Clinical trial NCT04256616: Immunogenic Cell Death as a Novel Mechanism of Mitomycin C Activity in Bladder Cancer
Official title: Immunogenic Cell Death as a Novel Mechanism of Mitomycin C Activity in Bladder Cancer
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Bladder Cancer
Lead sponsor: Istituto Clinico Humanitas
Sponsor class: OTHER
First posted: 2020-02-05
Enrollment: 110
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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.

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).

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

Primary outcomes:
measure: MMC-induced ICD
timeFrame: 3 years
Secondary outcomes:
measure: ICD signature analyzed by RNAseq analysis
timeFrame: 3 years
measure: Microbiota study
timeFrame: 3 years
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: Humanitas reseach hospital (ICH)
state: Milan
Study officials:
References:
citation: 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.