The aim of this project is to descriptively explore the trend of torquetenovirus viral load TTV during therapy with immune checkpoint inhibitor ICI in these patients, to evaluate a possible role of this virus as a biomarker of response.

The study involves the prospective recruitment of patients with metastatic clear cell renal cell carcinoma who begin a first line of treatment with immunotherapy at the UOC of Medical Oncology 1 of the Regina Elena Cancer Institute in Rome. Participants will undergo the following extra-clinical procedures and provided for by the protocol:

• Explanation, reading and signing of the informed consent;
• Performing a blood sample (approximately 7 ml);
• Collection of fecal material at different timepoints. It should be noted that the procedures necessary for conducting the study will not affect the diagnostic and therapeutic process of the patients and will only have research purposes.

The biological material collected, appropriately labeled, processed at the reference laboratories, where it will be used to perform the planned analyses. Blood and/or stool samples will be collected at different timepoints:

• Time zero (T0): before the start of therapy (blood and stool)
• C2 (T1): before the start of cycle 2 (blood)
• C4 (T2): after cycle 4, i.e. coinciding with the first radiological reassessment (blood and stool)
• 22W or 19W (T3): after 12 weeks from C4 i.e. coinciding with the radiological reassessments (blood and stool), i.e. at the last timepoint of this study.

Additional blood sampling will be performed in the case of immune-related toxicity (≥ G2 according to CTCAE) requiring steroid administration.

An additional sampling, as assessed by the investigating physician, will be collected at the time of disease progression (PD) (T4).

For each patient included in the study, the following data will be collected (obtained from the clinical documentation from the analyses conducted): personal/socio-demographic data (year of birth, sex, gender), complete histology and date of first diagnosis, surgical treatments, clinical data (e.g., laboratory tests), clinical data relating to the treatment (start and end date of each therapy with number of cycles administered, response to treatment, date of disease progression), date and location of each disease progression, patient status, date of last available follow-up, date of any death, data obtained from the analyses carried out within the present project.

Inclusion Criteria:

• Patients over 18 years of age;
• Histological diagnosis of clear cell renal cell carcinoma;
• Evidence of advanced or metastatic disease;
• Patients diagnosed with metastatic clear cell renal cell carcinoma about to start first-line immunotherapy (ICI + ICI or ICI + TKI);
• Patients able to comply with the study procedures.
• Patients who give written informed consent personally or through a witness (study participation and data processing), before any study-specific procedure is started.

Exclusion Criteria:

• Previous neoplasms;
• Previous antineoplastic treatments;
• Previous steroid treatments;
• Active viral infections (e.g., HCV, HIV, etc.);
• Lack of autonomy in adhering to study procedures.

Patients with metastatic clear cell renal cell carcinoma starting first-line immunotherapy