Christian Rolfo

CD70: An emerging target in cancer immunotherapy

Over the last decades, advances in the knowledge of immunology have led to the identification of immune checkpoints, reinvigorating cancer immunotherapy. Although normally restricted to activated T and B cells, constitutive expression of CD70 in tumor cells has been described. Moreover, CD70 is implicated in tumor cell and regulatory T cell survival through interaction with its ligand, CD27. In this review, we summarize the targetable expression patterns of CD70 in a wide range of malignancies and the promising mechanism of anti-CD70 therapy in stimulating the anti-tumor immune response. In addition, we will discuss clinical data and future combination strategies.

Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients.

Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer. The development of sensitive and accurate techniques such as Next-Generation Sequencing (NGS); Beads, Emulsion, Amplification, and Magnetics (BEAMing); and Digital PCR (dPCR), have made it possible to detect the specific genetic alterations (e.g. EGFR mutations, MET amplifications, and ALK and ROS1 translocations) for which targeted therapies are already available. Moreover, the ability to detect and quantify these tumor mutations has enabled the follow-up of tumor dynamics in real time. Liquid biopsy offers opportunities to detect resistance mechanisms, such as the EGFR T790M mutation in the case of EGFR TKI use, at an early stage. Several studies have already established the predictive and prognostic value of measuring ctNA concentration in the blood. To conclude, using ctNA analysis as a liquid biopsy has many advantages and allows for a variety of clinical and investigational applications.

Immunotherapy in NSCLC: A Promising and Revolutionary Weapon

Lung cancer is the leader malignancy worldwide accounting 1.5 millions of deaths every year. In the United States the 5 year-overall survival is less than 20% for all the newly diagnosed patients. Cisplatin-based cytotoxic chemotherapy for unresectable or metastatic NSCLC patients in the first line of treatment, and docetaxel in the second line, have achieved positive results but with limited benefit in overall survival. Targeted therapies for EGFR and ALK mutant patients have showed better results when compared with chemotherapy, nevertheless most of patients will fail and need to be treated with chemotherapy if they still have a good performance status.Immunotherapy recently has become the most revolutionary treatment in solid tumors patients. First results in unresectable and metastatic melanoma patients treated with an anti CTLA-4 monoclonal antibody showed an unexpected 3-year overall survival of at least 25%.Lung cancer cells have multiple immunosuppressive mechanisms that allow to escape of the immune system and survive, however blocking CTLA-4 pathway with antibodies as monotherapy treatment have not achieved same results than in melanoma patients. PD-1 expression has been demonstrated in different tumor types, suggesting than PD-1 / PD-L1 pathway is a common mechanism used by tumors to avoid immune surveillance and favoring tumor growth. Anti PD-1 and anti PD-L1 antibodies have showed activity in non-small cell lung cancer patients with significant benefit in overall survival, long lasting responses and good safety profile, including naïve and pretreated patients regardless of the histological subtype. Even more, PD-1 negative expression patients achieve similar results in overall survival when compared with patients treated with chemotherapy. In the other side high PD-1 expression patients that undergo immunotherapy treatment achieve better results in terms of survival with lesser toxicity. Combining different immunotherapy treatments, combination of immunotherapy with chemotherapy or with targeted treatment are under research with some promising PRELIMINARY results in non-small cell lung cancer patients.This chapter attempts to summarize the development of immunotherapy treatment in non-small cell lung cancer patients and explain the results that have leaded immunotherapy as a new standard of treatment in selected NSCLC patients.

MicroRNAs in Colorectal Cancer Drug Resistance: Shooters become Targets

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Ramucirumab and its use in gastric cancer treatment.

The inhibition of the mechanisms of tumor neo-angiogenesis represents a milestone that in the last 10 years has seen the advent of numerous molecules to target action against the vascular endothelial growth factor (VEGF). More recently, new molecules have been developed that inhibit tumor spread by the blockade of specific VEGF receptors (VEGFRs), thereby preventing the binding of a ligand to its receptor and the cascade of proliferative events downstream. Ramucirumab is a fully humanized IgG1 monoclonal antibody that performs its action by blocking the isoform 2 of the VEGF receptor (VEGFR-2). Numerous preclinical and clinical studies have demonstrated its activity in several solid tumors, demonstrating a remarkable efficacy in terms of progression-free survival and overall survival in addition to a favorable toxicity profile. This review analyzes in detail the role of ramucirumab in the treatment of advanced gastric and gastroesophageal junction cancers.

Cardiovascular Damage in Clinical Trials

The Cardio-oncology field has grown considerably in the last two decades. The remarkable increase in the number of molecules used in oncology has brought with it a huge set of cardiovascular adverse events. For this reason, it is necessary to intervene on the early stages of drug development. This is what the Food and Drug Administration aims to do. This purpose can be achieved through a more careful analysis of the adverse event, development of guidelines, and identification of objective parameters that could guide the researcher in defining precisely the adverse event. It is also necessary to use additional methods not yet used in clinical trials that can allow an early detection of adverse events and to highlight subclinical damage. These measures will allow the researcher to intervene and treat them even before it can expose the patient to more serious complications or the drug can determine deaths in the post-marketing phase for unacknowledged cardiovascular adverse events.

Indications for Locoregional Tumor Therapies: CRC Liver Metastases

The liver represents the most affected site in patients affected by colorectal carcinoma (mCRC) [1]. More than half cases develop colorectal liver metastases (CLMs) during the evolution of the disease, and about one-quarter occur at the disease onset [1, 2]. To date, the standard treatment of CLM is represented by liver surgery, which has allowed to achieve interesting long-term survival rates (40–60%) [3] in reported series, while it is less than 25% for patients who do not undergo surgery [4]. Unfortunately, most patients (80%), however, are not immediately eligible for surgery [5, 6]. For these patients, surgical treatment may be administered in combination with chemotherapy regimens (+/− target agents) aiming to downsize neoplasm and to allow a surgically and oncologically radical intervention. In addition, the greater effectiveness of the abovementioned new chemotherapeutic options has allowed to revolutionize the liver resection criteria considered until recently, thus widening the proportion of patients able to obtain long-term benefit from surgery. Locoregional liver treatments (including ablative technologies and transarterial treatments) can be considered additional options able to downsize CLMs and have been shown to improve quality of life, prolonging time to local progression and overall survival [7, 8]. Of course, to achieve optimal results, it is necessary to set up a multidisciplinary team, including interventionist radiologists, able to evaluate individual cases in order to select the best therapeutic strategy for each patient.

Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy?

Background There are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy. Methods We performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024). Results Female patients with NSCLC have a reduced risk of death compared with men (HR=0.73; 95%u2009CI 0.67 to 0.79; p<0.00001). Women had a better benefit from EGFR inhibitors than men (HR=0.34; 95%u2009CI 0.28 to 0.40; p<0.00001u2009vs HR=0.44; 95%u2009CI 0.34 to 0.56; p<0.00001, respectively). The benefit from ALK inhibitors was similar for both genders (HR=0.51; 95%u2009CI 0.42 to 0.61; p<0.00001u2009vs HR=0.48; 95%u2009CI 0.39 to 0.59; p<0.00001, for women and men, respectively). Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy (HR=0.76; 95%u2009CI 0.68 to 0.86; p<0.00001); in contrast, women showed no benefit in 5/5 randomised trials (HR=1.03; 95%u2009CI 0.89 to 1.20; p=0.69). Conclusions In this exploratory study, some targeted treatments were influenced by gender. Despite differences in outcomes that could be attributed to different histology, EGFR and smoking status, gender should be evaluated more deeply as prognostic variable in patients with NSCLC.

CSF-1 and Ang-2 serum levels — prognostic and diagnostic partners in non-small cell lung cancer

Background Lung cancer is the most incident and lethal form of cancer, with late diagnosis as a major determinant of its bad prognosis. Immunotherapies targeting immune checkpoints improve survival, but positive results encompass only 30%–40% of the patients, possibly due to alternative pathways to immunosuppression, including tumour-associated macrophages (TAM). Colony stimulating factor-1 (CSF-1) is implicated in TAM differentiation and recruitment to tumours and in tumour angiogenesis, through a special setting of Tie-2-expressing macrophages, which respond to angiopoietin-2 (Ang-2). We evaluated the role of serum levels of CSF-1 in non-small cell lung cancer (NSCLC) prognosis and whether these could serve as biomarkers for NSCLC detection, along with Ang-2. Participants and methods We prospectively studied an unselected cohort of 145 patients with NSCLC and a group of 30 control individuals. Serum levels of Ang-2 and CSF-1 were measured by ELISA prior to treatment. Results Serum levels of CSF-1 and Ang-2 are positively correlated (p<0.000001). Individuals with high serum levels of CSF-1 have a 17-fold risk for NSCLC presence and patients with combined High Ang-2/CSF-1 serum levels present a 5-fold increased risk of having NSCLC. High Ang-2/CSF-1 phenotype is also associated with worst prognosis in NSCLC. Conclusions Combined expression of CSF-1 and Ang-2 seems to contribute to worst prognosis in NSCLC and it is worthy to understand the basis of this unexplored partnership. Moreover, we think CSF-1 could be included as a biomarker in NSCLC screening protocols that can improve the positive predictive value of the current screening modalities, increase overall cost effectiveness and potentially improve lung cancer survival.

Potential new biomarkers for squamous carcinoma of the uterine cervix

Aim An in silico pathway analysis was performed in an attempt to identify new biomarkers for cervical carcinoma. Methods Three publicly available Affymetrix gene expression data sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total 9 cervical cancer cell lines, 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples. An Agilent data set (GSE7410; 5 normal cervical samples, 35 samples from invasive cervical cancer) was selected as a validation set. Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. We compared the lists of differentially expressed genes between normal and CIN3 samples on the one hand (n=1923) and between CIN3 and invasive cancer samples on the other hand (n=628). Results Seven probe sets were identified that were significantly overexpressed (at least 2 fold increase expression level,u2009and false discovery rate <5%) in both CIN3 samples respective to normal samples and in cancer samples respective to CIN3 samples. From these, five probes sets could be validated in the Agilent data set (P<0.001) comparing the normal with the invasive cancer samples, corresponding to the genes DTL, HMGB3, KIF2C, NEK2 and RFC4. These genes were additionally overexpressed in cervical cancer cell lines respective to the cancer samples. The literature on these markers was reviewed Conclusion Novel biomarkers in combination with primary human papilloma virus (HPV) testing may allow complete cervical screening by objective, non-morphological molecular methods, which may be particularly important in developing countries