A pilot study of the Bruton's tyrosine kinase inhibitor ibrutinib in combination with nivolumab in patients with metastatic solid tumors
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ABSTRACT: Background: Preclinical work has demonstrated that ibrutinib inhibits the generation, migration and immunosuppressive function of myeloid-derived suppressor cells (MDSC). A pilot study tested the combination of ibrutinib and nivolumab in patients with metastatic solid tumors. Methods: Sixteen patients with metastatic solid malignancies were treated with ibrutinib (420 mg) daily and nivolumab (240 mg) IV on days 1 and 15 of 28 day cycles. Ibrutinib dosing started 7 days before cycle 1 of nivolumab and was given until cycle 1, day 8 of nivolumab. The effect of ibrutinib alone and in combination with nivolumab on circulating MDSC and immune subsets and cytokine/chemokine levels were measured. Single-cell RNA and TCR sequencing was also performed. Results: The most common treatment-related AEs were fatigue (31%) and anorexia (31%). Five patients had a clinical response (4 partial, 1 complete). Four patients had stable disease at 3 months. Median progression-free survival was 3.5 months and median overall survival 10.8 months. MDSC levels increased following 7 days of single-agent ibrutinib compared to baseline (21.91% vs. 27.67%). There was increased T cell proliferation in response (33.9% vs. 40.06%, p<0.01) to the combination regimen. Plasma levels of CCL2, CCL3, CCL4, CCL13, IL- 8, and VEGF-α decreased with ibrutinib treatment. Ibrutinib treatment altered the transcriptional state of the myeloid cell compartment and led to increased cancer-associated TCR clonotypes. Conclusion: The combination of ibrutinib and nivolumab was well tolerated and ibrutinib significantly impacted MDSC and T cell function in patients with solid metastatic tumors.
ORGANISM(S): Homo sapiens
PROVIDER: GSE178882 | GEO | 2022/06/24
REPOSITORIES: GEO
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