Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Do Waiting Times in Dental Offices Affect Patient Satisfaction and Evaluations of Patient-Provider Relationships? A Quasi-experimental Study.

PURPOSE: Spending time in waiting rooms prior to dental visits is not uncommon for dental hygiene patients. The objectives were to determine if the length of a patients' waiting time affected their satisfaction with the appointment and their evaluation of their provider. In addition, the patient's level of education and whether the dental visit is a first visit will be examined to determine if these affected the outcome. METHODS: Survey data were collected from 399 adult patients who came for regularly scheduled visits to a dental school clinic. The patients ranged in age from 19 to 93 years (mean=52 years; SD=16.9). For 29% of the patients, this visit was the first visit with this provider. RESULTS: The patients whose providers were early (n=65) were more satisfied, more likely to plan to follow their provider's recommendation and evaluated their relationship with their provider more positively than patients whose providers were on time (n=283), while the patients in the "late" group (n=32) showed the most negative responses to all questions. Patients from higher educational backgrounds were most negative in their responses when their providers were late. Patients with a first visit whose providers were late had the most negative evaluations of the patient-provider relationship. CONCLUSION: Long waiting times prior to a scheduled dental appointment have a negative effect on patients' satisfaction with their visit, the evaluations of the patient-provider relationship and the patients' intentions to return.