Immunology, Transplantation and Infectious diseases

AIRC 5x1000 | Advanced Therapies for Liver Metastases

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Principal Investigator

Chiara Bonini

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Program manager

Giulia Di Lullo

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Colorectal and pancreatic ductal adenocarcinomas are the second and fourth most common cause of cancer death, respectively.AIRC5x1000Patients affected by these cancers often die of liver metastases, which represent the major unmet clinical need for these malignancies.

Based on preliminary data and published observations, we believe that innovative cancer immune gene and cell therapy approaches might overcome the tolerogenic liver microenvironment and represent powerful therapeutic tools for colorectal and pancreatic ductal adenocarcinomas derived liver metastases.

AIRC_GANTT

Download the complete GANTT of the program.

Mission

The ultimate mission of this AIRC translational project is to develop, validate and implement clinical testing of new advanced therapy medicinal products (ATMP), based on immune gene and cell therapies, for liver metastases that arise from colorectal and pancreatic ductal adenocarcinomas.

Resources & expertise

The project will gather together 14 basic research units (see below) – working on topics ranging from tumor immunology to gene therapy, from genomics to advanced imaging – and 5 clinical units of IRCCS Ospedale San Raffaele:

It will exploit shared state-of-the-art omics, including at single-cell level, advanced imaging, flow cytometry, and histological platforms, and will take advantage of the roadmaps previously established at San Raffaele for the development of gene and cell therapies in other indications.

Experimental Design

The proposal spans 7 years and is built on 4 highly integrated programs:

  • Program 1 (coordinators: Paolo Dellabona; Luca Aldrighetti) aims at unraveling - using biological samples collected through an observational clinical study (LiMeT) - the immune infiltrate and cancer cell profiles in liver metastasis from colorectal and pancreatic ductal adenocarcinomas, to identify tumor associated antigens 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 metastasis by rational and targeted modification of the immune effectors within the tumor microenvironment, through state-of-the-art cell therapies and gene transfer/editing tools.
  • Program 2 (coordinators: Chiara Bonini; Massimo Falconi) aims at harnessing T cells with genetic tools that allow their retargeting against cancer cells, while ensuring resistance to the immunosuppressive tumor microenvironment.
  • Program 3 (coordinators: Luigi Naldini; Michele Reni) will modify the immunosuppressive microenvironment 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.

The most promising ATMPs generated by the 3 Programs will be selected for further development in a successive phase (Program 4): they will be stringently assessed for efficacy and toxicity in preclinical models and the best performing products will be prioritized for early phase clinical trials launched towards the end of the funding period.