Project Funding Details

Colorectal (CRC) and pancreatic ductal (PDAC) adenocarcinomas are the second and fourth most common cause of cancer death, respectively. Patients affected by these cancers die of liver metastases (MTS), which therefore represent the major unmet clinical need for these malignancies. Based on preliminary data and published observations from our and other groups, we hypothesize that innovative cancer immune gene and cell therapy approaches might overcome the tolerogenic liver microenvironment and represent powerful therapeutic tools for CRC- and PDAC-derived liver MTS. The overall mission of this translational proposal is to develop new advanced therapy medicinal products (ATMP) based on immune gene and cell therapies for liver MTS that arise from PDAC and CRC. The proposal is built on 4 highly integrated programs, conceived in hypothesis generating and hypothesis testing activities. Program 1 aims at unraveling, at high resolution, the immune infiltrate and cancer cell profiles in liver MTS from CRC and PDAC, to identify tumor associated antigens (TAAs) and immune suppressive and regulatory pathways to be targeted in these two diseases. Results of this discovery program will progressively shape two independents but potentially combinatorial translational Programs, tackling hepatic MTS by rational and targeted modification of the immune effectors within the tumor microenvironment (TME), through state-of-the-art cell therapies and gene transfer/editing tools. Program 2 aims at harnessing T cells with genetic tools that allow their retargeting against cancer cells, while ensuring resistance to the immunosuppressive TME. Program 3 will modify the immunosuppressive TME through novel targeted in vivo gene therapies, aimed at enhancing spontaneous innate and adaptive immunity against the tumor, as well as the efficacy of exogenous T cell responses. Each candidate ATMP will be stringently assessed for efficacy and toxicity in suitable experimental models and the best performing one prioritized for further preclinical development according to the activities outlined in Program 4 and translated into early-phase clinical trials to be launched towards the end of the funding period. Overall, the project will exploit: a) dedicated samples harvested from patients with liver MTS from CRC and PDAC; b) shared state-of-the-art omics, including at single-cell level, flow cytometry and histological platforms for multidimensional profiling of the human and mouse hepatic TME; c) relevant immune-competent and deficient mouse models, and will take advantage of the roadmaps previously established at SRSI for the development of gene/cell therapies in other indications (ie genetic diseases, hematological malignancies). These include safety/toxicity and biodistribution studies in small and large animal models, scale-up of manufacturing of viral vectors and cell products according to GMP-ready protocols, consultation for advice on pre-clinical studies and clinical protocol design with the European Medicines Agency (EMA), and - eventually - filing an application to regulatory bodies for the first-in-human testing of the selected ATMP. With this project we expect to develop, validate and implement clinical testing of innovative immunotherapeutic ATMPs for liver MTS of PDAC and CRC. The expected results will have a relevant impact not only for CRC and PDAC but also represent platforms for broader application of immunotherapy to other solid tumors.