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

BACKGROUND: In 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. METHODS: Previously 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. RESULTS: In 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. CONCLUSION: Ibrutinib 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 NUMBER: NCT02562898.

Being Present 2.0: Online Mindfulness-Based Program for Metastatic Gastrointestinal Cancer Patients and Caregivers.

PURPOSE: A metastatic cancer diagnosis is associated with high levels of distress in patients and caregivers, which may be alleviated by mindfulness interventions. Research on scalable, tailored, online mindfulness training programs is needed. We sought to test the feasibility and acceptability of a remotely delivered 8-week mindfulness-based intervention, Being Present 2.0 (BP2.0). METHODS: We performed a single-arm feasibility study of BP2.0 among patients with any metastatic gastrointestinal cancer receiving chemotherapy, with or without an informal caregiver. Participants were instructed to practice mindfulness using pre-recorded guided meditations 5 times per week using a study-specific website and to attend a weekly live, interactive virtual meeting facilitated by a trained instructor. The web-based platform enabled direct measurement of adherence. RESULTS: The study enrolled 46 of 74 (62%) patients contacted, together with 23 caregivers (69 participants total), from May to October 2018. Median patient age was 52 (range 20-70 years), 39% were male, 67% non-Hispanic white, 65% had colorectal cancer, and 78% lived outside of San Francisco. The top reasons cited for participation were to reduce stress/anxiety and learn how to meditate. Mean baseline National Comprehensive Cancer Network Distress Thermometer (NCCN DT) scores were 4.7 (patients) and 5.8 (caregivers). The study discontinuation rate was 20% (eight patients and six caregivers). Among the remaining 55 participants, 43 (78%) listened to at least one audio recording and/or attended at least one virtual meeting, although adherence data was incomplete. The retention rate was 71%, with 39 participants completing at least one follow-up assessment. In post-intervention qualitative interviews, 88% of respondents reported a positive experience. Compared to baseline, participants reported significantly reduced post-intervention NCCN DT scores (mean 3.1; P = .012). CONCLUSION: The BP2.0 online mindfulness-based program is feasible and acceptable for patients with metastatic gastrointestinal cancer and caregivers. These results will guide plans for a follow-up efficacy study. ClinicalTrials.gov Identifier: NCT03528863.