Phase I/II study of the anti-P-selectin antibody crizanlizumab for newly-diagnosed unmethylated glioblastoma

Background: Central nervous system (CNS) tumors, whether primary or secondary, present significant therapeutic challenges, partly due to the unique environment of the brain, which is both highly immunosuppressive and difficult to penetrate due to the blood-brain barrier (BBB). Glioblastoma (GB) is the most lethal and common CNS cancer, exhibiting a highly invasive and aggressive nature. Within the brain microenvironment, microglia have been shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia behavior are not fully understood. We previously demonstrated that P-selectin mediates microglia-enhanced GB proliferation and invasion by modulating microglial activation states. We demonstrated this phenomenon in several models, by neutralizing antibody (Ab), pharmacological (small molecule), and molecular inhibition (shRNA) of P-selectin, which led to reduced tumor growth and increased survival in GB mouse models. Moreover, P-selectin inhibition led to increased infiltration and activation of CD8 cytotoxic T cells, as well as reduced infiltration of T regulatory cells. This suggests that P-selectin inhibition may enhance the susceptibility of GB tumors to existing immunotherapies, thereby sensitizing these non-responsive tumors to become immune checkpoint therapy (ICT)-responsive. Our work sheds light on the function of tumor-associated microglia and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a therapeutic target in GB patients. Methods: NCT05909618 is a single-center, open-label, 3-arm, non-randomized phase I/II study to evaluate the efficacy, safety, and tolerability of an anti-P-selectin antibody, crizanlizumab, alone (cohort 2) or in combination with nivolumab (cohorts 1 and 3) in patients with GB and melanoma brain metastases. Herein, we report preliminary information on Cohort 2, which enrolls patients with newly diagnosed MGMT-unmethylated GB to receive crizanlizumab maintenance therapy following completion of primary radiation therapy. Clinical Trial Registry Number: NCT05909618 Enrollment Status: The trial opened in August 2023 with a planned sample size of 33 subjects (11 patients to cohort 2). As of the time of submission, approximately 50% of the target accrual has been enrolled across the cohorts. The study remains open, and recruitment is ongoing.