Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma

Abstract

BackgroundIn preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.MethodsPreviously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.ResultsIn the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+EOMES+) CD8+T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.ConclusionIbrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration numberNCT02562898.

Modulation of the Tumor Stroma and Associated Novel Nanoparticle Strategies to Enhance Tumor Targeting

“…Monotherapy with ibrutinib modulated the immune response in the TME towards an activated T-cell, monocyte, and DC phenotype. Interestingly, combination therapy of ibrutinib with a standard treatment of gemcitabine and nab-paclitaxel did not exhibit this effect [58]. As mentioned previously, CD40 is a prominent target for modulation in the TME of PDAC patients.…”

Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer

“…A total of 40 mL of blood at each timepoint was collected into five CPT sodium heparin tubes and processed to PBMCs at the DFCI Center for Immuno-Oncology Immune Assessment Laboratory within 2 hours of collection, aliquoted into four cryovials, then batch shipped to the UCSF Cancer Immunotherapy Lab for long-term storage in liquid nitrogen. Available cryopreserved PBMCs were thawed, barcoded, and stained with heavy metal-labeled antibodies (Supplementary Table S1) for analysis by mass cytometry by time-of-flight (CyTOF) as described previously ( 24 ). The samples were then washed and acquired on a mass cytometer (Helios, Fluidigm).…”