Individualized therapy in bladder cancer: biomarkers and the tumor-immune microenvironment
Bladder cancer is a common cancer, with a worldwide prevalence of 2.7 million patients. Although bladder cancer is often superficial at diagnosis, 30-40% of patients present with more advanced disease or progress to more aggressive disease. For patients with locally advanced or metastatic bladder cancer, platinum-based chemotherapy is the mainstay of treatment. Most patients will eventually die of their disease. In recent years, immunotherapy has shown to be active in bladder cancer. Impressive responses are seen, however only a minority of patients benefits from these treatments and it is unclear which patients respond. We aim to advance the development of a personalized approach to bladder cancer by exploring and targeting the tumor-immune microenvironment and finding biomarkers that can guide systemic therapy. Our key focus is on the neoadjuvant setting, as we believe the highest gains in cure rates can be achieved here. Through the large number of bladder cancer patients, excellent multidisciplinary collaboration and broad availability of clinical trials with novel therapeutics at the NKI/AVL, discoveries can rapidly be translated into clinical trials.
Neoadjuvant treatment with combination Immunotherapy
In 2020, the first cohort of the NABUCCO study was published. In this study, we investigate the feasibility of pre-operative ipilimumab/nivolumab in locoregionally advanced bladder cancer. 24 patients were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle, meeting the primary endpoint. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 11/24 patients (46%) achieved a pCR. 3 additional pts (12%) had a small focus of noninvasive cancer at resection (2 CIS, 1 pTa). In a subset of the remaining patients, clear signs of response were noted. Translational analysis of this unique set of 24 paired pre/post tumor samples showed that pathological response was not associated with pre-existing T-cell immunity. This suggests that anti-CTLA4/PD1 combination therapy may be able to induce immune responses in “cold” tumors. A follow-up cohort of 30 patients, testing adjusted dosing schedules, is enrolling.