Biological and Exploitable Crossroads for the Immune Response in Cancer and COVID-19.

The outbreak of novel coronavirus disease 2019 (COVID-19) has exacted a disproportionate toll on cancer patients. The effects of anticancer treatments and cancer patients' characteristics shared significant responsibilities for this dismal outcome; however, the underlying immunopathological mechanisms are far from being completely understood. Indeed, despite their different etiologies, SARS-CoV-2 infection and cancer unexpectedly share relevant immunobiological connections. In the pathogenesis and natural history of both conditions, there emerges the centrality of the immune response, orchestrating the timed appearance, functional and dysfunctional roles of multiple effectors in acute and chronic phases. A significant number (more than 600) of observational and interventional studies have explored the interconnections between COVID-19 and cancer, focusing on aspects as diverse as psychological implications and prognostic factors, with more than 4000 manuscripts published so far. In this review, we reported and discussed the dynamic behavior of the main cytokines and immune system signaling pathways involved in acute vs. early, and chronic vs. advanced stages of SARS-CoV-2 infection and cancer. We highlighted the biological similarities and active connections within these dynamic disease scenarios, exploring and speculating on possible therapeutic crossroads from one setting to the other.

Efficacy of CAR-T immunotherapy in MET overexpressing tumors not eligible for anti-MET targeted therapy.

BACKGROUND: Aberrant activation of the MET receptor in cancer is sustained by genetic alterations or, more frequently, by transcriptional upregulations. A fraction of MET-amplified or mutated tumors are sensible to MET targeting agents, but their responsiveness is typically short-lasting, as secondary resistance eventually occurs. Since in the absence of genetic alterations MET is usually not a tumor driver, MET overexpressing tumors are not/poorly responsive to MET targeted therapies. Consequently, the vast majority of tumors exhibiting MET activation still represent an unmet medical need. METHODS: Here we propose an immunotherapy strategy based on T lymphocytes expressing a Chimeric Antigen Receptor (CAR) targeting MET overexpressing tumors of different histotypes. We engineered two different MET-CAR constructs and tested MET-CAR-T cell cytotoxic activity against different MET overexpressing models, including tumor cell lines, primary cancer cells, organoids, and xenografts in immune-deficient mice. RESULTS: We proved that MET-CAR-T exerted a specific cytotoxic activity against MET expressing cells. Cell killing was proportional to the level of MET expressed on the cell surface. While CAR-T cytotoxicity was minimal versus cells carrying MET at physiological levels, essentially sparing normal cells, the activity versus MET overexpressing tumors was robust, significantly controlling tumor cell growth in vitro and in vivo. Notably, MET-CAR-T cells were also able to brake acquired resistance to MET targeting agents in MET amplified cancer cells carrying secondary mutations in downstream signal transducers. CONCLUSIONS: We set and validated at the pre-clinical level a MET-CAR immunotherapy strategy potentially beneficial for cancers not eligible for MET targeted therapy with inhibitory molecules, including those exhibiting primary or secondary resistance.

Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST.

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting.

Clinical and socio-economic correlates of quality of life and treatment satisfaction in patients with type 2 diabetes.

BACKGROUND AND AIM: The aim of the present study was to assess health-related quality of life (HRQOL) and treatment satisfaction in a large, ambulatory based sample of patients with type 2 diabetes. In particular, we evaluated a large array of socio-economic, clinical, and management-related factors, to investigate the extent to which they correlate with physical and psychological well-being, and with treatment satisfaction. METHODS AND RESULTS: Patients were requested to fill in a questionnaire including the SF-36 Health Survey (SF-36), the WHO-Well Being Questionnaire (WBQ), and the WHO-Diabetes Treatment Satisfaction Questionnaire (DTSQ). The analyses were based on multivariate analyses, adjusted for patient clinical and socio-demographic characteristics. The study involved 2499 patients, enrolled in 203 diabetes outpatient clinics. Female gender and diabetes complications were associated with worse physical and psychological well-being, while socioeconomic variables were mainly related to general well-being. The perceived frequency of hyperglycemic episodes was negatively associated with all the dimensions explored. Treatment satisfaction was inversely related to female gender, insulin treatment, perceived frequency of hyperglycemic episodes and diabetes complications. Blood glucose self-monitoring, and among patients treated with insulin, self-management of insulin doses and the use of pen for insulin injections, were associated with higher levels of satisfaction. Finally, higher levels of satisfaction were associated with a better perception of physical and psychological well-being. CONCLUSIONS: Health related quality of life and treatment satisfaction are associated with each other and are both affected by a complex interplay between clinical and socio-economic variables. Some negative aspects, mainly associated with insulin treatment and poor perceived metabolic control, can be attenuated by a deeper involvement of the patients in the management of the disease.