Molecular target therapy and immunotherapy of rare lung tumors

Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

: The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies

Monitoring tumor growth rate to predict immune checkpoint inhibitors' treatment outcome in advanced NSCLC

Introduction: Radiological response assessment to immune checkpoint inhibitor is challenging due to atypical pattern of response and commonly used RECIST 1.1 criteria do not take into account the kinetics of tumor behavior. Our study aimed at evaluating the tumor growth rate (TGR) in addition to RECIST 1.1 criteria to assess the benefit of immune checkpoint inhibitors (ICIs). Methods: Tumor real volume was calculated with a dedicated computed tomography (CT) software that semi-automatically assess tumor volume. Target lesions were identified according to RECIST 1.1. For each patient, we had 3 measurement of tumor volume. CT-1 was performed 8-12 weeks before ICI start, the CT at baseline for ICI was CT0, while CT + 1 was the first assessment after ICI. We calculated the percentage increase in tumor volume before (TGR1) and after immunotherapy (TGR2). Finally, we compared TGR1 and TGR2. If no progressive disease (PD), the group was disease control (DC). If PD but TGR2 < TGR1, it was called LvPD and if TGR2 > TGR1, HvPD. Results: A total of 61 patients who received ICIs and 33 treated with chemotherapy (ChT) were included. In ICI group, 18 patients were HvPD, 22 LvPD, 21 DC. Median OS was 4.4 months (95% CI: 2.0-6.8, reference) for HvPD, 7.1 months (95% CI 5.4-8.8) for LvPD, p = 0.018, and 20.9 months (95% CI: 12.5-29.3) for DC, p < 0.001. In ChT group, 7 were categorized as HvPD, 17 as LvPD and 9 as DC. No difference in OS was observed in the ChT group (p = 0.786) Conclusion: In the presence of PD, a decrease in TGR may result in a clinical benefit in patients treated with ICI but not with chemotherapy. Monitoring TGR changes after ICIs administration can help physician in deciding to treat beyond PD

scheda tesi

scheda tesi: Nuovo Mondo e mondializzazione iberica. Lo sguardo degli Italian

A putative role for interleukin 1 pathway in resistance to EGFR blockade

Cetuximab (CX) is a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), which is commonly utilized to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, clinicians often observe a residual disease, with a population of cells surviving the treatment and eventually enabling CX resistance. Our previous studies, performed with a cohort of 150 CRC xenopatients, associated poor response to CX with increased abundance of a set of inflammatory cytokines, including IL1A, B and IL8. Stemming from these observations, our working hypothesis assumes that, resistance to CX is acquired, in a subset of CRC patients, through cell plasticity and consequent rewiring of signalling networks, which confer to tumors dependency on the IL1 pathway. In order to assess the effect of IL1 activity, we employed a colon cancer model unresponsive to cetuximab, as previously characterized in our laboratory. To inhibit activation of the IL1 pathway we used anakinra, an IL1-receptor antagonist and parthenolide, which modulates the activity of NF-kB, the transcription factor involved in the feed-forward loop of inflammation mediators. Furthermore, we employed a recombinant decoy (IL1R-Fc), namely a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of IL1-receptor, with the ability to sequester IL1 directly from the medium. We generated stable clones of CXresistant cells expressing IL1R-Fc. Our preliminary results show that inhibition of IL1R leads to a proliferation decrease of colorectal cancer cells. These findings support the hypothesis of a compensatory activation of the IL1-receptor pathway in cetuximab-resistant CRC cells. Hence, modulating IL1 signalling might represent a new therapeutic strategy suitable for patients who acquired refractoriness to monoclonal antibody therapy

Molecular mechanisms of resistance to cetuximab mediated by IL-1 signaling

Cetuximab (CTX) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), which is commonly employed to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, clinicians often observe a failure of the therapy with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous studies, employing a cohort of 150 CRC xenopatients, associated poor response to CTX with increase abundance of a set of inflammatory cytokines, namely IL-1, IL-1 and IL-8 (Gelfo et al., 2016). In the time frame of my first year of Ph.D, we found that in patients, undergoing CTX treatment, overexpression of IL-1 Receptor (IL-1R) correlates with reduced response. Stemming from these observations, we assumed that resistance to CTX is acquired, in a subset of CRC patients, through cell plasticity, as a consequent rewiring of signaling networks. Employing a recombinant decoy (IL1R-Fc) able to sequester IL-1 directly from the medium, our results show that IL1R decoy successfully dampens pSTAT3 activation along with MAPK and PI3K axes, thus decreasing proliferation and colon spheres formation. Furthermore, we report that IL1R abundance predicts disease relapse free survival in a cohort of 1700 colorectal cancer patients, and it appears associated to a specific subtype, namely the consensus molecular subtype 1 (CMS1). Our data therefore suggest that a loop mediated by the IL1 and its cognate receptor mediates CTX resistance in a specific subtype of colorectal cancer. Mechanistically, our preliminary data show that CTX treatment promotes an increase in inflammatory cytokines leading to a post-senescent phenotype, as detected by -galactosidase, HP1- and p21 markers