outcome biomarker?

BACKGROUND: 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival. MATERIALS AND METHODS: Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome. RESULTS: 133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed. CONCLUSION: 5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes