Expected outcomes. A rapid and direct identification of PMN-MDSC (with the consequent distinction from other myeloid cells) may improve the diagnosis and therapeutic procedures of the studied pathologies. Until now it has not been possible but the identification of CD111 as a specific marker of PMN-MDSC can lead to extraordinary improvements in the diagnostic and clinical field. We expect to directly identify and isolate PMN-MDSC on the basis of CD111 marker expression. The analysis of CD111+PMN- MDSC may allow the identification of "biosignatures" possibly associated with the prospective risk of disease (e.g. tumor relapses), response to therapy, and clinical outcome. This collaborative project, thanks to the complementary expertise of NEC-WORK Consortium (Units 1,2,3,4) will allow to validate the dynamic changes of PMN-MDSC by integrating data of IHC, molecular biology, and flow cytometry. We also expect to characterize the molecular mechanisms involved in the interaction between these cells and immune cells. Given their relevance we will investigate the signaling pathways regulating PMN-MDSC proliferation, maturation, differentiation and, as a consequence, the disease outcome. It is of note that targeting MDSC and/or their function may represent a more general and highly promising tool to implement the therapeutic efficacy and the clinical outcome of patients. A particular relevance of this proposal is the establishment of an active interface between basic research, preclinical studies, and clinical translation. We expect that the present study will generate important know-how leading to significant improvements in Immunotherapy-based approaches to tumors and inflammatory diseases. In addition, our studies may lead to the development and validation of new patents with relevant clinical applicability.
Expected outcomes. About 60% of r/r DLBCL patients fail to respond or relapse after CD19-directed CAR-T cells mainly because of low T cell fitness or CD19 antigen loss. Similarly in MM, reduction of BCMA expression or complete antigen loss have been reported under BCMA-directed CAR T-cell therapy, as a mechanism of resistance. Moreover, PDL1 expression by tumor and/or microenvironmental cells have shown to inhibit CAR-T cell function. Thus, there is an urgent need for novel CAR targeting strategies in r/r DLCBL and MM. With this project, we expect to overcome the above limitations by pre-clinically developing innovative CD79b-directed CAR- T cells coexpressing an anti-PDL1 CCR and by proofing the manufacture of such a novel dual targeting cell product. The latter is expected to have, based on the pre-clinical data generated within this project, a strong clinical potential for improving CAR-mediated antitumor response in r/r DLBCL and MM by: i) targeting a different antigen (CD79b instead of CD19 or BCMA); ii) reducing CAR-T cell exhaustion through blockade of the PDL1/PD1 axis between PDL1+ tumor and/or microenvironmental cells and PD1+ CAR-T cells; and iii) increasing CAR-T cells proliferation and persistence towards stimulation through the anti-PDL1 costimulatory receptor. A key expected outcome of the current project is to finally proof the translability of our preclinically generated CAR T cells to a simulated clinical setting, thereby building a solid basis for a subsequent phase-I clinical trial conducted in patients with r/r CD79+ B-NHL and MM with autologous T cells, engineered to co-express the anti-CD79 CAR and the anti-PDL1 CCR to improve clinical efficacy with a single administration of the cellular drug product. In summary, the proof-of-concept output of this project has a high potential to attract the interest of a variety of partners (academic, pharmas or biotechs) for the further clinical and commercial development of these novel CAR T cell products.
Expected outcomes. Aim1 TLS observation in immunohistology after neoadjuvant (pre-surgical) therapy, correlation between TLS presence and maturity and innate lymphocytes in human cancers.
1 Observation of fewer and lesser mature TLS in absence of innate lymphocytes (at least in the absence of one specific subset).
2 Obtaining a list of molecules with potential role in TLS formation in presence of a higher concentration one or more human innate lymphocyte subset. Identification of the effects of the molecules identified in Aims 1 and 2 on:
1. TSL and tumor microenvironment composition in vivo
2. ILC3s, NK cells and g/d T cells lymphoid tissue-inducing properties ex vivo
3. The direct NK and g/d T cells contribution to improved responsiveness to ICI treatment in vivo
Expected outcomes. Aim1: TO CREATE A NETWORK OF CENTERS WITH EXPERTISE IN RCVD throughout ITALY. Through the ALIGNED project, we would like to make the effort to strengthen cooperation not only in research, but also at health care level to improve the diagnostic and therapeutic pathways. The project will promote the creation of a network, connecting experts and researchers from nationally dispersed hospitals, promptly ensuring the highest available quality of care also to rural areas. It is expected to decrease patients' travels to secondary or tertiary centers, then reducing their difficulties and expenditures but also the waiting lists and costs for the National Health System. Through the ALIGNED project, peripheral hospitals would easily interact with the most experienced Italian centers. This will represent an advantage not only for healthcare professionals but, above all, for patients, who will no longer have the need to physically move to third-level healthcare facilities to obtain a diagnosis.
Expected outcomes. Based on our research, we anticipate observing alterations in HERV-K expression in the biological samples of a specific subgroup of patients diagnosed with ALS and other neurological disorders. Through our investigations, we aim to identify the molecular targets that are influenced by the dysregulation of HERV-K. Furthermore, we will assess the impact of inhibiting HERV-K using ASO or other molecules on the phenotypes associated with ALS in various models. Successful validation of our proof-of-concept findings would provide compelling evidence supporting the role of HERV-K as a potential biomarker and therapeutic target for the treatment of ALS patients. By demonstrating the modulatory potential of HERV-K, we aim to contribute to the development of novel therapeutic strategies for ALS.
Expected outcomes. Establish human liver slice cultures as preclinical platform to explore pathological fibrosis processes and screen for new biomarkers and/or therapeutic approaches - Identify novel putative liver fibrosis gene signatures and biomarkers - Identify HIPK2 functions in liver fibrosis - Validate HIPK2 as perspective target for prevention/treatment of liver fibrosis
Expected outcomes. Hydrocephalus is a chronic disease that represents a social problem with a relevant health burden. To date, its incidence is underestimated, and a significant increase in frequency is estimated in the next 10 years due to the general aging of the population. The importance of a multidisciplinary team in its diagnosis, treatment and follow-up therefore becomes mandatory for the correct management of this pathology.
Expected outcomes. Improved mental and physical well-being in the targeted group of people treated with SGA. - Development of a biobank of biological materials related to the study of MetS in people treated with SGA. - Creation of a strong evidence base for programmes aimed at improving the physical health of people treated with SGA. - Development of preventative strategies which may have a real effect of reducing comorbidities associated with SGA utilization.
Expected outcomes. In general terms, the ENIGMA project may have the potential to transform the delivery of care, contributing to the overall improvement and re-organization of some pathways of relevance for the healthcare systems, with positive impacts on the patients¿ acceptance and adherence, improving the access to care and the equitable distribution of healthcare resources. As such, the project could improve the overall patients¿ pathway: the generation of several data and insights into the management, treatment, and outcomes could be used to refine and/or develop more personalized treatment approaches or to adapt the pathways. The main project¿s expected outcome is related to the generation of evidence that may inform clinical decision maker concerning the best process pathway able to maximize the patients¿ outcomes. Taking that way, results will impact not only on improving health outcomes but also on overcoming the obstacles of the maldistribution of professional resources and cost. As such, the main impacts could be classified as follows: i) improved efficacy and safety; ii) enhanced patient engagement and adherence; iii) personalized care; iv) increased efficiency and cost-savings; v) improved accessibility.
Expected outcomes. Optimization of organ donation and transplantation process targeted by this network of studies will ensure that all potential organ donors are early identified, therefore increasing donor pool. Targeting Sicily region PDTA for well-defined ventilatory strategy will preserve organ function in the patient with acute neurologic injury admitted to ICU, while preserving neuroprotection. Cerebral ultrasound monitoring and neuroimaging studies will allow timely diagnosis of BD when it will occur. We expect that inflammatory profiling of harvested organs undergoing reconditioning will add in a better definition of organ suitability for transplant, increasing number of organs transplanted and increasing safety of recipient.