Longitudinal Assessment of Marrow and Blood in Patients With Glioblastoma

Description

The investigators’ recent studies show that large numbers of T cells in patients and mice with intracranial tumors are sequestered in bone marrow. This phenomenon mysteriously confines a pool of functional, naïve T cells with anti-tumor capacity to a compartment where they are unable to access tumor, eliciting a mode of T cell dysfunction categorized as “ignorance.” The investigators have uncovered that loss of the sphingosine-1-phosphate receptor 1 (S1P1) from the surface of T cells mediates their sequestration in bone marrow, while blocking internalization of S1P1 facilitates stabilization of the receptor on T cells and frees them for anti-tumor activities. As the investigators look to design interventions targeting β-arrestin mediated S1P1 internalization as a novel anti-tumor strategy, they need to better understand variations in sequestration across patients, over time, and with treatment. Assessing these variations and biomarkers that may accompany them will help to establish a target treatment population, as well as the optimal timing for intervention.

Primary Objectives:

1. Assess variations in blood and bone marrow T cell counts as they relate to treatment time-points in patients with glioblastoma (GBM).
2. Assess variations in S1P1 levels and their correlation with blood and bone marrow T cell counts over the course of treatment in patients with GBM

Exploratory Objectives:

1. Assess the associations between tumor size and degree of lymphopenia and bone marrow T cell sequestration observed.
2. Compare The Cancer Genome Atlas (TCGA) subclasses with respect to the degree of lymphopenia and bone marrow T cell sequestration observed at diagnosis.
3. Examine patient plasma, tumor supernatant, and tumor ribonucleic acid (RNA) for markers that are associated with lymphopenia, T cell S1P1 levels, and bone marrow T cell sequestration. Initial candidates will include transforming growth factor-β (TGFβ) 1/2, tumor necrosis factor (TNF), interleukin (IL)-33, IL-6, catecholamines, signal transducer and activator of transcription 3 (STAT3) RNA, and Kruppel-like factor 2 (KLF2) RNA.
4. Compare T cell phenotypes in the blood and bone marrow of patients exhibiting versus not exhibiting T cell lymphopenia or sequestration.
5. Compare differences in tumor-infiltrating lymphocyte numbers and phenotypes between patients with and without lymphopenia / sequestration at diagnosis.
6. Establish baseline β-arrestin 1 and 2 expression in patients and assess variation across individuals.
7. Archive samples for subsequent assessment of β-arrestin recruitment to the cytoplasmic component of T cell S1P1, as well as the capacity to inhibit such recruitment in vitro with candidate small molecules.