Clinical trial NCT04622423: Advanced Therapies for Liver Metastases
Official title: Advanced Immune Gene and Cell Therapies for Liver Metastases
Study type: OBSERVATIONAL
Overall status: RECRUITING
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
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
Collaborators: name: Università Vita-Salute San Raffaele
First posted: 2020-11-10
Enrollment: 475
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: Background and rationale - CRC and PDAC are the second and fourth most common cause of cancer death, respectively. Patients affected by these cancers die of liver MTS. Conventional therapies are active in either primary tumors but fail in metastatic disease. The effectiveness of immunotherapy by immune checkpoint blockade and adoptive cell therapy with tumor-specific T cells is only partial or temporary in MTS from solid tumors, because of local immunosuppressive mechanisms. This is particularly relevant for hepatic MTS, in which a natural tolerogenic milieu may further sustain immunosuppression induced by cancer cells and infiltrating immune cells, such as tumor associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), neutrophils, and regulatory T or B cells.

In this regard, evidence suggests that progression of primary or metastatic CRC correlates with poor immune infiltration and inflammation. Moreover, our published results in primary PDAC support a correlation between tumor progression and a strong type 2 anti-inflammatory/immunosuppressive signature. Efficacy of chemotherapy is known to rely also on reactivation and/or repolarization of tumor targeting immune responses. Pre-surgical chemotherapy may induce beneficial effects and potentially targetable changes in the immune profile of CRC or PDAC MTS.

The investigators hypothesize that a combination of: i) direct cancer cell killing by adoptively transferred tumor-specific T cells and ii) indirect control of tumor progression via reprogramming of the tumor microenvironment would control hepatic MTS of CRC and PDAC.

Thus the investigators propose a thorough characterization of the metastatic milieu in these two cancer types to rationally shape, on the basis of similarities and differences, innovative ATMPs.

Experimental results obtained from biological samples will be correlated: i) with clinical data from patients at the time of enrollment and along their follow-up; and ii) for a subgroup of patients, with biochemical and immunological data from peripheral blood samples routinely collected as a part of their clinical follow-up, with the additional aim to identify novel biologic parameters and/or signatures to help the stratification of patients and the tailoring of treatments.

Objectives - The investigators want to study:

1. the tumor mutational burden and the composition of the metastatic tumor microenvironment in the liver;
2. the inhibitory pathways that constrain immunity in liver MTS;
3. the antigenic and clonal breadth of anti-tumor T cell responses;
4. the spatial-temporal variations of effector and regulatory immune cells upon therapy;
5. the characteristics of tumor cells and their microenvironment in liver MTS versus (vs) primary tumor;
6. the longitudinal variations of clinical parameters as well as blood-derived biological and immunological markers during the medical follow-up of patients.
7. Moreover, they want to collect and biobank patients'samples to support the validation and selection of the newl ATMPs developed by the other partners of the translational program.

The primary objectives will be:

1. to identify immune suppressive/exhaustion pathways
2. to develop a library of tumor-specific TCR (N≥5/tumor type) and identify new CAR targets (N≥1/tumor type) in CRC and PDAC MTS

Study design - This clinical protocol aims at deeply characterizing MTS tumor cells and their microenvironment, including possibly informative dynamic modifications from pro-tumor to anti-tumor profiles that may follow chemotherapy, which is administered pre-surgery (neo-adjuvant) to a substantial fraction of patients. PDAC and CRC MTS patients will be therefore characterized by either cross-sectional or longitudinal investigations on chemotherapy-naïve vs -treated patients.

In addition, the investigators aim at comparing hepatic MTS with primary tumor, in order to highlight dynamic qualitative modifications in cancer cells, immune infiltrates and not-immune microenvironment that could facilitate disease progression toward metastatic spread. These modifications may offer a window of opportunity for the optimal application of our ATMPs. To this purpose, primary non-metastatic PDAC patients undergoing surgical resection will be enrolled in this study and followed-up for monitoring the development of metachronous liver MTS, that, whenever possible, will be characterized and compared to their matched/not matched, previously collected, primary tumor samples. Peripheral blood samples at the time of liver MTS diagnosis will be also collected and analyzed. Also, in those CRC MTS patients undergoing synchronous resection of primary CRC and hepatic MTS, comparative analyses will be carried out on tumor from both sites, allowing intra- and inter-patient profiling of both tumor niches.

Moreover, results from multi-level research analyses will be correlated with clinical data collected from all patients at the time of enrollment in the study and during their clinical follow-up, whenever possible for up to 2 years, considering PDAC patients, and 3 years, considering CRC.

In particular, for metastatic CRC patients, the clinical follow-up will be associated with concurrent collection of blood samples at serial timepoints, that will be prospectively biobanked for further analyses aimed at: i) studying biological and immunological correlates of the patient's clinical status; ii) evaluating key discriminants previously identified in blood samples analyzed at the time of liver MTS surgery, to serve as early predictors of liver progression or recurrence and possibly as indicators for therapeutic stratification.

The investigators expect to collect tissue/blood samples and clinical data from at least:

* 200 metastatic CRC patients (either synchronous or metachronous);
* 150 non-metastatic PDAC patients;
* 75 synchronous PDAC MTS patients and about 20 metachronous PDAC MTS patients, the latter originally enrolled as primary non-metastatic patients for the longitudinal study, for a total of 95 metastatic PDAC patients;
* 30 healthy volunteers, as negative controls.

Different biological samples (peripheral blood, primary and/or metastatic tumor tissue, portal blood) will be collected, in the course of the standard diagnostic and therapeutic care of those patients, and will be in part directly analyzed and in part biobanked for further studies. In parallel, clinical data will be collected from patients at the time of enrollment in the study and, whenever possible, for a follow-up period of up to 2 years, for PDAC patients, and 3 years, for CRC patients.

The statistical analysis of collected data will be performed throughout the clinical study, starting 6 months after the enrollment of the first patient until 6 months after the end of patients' follow-up, for a total of 7 years. The study will last 7 years.

Different biological samples (peripheral blood, primary and/or metastatic tumor tissue, portal blood) will be collected, in the course of the standard diagnostic and therapeutic care of those patients, and will be in part directly analyzed and in part biobanked for further studies. In parallel, clinical data will be collected from patients since the time of enrollment in the study for a follow-up period of 2 years, for PDAC patients, and of 3 years, for CRC patients.

The statistical analysis of the collected clinical and experimental data will be carried out all along the duration of the clinical study, starting 6 months after the enrollment of the first patient until the end of patients' follow-up, for a total of 7 years. The study will last 7 years.

The research activities will be organized and integrated in 6 work packages (WPs):

1. Collection and biobanking of the material from patients with CRC and PDAC MTS to the liver and with primary non-metastatic resectable PDAC.
2. Definition of the tumor mutational burden, epigenetic and gene expression profile of the CRC and PDAC metastatic liver at bulk and at single cell level.
3. Evaluation of the molecular and cellular composition of CRC and, if possible, PDAC liver MTS by spatial transcriptomics technologies (NICHE-seq and Visium).
4. Characterization of the immune landscapes of CRC and, if possible, PDAC liver MTS by high dimensional flow cytometry.
5. Validation of the molecular results obtained in 2) and 4).
6. Definition of the antigenic landscape and TCR repertoire of CRC and PDAC liver MTS.

The results obtained by the above mentioned WPs will be crossed with clinical follow-up data and serve to calibrate the program activities focused on novel ATMPs development.

Eligibility criteria: Inclusion and exclusion criteria - CRC patients

Inclusion criteria:

1. Patients with histologically or cytologically confirmed diagnosis of CRC metastatic to the liver (stage IV disease, AJCC)
2. Patients with indication to surgical resection and/or chemotherapy treatment
3. Age ≥18
4. ECOG PS 0-1 at enrollment
5. Written informed consent
6. Patients will be treated in IRCCS San Raffaele

Exclusion criteria:

1. Pregnancy or lactation
2. Inability to provide a written informed consent
3. Extraepatic disease with the exception of selected cases in which the coexistence of extrahepatic disease does not constitute an exclusion criterion for hepatic resective surgery (for example in patients with extraepatic lesions in remission or in any case stabilized by chemotherapy)
4. Severe comorbidities (e.g. cardiac diseases, history of psychiatric disabilities, HIV, autoimmune disorders)
5. 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
6. Other conditions (medical or psychiatric) that in the judgment of Investigators would make the patient an inappropriate candidate for the study

Inclusion and exclusion criteria - PDAC patients

Inclusion criteria:

1. Patients with clinical/radiological diagnosis/suspicious of pancreatic adenocarcinoma metastatic to the liver, with subsequent cytological/histological confirmation (stage IV disease, AJCC)
2. Age ≥18
3. Karnofsky performance status ≥50
4. 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)
5. Written Informed consent
6. Patients with clinical/radiological diagnosis of not metastatic primary PDAC that will undergo pancreatic resection at IRCCS San Raffaele

Exclusion criteria:

1. Severe comorbidities (e.g., cardiac diseases, history of psychiatric disabilities) representing an absolute contraindication for whole or core liver metastasis biopsy
2. Pregnancy or lactation
3. Inability to provide a written informed consent
4. Metastatic pancreatic adenocarcinoma patients enrolled in other research trials entailing the analysis of the liver metastasis histological sample

Primary outcomes:
measure: Definition of tumor mutational burden, epigenetic and gene expression profile of the CRC and PDAC metastatic liver at bulk and at single cell level
timeFrame: After liver metastasis/primary tumor resection/biopsy, usually within 12 months
measure: Characterization of the immune landscapes of CRC and, if possible, PDAC liver MTS by high dimensional flow cytometry
timeFrame: 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)
measure: Histological validation of the molecular results obtained in 1. and 2.
timeFrame: After liver metastasis/primary tumor resection/biopsy, usually within 12 months
measure: Definition of the antigenic landscape and TCR repertoire of CRC and PDAC liver MTS
timeFrame: After liver metastasis/primary tumor resection/biopsy, usually within 12 months
Secondary outcomes:
measure: Evaluation of the molecular and cellular composition of CRC and, if possible, PDAC liver MTS by spatial transcriptomics technologies (NICHE-seq and Visium)
timeFrame: After liver metastasis/primary tumor resection/biopsy, usually within 12 months
measure: Collection of clinical follow-up data
timeFrame: 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
measure: Collection and biobanking of follow-up samples from patients with CRC and metachronous PDAC MTS to the liver
timeFrame: 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
measure: Biobanking of biospecimens collected from CRC and PDAC patients and from healthy donors
timeFrame: Throughout the protocol (7 years)
Other outcomes:
Locations:
city: Milan
country: Italy
facility: IRCCS San Raffaele
Study officials:
affiliation: Vita-Salute San Raffaele University, IRCCS San Raffaele
name: Chiara Bonini, MD
role: PRINCIPAL_INVESTIGATOR
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