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. 
    The results of this discovery program will progressively shape two independent but potentially combinatorial translational programs (Program 2 and 3), 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 and the efficacy of exogenous T cell responses. Program 2- and 3-generated ATMPs will be tested as single therapies as well as in combination, to exploit synergistic effects.
  • Data and therapeutic candidates generated in the first 4 years by the three concurring programs (1-3) will pave the way for the successive phase, in which Program 4, through the integrated work of all the participating units and the support of intramural facilities, will stringently assess the most promising ATMPs for efficacy and toxicity, select the best-performing products for further development and prioritize the top lead(s) for early phase clinical trials launched towards the end of the funding period.

Achievements

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

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

The institutional biobank (Center of Biological Resources, CRB) collects several biological specimens from patients enrolled in LiMeT clinical study (almost 1000 patients since its authorization in November 2019), including follow-up samples, allowing cross-sectional and longitudinal analyses planned by Program 1.

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

By an optimized pipeline for T cell gene editing, 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, tested for specific antitumor activity, and are now under safety validation. Three best-performing T cell products have been selected for further development towards clinical use (third milestone achieved).

Program 3 has designed and produced different peptide-based formulations for tumor/stroma targeting and a tunable lentivirus(LV)-based platform for liver-targeted cytokine delivery, 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. One peptide-based and one LV-based approach have been selected for clinical translation (fourth milestone achieved). In particular, one of them will be further developed in combination with one T cell product selected by Program 2 to widen and synergize their clinical applications (fifth milestone achieved).

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

The Program passed the 3rd- and 5th-year midterm reviews, in March 2022 and 2024, respectively, obtaining enthusiastic consensus endorsement by a panel of 9 international experts in translational oncology, clinical immunology and genetics.

Program 4 is in full swing, with the five selected ATMPs (the “TOP 5”) progressing through biodistribution and toxicity studies, while protocols for GMP-compliant manufacturing, scaled-up production and quality control testing are being set-up with the support of intramural facilities and external collaborations.

Last updated: 29.11.2024