Immunogenic Cell Death as a Novel Mechanism of Mitomycin C Activity in Bladder Cancer

NCT ID: NCT04256616

Last Updated: 2020-07-07

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 110 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-06-27
• Study Completion Date: 2020-09-30

Brief Summary

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

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).

Conditions

Bladder Cancer

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

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

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.

Intervention Type: OTHER

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.

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.

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Istituto Clinico Humanitas

OTHER

Sponsor Role: lead

Responsible Party

Michele Tedeschi

Head of Clinical Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Humanitas reseach hospital (ICH)

Rozzano, Milan, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Maria Rescigno, PhD

Role: CONTACT

maria.rescigno@hunimed.eu

+390282245431

Facility Contacts

Maria Rescigno, PhD

Role: primary

maria.rescigno@hunimed.eu

+390282245431

References

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.

Reference Type: DERIVED

PMID: 33408185 (View on PubMed)

Other Identifiers

2041

Identifier Type: -

Identifier Source: org_study_id