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.

The program gathers together 14 basic research units  – 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 exploits shared state-of-the-art omics, including at single-cell level, advanced imaging, flow cytometry, and histological platforms, and takes advantage of the roadmaps previously established at San Raffaele for the development of gene and cell therapies in other indications.

AIRC_GANTT

Download the complete GANTT of the program.
A lay (and up-to-date) description of the program, in Italian, can be found here.

Mission

The ultimate mission of this AIRC translational program 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.

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.

Achievements

By matched and multi-level analyses on patients’ biological samples, Program 1 has:

  1. identified different immunoregulatory receptors and molecules involved in the immune suppression and exhaustion distinctive of hepatic metastases (first milestone achieved);
  2. selected several tumor antigens eligible for CAR development and/or TCR redirection (second milestone achieved).

By an optimized pipeline for T cell gene editing (patent application submitted), Program 2 has established the genetic deletion of those immunoregulatory receptors identified by Program 1. Moreover, new CAR- and TCR-T cell products have been generated and are now under functional and safety validation, either administered alone or in combination with novel agents able to enhance adoptive T cell therapy.

Program 3 has designed and produced different peptide-based formulations for tumor/stroma targeting and a tunable lentivirus-based platform for liver-targeted cytokine delivery (patent application submitted), by which a candidate antitumoral cytokine has been selectively expressed in liver metastases of tumor-bearing mice, exerting promising therapeutic effects in the absence of systemic toxicity.

The institutional biobank (Center of Biological Resources, CRB) assures the availability of several biological specimens from patients enrolled in LiMeT clinical study (over 400 patients since its authorization in November 2019), including follow-up samples, that allow cross-sectional and longitudinal analyses planned by Program 1.

Patients’ clinical data are collected at enrollment and during follow-up visits and archived in a GDPR-compliant intramural database (Cohort Genomics Platform, CGP), providing clinical correlates of experimental results from Program 1.

Different ex-vivo and in vivo models have been developed and shared by the AIRC5x1000 consortium, to recapitulate and intervene on hepatic metastases of colorectal and pancreatic ductal adenocarcinomas. They will be instrumental for efficacy and toxicity studies planned by Program 2 and 3.

In March 2022 the Program has passed the 3rd-year midterm review by a panel of 9 international experts in translational oncology, clinical immunology and genetics, who confirmed the viability of the projects and endorsed the merit of clinical and research teams. The next midterm review will be in the 5th year.

Last updated: 27.05.2022