longitudinal assessment of marrow and blood in patients with glioblastoma

Conditions: Glioblastoma

Summary: the main goal of this study is to provide foundational data to drive translational approaches for an entirely novel category of immunotherapy.

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.

Eligibility criteria:
inclusion criteria: * age ≥18 years of age. * suspected newly-diagnosed gbm, world health organization (who) grade iv with intent for gross total resection (as defined above). * accessibility for treatment and follow up. * patient consent obtained according to duke institutional policy. * women of child bearing potential (wocbp) must have a negative serum pregnancy test according to standard of care prior to surgery. exclusion criteria: * prior therapy (other than steroids or stereotactic biopsy) or concomitant immunotherapy. * pregnant or breast-feeding during the study period. * patients with an active infection, or febrile within 24 hours of surgery. * patients with inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, or other autoimmune disease. * patients with history of or active hematologic or bone marrow diseases, including but not limited to diagnosed lymphomas, leukemias, sickle cell or other anemias not associated with their current condition or polycythemia vera. * prior bone marrow harvests preceding this study. * patients with known or suspected immunodeficiency or human immunodeficiency virus (hiv). * hematocrit \< 24 % pre-operatively. * patients with a serious active infection or other serious underlying medical conditions that would impair the ability of the patient to receive protocol treatment or comply with protocol.

Keywords: glioblastoma, t cells, sequestration sphingosine-1-phosphate receptor 1 β-arrestin, bone marrow, immunotherapy