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

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.

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Publication Details

Journal
JCI Insight
Published
2024-11-07
DOI
https://doi.org/10.1172/jci.insight.169927
Citations
5
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
2.19

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article

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

Hiral Shah, Manisha R. Shah, Bradley W. Blaser, Anne M. Noonan et al.
5 citations
JCI Insight
Chronic Lymphocytic Leukemia Research
2.19
article

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

Hiral Shah, Manisha R. Shah, Bradley W. Blaser, Anne M. Noonan, Kyeong Joo Jung, Steven Sun, Emily Schwarz, Xueliang Pan, Gregory K. Behbehani, Robert Wesolowski, Lai Wei, Bhavana Konda, Yang Hu, Kari Kendra, Kristin Bixel, Jianying Li, Himanshu Savardekar, Dionisia Quiroga, William Edgar Carson, Olivier Elemento, Jami Shaffer, Luke Scarberry, Brooke Benner, Megan Duggan, Dongjun Chung, Gabriella Lapurga, Logan M. Good, Paul Monk, Gang Xin, John Hays, Robert D. Rupert, Claire Verschraegen
article en
5 citations

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.

JCI InsightVol. 9(21)
Gynecologic Oncology Group (US), Cornell University (US), Lander Institute (IL), Comprehensive Blood & Cancer Center (US), U-M Rogel Cancer Center (US), The Ohio State University (US)
Foundation for the National Institutes of Health, Ohio State University, Pelotonia, National Institutes of Health, National Cancer Institute, National Center for Advancing Translational Sciences
Openalex Percentile: Top 12%
Chronic Lymphocytic Leukemia Research
2.19
DOIOpen Access PDFOpenAlex
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