Englander Institute for Precision Medicine

Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors.

TitleInhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors.
Publication TypeJournal Article
Year of Publication2024
AuthorsSchwarz E, Benner B, Wesolowski R, Quiroga D, Good L, Sun SH, Savardekar H, Li J, Jung KJoo, Duggan MC, Lapurga G, Shaffer J, Scarberry L, Konda B, Verschraegen C, Kendra K, Shah M, Rupert R, Monk P, Shah HA, Noonan AM, Bixel K, Hays J, Wei L, Pan X, Behbehani G, Hu Y, Elemento O, Chung D, Xin G, Blaser BW, Carson WE
JournalJCI Insight
Volume9
Issue21
Date Published2024 Nov 08
ISSN2379-3708
KeywordsAdenine, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Lymphocyte Activation, Male, Middle Aged, Myeloid-Derived Suppressor Cells, Neoplasms, Nivolumab, Piperidines, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Pyrimidines, T-Lymphocytes
Abstract

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

DOI10.1172/jci.insight.169927
Alternate JournalJCI Insight
PubMed ID39513363
PubMed Central IDPMC11601564
Grant ListT32 CA247815 / CA / NCI NIH HHS / United States
UM1 CA186712 / CA / NCI NIH HHS / United States
UL1 TR002733 / TR / NCATS NIH HHS / United States
T32 TR004543 / TR / NCATS NIH HHS / United States
T32 AI106704 / AI / NIAID NIH HHS / United States
U54 CA232561 / CA / NCI NIH HHS / United States

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