Advanced Therapies for Liver Metastases

NCT04622423 | Recruiting

• 2 other identifiers: LiMeT22737
• Study Type: observational
• Target: 475
• Locations: 1 country
• Sites: 1

Brief Summary

Liver metastases (MTS) are the main cause of death for patients affected by colorectal carcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC), thus representing the major unmet clinical need for these malignancies. Based on preliminary and published data, the investigators hypothesize that innovative immune, gene and cell therapy approaches might overcome the tolerogenic liver microenvironment and represent powerful therapeutic tools for liver MTS of PDAC and CRC. The investigators have therefore planned an observational clinical study to enroll distinct cohorts of patients (i.e., metastatic CRC, metastatic and non-metastatic PDAC) and finely characterize, through integrated state-of-the-art -omics, the immune and non-immune microenvironment of their primary tumor and/or liver metastases as well as correlate changes in the activation status and phenotype of peripheral blood leukocytes. Healthy volunteers will be enrolled as negative controls. The investigators aim at identifying: i) actionable tumor associated antigens (TAAs) and local immune suppressive and regulatory pathways; ii) biological parameters for early diagnosis of relapse; iii) the effect of therapies on the shaping of anti-tumor immune responses. Data collected will be instrumental for the generation of novel advanced therapy medicinal products (ATMPs). Indeed, this protocol is part of a multi-partner translational program, supported by the AIRC 5 per Mille 2019 grant, focused on the development, validation and implementation for clinical testing of ATMPs to ameliorate the cure of CRC and PDAC and possibly help the study of other solid tumors. Moreover, the systematic and long-term follow-up of enrolled patients will possibly point at early predictors of differential prognosis and patients' categories eligible for tailored therapies, including those with the novel ATMPs.

Conditions

Pancreatic Ductal Adenocarcinoma (PDAC); Colorectal Cancer (CRC); Liver Metastasis

Keywords

Pancreatic ductal adenocarcinoma; Colorectal cancer; PDAC; CRC; Liver metastases; Tumor microenvironment; Immunosuppression; Immune therapy; Cell therapy; Gene therapy; Tumor infiltrating lymphocytes; ATMP

Outcome Measures

Primary Outcomes (4)

• Definition of tumor mutational burden, epigenetic and gene expression profile of the CRC and PDAC metastatic liver at bulk and at single cell level

  CRC/PDAC MTS samples will be analyzed by: * Whole exome DNA sequencing * RNA sequencing * ATAC sequencing * Single cell RNA sequencing on sorted myelomonocytic and T cells infiltrating CRC/PDAC MTS samples. Naive vs chemotherapy treated lesions as well as primary vs MTS lesions will be compared to evaluate chemotherapy-induced modifications and the molecular evolution in the distinct tumor sites, respectively.

  After liver metastasis/primary tumor resection/biopsy, usually within 12 months

• Characterization of the immune landscapes of CRC and, if possible, PDAC liver MTS by high dimensional flow cytometry

  Single cell suspension of CRC and PDAC MTS and paired autologous PBMCs and portal blood harvested before and after pre-operatory chemotherapy, will be analyzed by a series of parallel polychromatic high dimensional 28 color flow cytometry panels to study: * Conventional MHC-restricted Tab cells, the main anti-tumor effectors; * Innate-like T cells; * B cells; * Myelomonocytic populations involved in the stimulation or suppression of anti-tumor responses. Whenever available, matched primary vs MTS lesions will be compared to evaluate the immune landscapes in the distinct tumor sites.

  For tissue specimens: immediately after tumor tissue resection/biopsy (analyses on fresh samples); for blood specimens: after blood drawing, usually within 12 months (analyses on fresh and/or thawed samples)

• Histological validation of the molecular results obtained in 1. and 2.

  Validation of relevant markers and molecular pathways in terms of anatomical distribution, performed by polychromatic immunofluorence (IF, up to 6 colors) and immunohistochemistry (IHC, up to 4 colors) stainings on MTS CRC and PDAC biopsies, perilesional parenchyma and, whenever available, matched primary tumor samples. In addition to multiplex IF and IHC, some specimens will be characterized more deeply with advanced spatial proteomics technologies, such as GeoMx Digital Spatial Profiler (Nanostring).

  After liver metastasis/primary tumor resection/biopsy, usually within 12 months

• Definition of the antigenic landscape and TCR repertoire of CRC and PDAC liver MTS

  Identification of tumor-reactive TCRs will be pursued through different and complementary strategies: * The most relevant inhibitory checkpoint genes/pathways expressed by MTS-TILs will be used to enrich for tumor specificities by cell sorting harvested from CRC/PDAC MTS tumors, portal, hepatic and peripheral blood sample. After their activation, responding T cell cultures will be subject to bulk and single-cell TCR seq; * In samples characterized by a low percentage of MTS-TILs, single cell immune profiling will be performed in order to simultaneously determine gene expression and correctly pair chain TCR sequences from individual T cells; * The library of tumor-specific TCRs identified will be transiently expressed in reporter Jurkat cells to confirm their tumor antigen specificity; * Identification and functional validation of transmembrane molecules enriched in cancer cells as possible targets for CAR design.

  After liver metastasis/primary tumor resection/biopsy, usually within 12 months

Secondary Outcomes (4)

• Evaluation of the molecular and cellular composition of CRC and, if possible, PDAC liver MTS by spatial transcriptomics technologies (NICHE-seq and Visium)

  After liver metastasis/primary tumor resection/biopsy, usually within 12 months

• Collection of clinical follow-up data

  CRC patients: throughout the postoperative follow-up, for a maximum of 36 months; PDAC patients: throughout the postoperative follow-up, for a maximum of 24 months

• Collection and biobanking of follow-up samples from patients with CRC and metachronous PDAC MTS to the liver

  CRC: during the postoperative follow-up (up to 36 months), at six-month intervals; PDAC: during the postoperative follow-up (up to 24-months), at time of liver recurrence

• Biobanking of biospecimens collected from CRC and PDAC patients and from healthy donors

  Throughout the protocol (7 years)

Study Arms (4)

PDAC liver-MTS

Adult patients with clinical /radiological diagnosis/suspicious of PDAC metastatic to the liver, with subsequent cytological/histological confirmation (stage IV disease, AJCC) from liver resection/metastasectomy or core liver biopsy.

CRC liver-MTS

Adult patients with histologically or cytologically confirmed diagnosis of CRC metastatic to the liver with indication to surgical resection (upfront or after neoadjuvant therapy).

Primary non-MTS PDAC

Adult patients with clinical/radiological diagnosis of primary non-metastatic PDAC, candidates for surgical resection with radical intent of the primary tumor (upfront surgery or after neoadjuvant therapy). These patients will be monitored for early diagnosis of metachronous hepatic PDAC MTS by follow up testing.

Healthy volunteers

Negative control for the clinical study.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

CRC and PDAC patients with hepatic MTS, primary non-metastatic PDAC patients and healthy volunteers. Eligible patients, chosen among those who receive health care assistance/treatment for their disease at IRCCS San Raffaele, will be asked to signing of the predisposed informed consent form in case they decide to participate in this study.

You may not qualify if:

• Patients with histologically or cytologically confirmed diagnosis of CRC metastatic to the liver (stage IV disease, AJCC)
• Patients with indication to surgical resection and/or chemotherapy treatment
• Age ≥18
• ECOG PS 0-1 at enrollment
• Written informed consent
• Patients will be treated in IRCCS San Raffaele
• Pregnancy or lactation
• Inability to provide a written informed consent
• Severe comorbidities (e.g. cardiac diseases, history of psychiatric disabilities, HIV, autoimmune disorders)
• Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy
• Other conditions (medical or psychiatric) that in the judgment of Investigators would make the patient an inappropriate candidate for the study
• Patients with clinical/radiological diagnosis/suspicious of pancreatic adenocarcinoma metastatic to the liver, with subsequent cytological/histological confirmation (stage IV disease, AJCC)
• Age ≥18
• Karnofsky performance status ≥50
• Metastatic pancreatic adenocarcinoma patients with histological specimens from whole liver metastasis biopsy or core liver biopsy collected at IRCCS San Raffaele and stored in the institutional biobank Centro Risorse Biologiche (CRB-OSR)

Sponsors & Collaborators

• IRCCS San Raffaele: lead
• Università Vita-Salute San Raffaele: collaborator

Study Sites (1)

IRCCS San Raffaele

Milan, 26431, Italy

RECRUITING

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Biospecimen

Retention: SAMPLES WITH DNA

1. Peripheral venous blood (from patients and healthy volunteers): additional volume collected during the diagnostic or perioperative routine/as a part of hematochemical follow-up tests/during blood donation drawings. 2. Tissue specimens from liver MTS (from metastatic CRC and PDAC patients): extra material collected during fine-needle ago-biopsies or in therapeutic/palliative surgical resections. 3. Tissue specimens from primary tumors (from non-metastatic PDAC patients and synchronous CRC MTS patients): extra material resected in therapeutic surgical resections. 4. Portal blood (from non-metastatic PDAC patients): directly collected from venous vessels which will be subsequently cut and removed during standard surgical procedure, but that drain directly into the portal vein.

MeSH Terms

Conditions

Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Chiara Bonini, MD

  Vita-Salute San Raffaele University, IRCCS San Raffaele

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chiara Bonini, MD

CONTACT

0226434790; bonini.chiara@hsr.it

Giulia Di Lullo, PhD

CONTACT

0226433823; dilullo.giulia@hsr.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 4, 2020
• First Posted: November 10, 2020
• Study Start: November 6, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: October 1, 2024

Record last verified: 2024-09

Locations

IT (1)