Immunogenic Cell Death as a Novel Mechanism of Mitomycin C Activity in Bladder Cancer (ICH-MIM-01)

The principal objective of this study consists in the assessment of Immunogenic Cell Death (ICD) induction in neoplastic tissues derived from bladder cancer patients treated ex vivo with Mitomycin C (MMC). The evaluation is performed using cellular and molecular analyses of treated versus untreated samples derived from the same patient

Study Overview

• Status: Unknown
• Conditions: Bladder Cancer
• Intervention / Treatment: Other: This is an observational study that does not concern a direct intervention on patients and control subjects and does not interfere with the clinical management of patients.

Detailed Description

Urothelial or transitional cell carcinoma of the bladder is the fourth most common cancer in males worldwide, with about 60-80% of newly diagnosed patients having non-muscle-invasive bladder cancer (NMIBC). NMIBC management consist in transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical treatment with the chemotherapeutic agent Mitomycin C (MMC) or the immunotherapy bacillus Calmette-Guérin. These therapies result in low progression rates, but are not efficacious in all patients, leading to high tumor recurrence. Immunogenic cell death (ICD) may be one of the mechanisms of action of MMC intravesical therapy in bladder cancer.

The primary objective of the study is to evaluate whether MMC is able to trigger ICD in patient-derived neoplastic tissues. As secondary targets we aim to:

1. identify an expression profile that is common to all tumors that undergo ICD upon MMC treatment ('ICD signature'),
2. asses the genetic and environmental factors- urinary microbiome composition- responsible for MMC treatment efficacy,
3. evaluate whether ICD induction correlates with clinical staging and response (clinical endpoints for MMC-treated patients are recurrence at three month and one year after enrollment).

• Study Type: Observational
• Enrollment (Anticipated): 110

Contacts and Locations

Study Locations

• Italy
  • Milan
    • Rozzano, Milan, Italy, 20089
      • Recruiting
      • Humanitas reseach hospital (ICH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

80 patients with carcinoma of the bladder; divided in 20 patients Ta (low grade), 20 patients Ta/T1 (high grade) and 20 patients T2. Only for liquid samples collection we will include 20 CIS (carcinoma in situ) patients.

30 age and sex-matched subjects not suffering from carcinoma of the bladder, already hospitalized in ICH; we expect to enroll 24 males and 6 females of which 10 of 40- 60 years old, 10 of 60-70 years old, 10 of >70 years old.

Description

Inclusion Criteria:

- Male and females, > 40 years old

For bladder cancer patients:

- bladder cancer patients- patinets with first tumor occurrence or patient with a recurrence after more than 2 years from the removal of the prior malignancy

Exclusion Criteria:

• Treated with immunomodulatory agents at time of enrollment or in the two months before enrollment
• Treated with antibiotics at time of enrollment or during the month before enrollment
• Positive history of sexually transmitted diseases
• Urinary infection ongoing or recent (during the three months before enrollment)
• Suffering from chronic intestinal inflammation

ONLY for controls:

• Treated with immunomodulatory agents at time of enrollment or in the two months before enrollment
• Treated with antibiotics at time of enrollment or during the month before enrollment
• Positive history of sexually transmitted diseases
• Urinary infection ongoing or recent (during the three months before enrollment)
• Suffering from chronic intestinal inflammation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Bladder cancer patients; 80 patients with carcinoma of the bladder; divided in 20 patients Ta (low grade), 20 patients Ta/T1 (high grade) and 20 patients T2. Only for liquid samples collection we will include 20 CIS (carcinoma in situ) patients	Other: This is an observational study that does not concern a direct intervention on patients and control subjects and does not interfere with the clinical management of patients.; urine collection: DNA is isolated from urine samples (catheterized, washout, midstream) and the 16S rRNA gene is sequenced. Specimen collection: Specimens collected during TURBT are selected by a pathologist and trasferred to the laboratory. The tissues are treated ex vivo with MMC.
Controls- Healthy subjects; 30 age and sex-matched subjects not suffering from carcinoma of the bladder, already hospitalized in ICH; we expect to enroll 24 males and 6 females of which 10 of 40- 60 years old, 10 of 60-70 years old, 10 of >70 years old.	Other: This is an observational study that does not concern a direct intervention on patients and control subjects and does not interfere with the clinical management of patients.; urine collection: DNA is isolated from urine samples (catheterized, washout, midstream) and the 16S rRNA gene is sequenced. Specimen collection: Specimens collected during TURBT are selected by a pathologist and trasferred to the laboratory. The tissues are treated ex vivo with MMC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MMC-induced ICD	The main aim of this study is to evaluate whether MMC is able to trigger ICD in patient-derived neoplastic tissues.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICD signature analyzed by RNAseq analysis	Identify an expression profile that is common to all tumors that undergo ICD upon MMC treatment ('ICD signature')	3 years
Microbiota study	Verify the existance of urinary microbiome using catheterized urines and identify changes in urinary microbiome composition correlating with bldder cancer, MMC efficacy and staging/progression of the disease	3 years

Collaborators and Investigators

• Sponsor: Istituto Clinico Humanitas

Publications and helpful links

General Publications

• Oresta B, Pozzi C, Braga D, Hurle R, Lazzeri M, Colombo P, Frego N, Erreni M, Faccani C, Elefante G, Barcella M, Guazzoni G, Rescigno M. Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer. Sci Transl Med. 2021 Jan 6;13(575):eaba6110. doi: 10.1126/scitranslmed.aba6110.

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2018
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): September 30, 2020

Study Registration Dates

• First Submitted: February 3, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: July 4, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: 2041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Research outcome

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No