New Preclinical and Clinical Approaches to Mesothelioma

New Preclinical and Clinical Approaches to Mesothelioma, an Archetypal Inflammatory Tumor

This study protocol involves the coordination between UO1 (IRCCS San Raffaele Hospital) and UO2 (Istituto Nazionale Tumori di Napoli - IRCCS G. Pascale) to explore the role of HMGB1 and CXCR4 in cancer treatment and metastasis. UO1 focuses on the role of HMGB1 in inflammation, mesothelioma progression, and tissue repair, as well as developing, in future, possible HMGB1 inhibitors for cancer therapy. UO2 specializes in CXCR4's role in cancer, developing CXCR4 antagonists, and tracking CXCR4-dependent metastasis. The hypothesis is that targeting HMGB1 and CXCR4 pathways will inhibit tumor progression and metastasis, enhancing anti-tumor immunity and improving therapeutic outcomes in cancer.

Study Overview

• Status: Recruiting
• Conditions: Mesothelioma

Detailed Description

This is a multicentric cross-sectional observational study with an additional blood volume collected during blood sampling performed for normal clinical practice. The enrollment will take

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Massimo Crippa, PhD; Phone Number: 02-26434833; Email: crippa.massimo@hsr.it

Study Locations

• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Recruiting
      • Istituto Nazionale Tumori IRCCS Fondazione G.Pascale
      • Contact: Vincenzo Sforza, MD; Phone Number: 081-17770705; Email: v.sforza@istitutotumori.na.it
      • Principal Investigator: Vincenzo Sforza, MD
  • Lombardia
    • Milan, Lombardia, Italy, 20132
      • Recruiting
      • IRCCS San Raffaele
      • Contact: Bianchi Marco, Professor; Phone Number: 2-26434765; Email: bianchi.marco@hsr.it
      • Sub-Investigator: Giovanna Musco, PhD
      • Sub-Investigator: Alessandro Bandiera, MD
      • Principal Investigator: Marco Bianchi, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

For this study, San Raffaele Hospital and Istituto Nazionale Tumori IRCCS Fondazione G. Pascale will enroll both:

• patients with a clinical suspicion of mesothelioma (cancer patients), and for which surgery is indicated and will be performed as per clinical practice. From the biopsies thus obtained in accordance with normal clinical practice (the biopsies provided to us by the clinic are considered waste material) whose biopsies mesothelioma organoids will be obtained;
• patients with a clinical suspicion or diagnosis different from that of mesothelioma, from whose biopsies (the biopsies provided to us by the clinic are considered waste material) non-tumoral organoids will be obtained to serve as controls for the tumoral ones.

Description

Inclusion Criteria:

• Patients with Mesothelioma:

Clinical suspicion or histologically confirmed diagnosis of pleural mesothelioma.

• Candidates for surgical intervention.
• Age 18 years or older. It is possible to include both male and female patients, male and female patients of reproductive age, as well as breastfeeding women.
• Capacity to comprehend the study nature and provide autonomously informed consent.

Control Group patients:

• Absence of pleural mesothelioma but presence of other histologically confirmed diseases (neoplastic, inflammatory, or infectious).
• Candidates for surgical intervention.
• Age 18 years or older. It is possible to include both male and female patients, male and female patients of reproductive age, as well breastfeeding women.
• Ability to understand the study nature and provide autonomously informed consent.

If the patient's diagnosis, whether provisional or definitive, does not confirm the clinical suspicion, they will not undergo further evaluation in the study.

Exclusion Criteria:

• Lack of biopsy material.
• pregnancy.
• Unwillingness to sign the Informed Consent.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To set up spheroids models to study and serve as a platform	Number of spheroids with infiltrated macrophages. About of 30% of macrophages infiltrated into spheroids.	0/baseline
To set up spheroids models and serve as a platform	Evaluation of macrophages polarization status M1 or M2 based on different genes and proteins expression using qPCR and Flow Cytometry.	0/baseline
To set up organoid models	Number of organoids formation. About of 30% of biopsies generated organoids.	0/baseline
Test inhibitors on spheroids and organoids and assess the response of individual patients to therapy	Rate of growth to test the efficacy of anti-CSF1R, BoxA and DFL using human mesospheres from MPM primary cell lines derived from patients and monocytes from controls.	0/baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate inhibitors of the CXCR4-CXCL12-HMGB1 axis on the crosstalk	Percentage of migrated or invaded MPM cell lines NCI-H2052 (BAP1 WT/NF2 MUT) vs NCI-H28 (BAP1 mut/NF2 WT) with and without macrophages in presence of CDDP-Nivolumab (NIVO)-Peptide R54.	0/baseline
To investigate inhibitors of the CXCR4-CXCL12-HMGB1 axis on the crosstalk	Percentage of cell death of Tregs/Macrophages from peripheral blood and pleural effusion derived from MPM patients treated with and without R54.	0/baseline
To investigate inhibitors of the CXCR4-CXCL12-HMGB1 axis on the crosstalk	Overall survival of mice with MPM treated with CDDP-anti-PD-1/R54.	In vivo experiment 3 weeks.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Repurposing Diflunisal as antitumor drug in MPM	Overall survival of MPM mice treated with DFL in combination with the gold-standard treatment of MM patients, i.e. checkpoint inhibitors (Nivolumab + Ipilimumab).	In vivo experiment 3 weeks.

Collaborators and Investigators

• Sponsor: Marco Emilio Bianchi
• Collaborators: Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
• Investigators: Principal Investigator: Marco Bianchi, Professor, Irccs Ospedale San Raffaele; Principal Investigator: Vincenzo Sforza, MD, Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale

Publications and helpful links

General Publications

• Shimizu Y, Dobashi K, Imai H, Sunaga N, Ono A, Sano T, Hikino T, Shimizu K, Tanaka S, Ishizuka T, Utsugi M, Mori M. CXCR4+FOXP3+CD25+ lymphocytes accumulate in CXCL12-expressing malignant pleural mesothelioma. Int J Immunopathol Pharmacol. 2009 Jan-Mar;22(1):43-51. doi: 10.1177/039463200902200106.
• Bianchi ME, Crippa MP, Manfredi AA, Mezzapelle R, Rovere Querini P, Venereau E. High-mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair. Immunol Rev. 2017 Nov;280(1):74-82. doi: 10.1111/imr.12601.
• Santagata S, Napolitano M, D'Alterio C, Desicato S, Maro SD, Marinelli L, Fragale A, Buoncervello M, Persico F, Gabriele L, Novellino E, Longo N, Pignata S, Perdona S, Scala S. Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer. Oncotarget. 2017 Aug 19;8(44):77110-77120. doi: 10.18632/oncotarget.20363. eCollection 2017 Sep 29.
• Li B, Zeng Y, Reeves PM, Ran C, Liu Q, Qu X, Liang Y, Liu Z, Yuan J, Leblanc PR, Ye Z, Sluder AE, Gelfand JA, Brauns TA, Chen H, Poznansky MC. AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression. Cancer Immunol Res. 2018 May;6(5):539-551. doi: 10.1158/2326-6066.CIR-17-0530. Epub 2018 Mar 6.
• Kinoshita Y, Hamasaki M, Yoshimura M, Matsumoto S, Iwasaki A, Nabeshima K. Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma. Mod Pathol. 2020 Feb;33(2):235-244. doi: 10.1038/s41379-019-0309-6. Epub 2019 Jun 23.
• D'Alterio C, Buoncervello M, Ierano C, Napolitano M, Portella L, Rea G, Barbieri A, Luciano A, Scognamiglio G, Tatangelo F, Anniciello AM, Monaco M, Cavalcanti E, Maiolino P, Romagnoli G, Arra C, Botti G, Gabriele L, Scala S. Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1. J Exp Clin Cancer Res. 2019 Oct 28;38(1):432. doi: 10.1186/s13046-019-1420-8.
• Zhang M, Luo JL, Sun Q, Harber J, Dawson AG, Nakas A, Busacca S, Sharkey AJ, Waller D, Sheaff MT, Richards C, Wells-Jordan P, Gaba A, Poile C, Baitei EY, Bzura A, Dzialo J, Jama M, Le Quesne J, Bajaj A, Martinson L, Shaw JA, Pritchard C, Kamata T, Kuse N, Brannan L, De Philip Zhang P, Yang H, Griffiths G, Wilson G, Swanton C, Dudbridge F, Hollox EJ, Fennell DA. Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment. Nat Commun. 2021 Mar 19;12(1):1751. doi: 10.1038/s41467-021-21798-w. Erratum In: Nat Commun. 2021 Jun 7;12(1):3569. doi: 10.1038/s41467-021-23867-6.
• Bertolini G, Cancila V, Milione M, Lo Russo G, Fortunato O, Zaffaroni N, Tortoreto M, Centonze G, Chiodoni C, Facchinetti F, Pollaci G, Taie G, Giovinazzo F, Moro M, Camisaschi C, De Toma A, D'Alterio C, Pastorino U, Tripodo C, Scala S, Sozzi G, Roz L. A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer. Mol Ther. 2021 Oct 6;29(10):2963-2978. doi: 10.1016/j.ymthe.2021.05.014. Epub 2021 May 21.
• Oien DB, Sarkar Bhattacharya S, Chien J, Molina J, Shridhar V. Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations. Front Pharmacol. 2021 Sep 21;12:750352. doi: 10.3389/fphar.2021.750352. eCollection 2021.
• Santagata S, Rea G, Castaldo D, Napolitano M, Capiluongo A, D'Alterio C, Trotta AM, Ierano C, Portella L, Di Maro S, Tatangelo F, Albino V, Guarino R, Cutolo C, Izzo F, Scala S. Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment. Hepatol Int. 2024 Apr;18(2):568-581. doi: 10.1007/s12072-023-10537-6. Epub 2023 May 4.
• Husain AN, Colby T, Ordonez N, Krausz T, Attanoos R, Beasley MB, Borczuk AC, Butnor K, Cagle PT, Chirieac LR, Churg A, Dacic S, Fraire A, Galateau-Salle F, Gibbs A, Gown A, Hammar S, Litzky L, Marchevsky AM, Nicholson AG, Roggli V, Travis WD, Wick M; International Mesothelioma Interest Group. Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2013 May;137(5):647-67. doi: 10.5858/arpa.2012-0214-OA. Epub 2012 Aug 28.

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2024
• Primary Completion (Estimated): July 25, 2025
• Study Completion (Estimated): January 25, 2027

Study Registration Dates

• First Submitted: July 26, 2024
• First Submitted That Met QC Criteria: July 31, 2024
• First Posted (Actual): August 2, 2024

Study Record Updates

• Last Update Posted (Actual): August 2, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant
• Other Study ID Numbers: PNRR-TR1-2023-12377199

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No