Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

T Cell Epitope Prediction and Its Application to Immunotherapy

T cells play a crucial role in controlling and driving the immune response with their ability to discriminate peptides derived from healthy as well as pathogenic proteins. In this review, we focus on the currently available computational tools for epitope prediction, with a particular focus on tools aimed at identifying neoepitopes, i.e. cancer-specific peptides and their potential for use in immunotherapy for cancer treatment. This review will cover how these tools work, what kind of data they use, as well as pros and cons in their respective applications

Evidence of T cell activation and intratumoral nivolumab-presence in glioblastoma patients treated with nivolumab and bevacizumab

Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. Salvage neurosurgical resection is performed if possible and GBM patients are hereafter treated with Stupp’s regime as standard treatment in the primary setting. However, after relapse, treatment in the recurrent setting shows very limited effect. We are monitoring the immune system of patients participating in a phase II clinical trial, where patients with recurrent GBM receive Nivolumab and Bevacizumab, treatments blocking PD1 and VEGF, respectively. The clinical trial consists of two arms. Arm A includes patients where surgical removal of the tumor is possible, and arm B includes patients who are only able to receive medical treatment. Arm A has received Nivolumab 7 days prior to surgery. Single cells suspension was produced from the resected tumors and blood samples was collected from patients through the course of treatment, wherefrom PBMCs (peripheral blood mononuclear cells) were purified. All samples were immunophenotyped using multi-color flow cytometry, to identify and follow the distribution of various immune cell types, and determine their expression of activating and inhibitory molecules over the course of treatment, in the periphery and in the tumor. An activated subset of T cells was characterized by CD103 (tissue residence), CD39 (antigen exposure) and CD69 (cytotoxicity). Such T cell populations were significantly enriched in the tumor. Importantly, we could demonstrate the presence of Nivolumab in the tumor, using an anti-IgG4 antibody to detect Nivolumab binding to T cells. We observed IgG4 positive T cell in the tumor digest, suggesting T cells binding Nivolumab are present in the tumor. Additional data analysis will be performed prior to the conference. With this we hope to gain further knowledge of the immune system’s role in tumor clearance in the brain and the impact of immunotherapy hereupon

Nivolumab and bevacizumab for recurrent glioblastoma; t-cell reactivity against autologous tumor cells

INTRODUCTION: Glioblastoma is an aggressive brain tumor with a median survival of 14.6 months. We have no standard treatment for relapse and known options have limited effect. Novel treatments are necessary to improve survival and quality of life. METHODS: We present our trial; phase II open label, two-armed translational study of Nivolumab and Bevacizumab for recurrent GBM, who have failed Stupp’s regimen. Patients are included in two arms depending on the possibility of salvage neurosurgical resection. Both arms receive Nivolumab and Bevacizumab administrated every second weekend, and the surgical arm also receive Nivolumab 7 days prior surgery. Forty-four patients were included by January 2021; 20 in each arm (four screen-failures). In the surgical arm, 20 fresh tumor samples as well as paired tissue from primary tumor were available. Tumor infiltrating lymphocytes (TILs) and tumor digest were produced in vitro from recurrent settings. Young TILs were expanded from fresh tumor fragments after minimal-culture, whereas rapidly expanded TILs (REP TILs) were obtained after massive expansion. By intracellular cytokine staining, we investigated the TIL reactivity after exposure to autologous tumor digest in order to evaluate whether the TILs were tumor-reactive, non-reactive or bystanders. RNA and whole exome sequencing were available before and after treatment. RESULTS: Material from 19 patients was analyzed (one out of the 20 collected biopsies was limited in size, therefore no tumor digest could be produced). Four out of 19 TIL samples showed tumor reactivity after exposure to the autologous tumor digest. Tumor reactivity was ranged between 1,2 to 13,6 tox% in CD8+ TILs and between 2,8 to 10,9 tox% in CD4+ TILs. By flowcytometry we found, IgG4+ CD3+ TILS from tumor biopsies, meaning that Nivolumab were found in the brain. Currently controls are included to evaluate these results. CONCLUSIONS: Updated results will be presented at SNO