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The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

Background Brain microdialysis is a minimally invasive technique for monitoring analytes, metabolites, drugs, neurotransmitters, and/or cytokines. Studies to date have centered on adults with traumatic brain injury, with a limited number of pediatric studies performed. This scoping review details past use of brain microdialysis in children and identifies potential use for future neuro-oncology trials. Methods In December 2020, Cochrane Library: CENTRAL, Embase, PubMed, Scopus, and Web of Science: Core Collection were searched. Two reviewers screened all articles by title and abstract review and then full study texts, using microdialysis in patients less than 18 yo. Results Of the 1171 articles screened, 49 were included. The 49 studies included 472 pediatric patients (age range 0–17 years old), in the brain (21), abdominal (16), and musculoskeletal (12) regions. Intracerebral microdialysis was performed in 64 collective patients, with a median age of 11 years old, and predominance in metabolic evaluations. Conclusion Historically, pediatric microdialysis was safely performed within the brain in varied neurologic conditions, except neuro-oncology. Adult brain tumor studies using intratumoral/peritumoral microdialysis sampling can inform future pediatric studies to advance diagnosis and treatment options for such aggressive tumors.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for “response” and ultimately lead to identification of effective treatments.

INTRODUCTION Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults, with documented 2 year survival rates of METHODS All participants will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. A maximally safe surgical resection for cortical high grade glioma or stereotactic needle biopsy for midline glioma will be performed in the OR and verified by brain CT. Continuous microdialysis sampling will be obtained over the course of the next 48 hours. We propose to evaluate 5 participants. RESULTS This is a safety and feasibility study to evaluate tumor pharmacokinetics (PK) and pharmacodynamics (PD) of abemaciclib in recurrent high grade glioma and midline glioma participants in need of surgical resection or biopsy respectively. If intratumoral or PK brain dialysate sampling concentrations are >10nmol/L, or PD findings suggest CDK inhibition (decreased expression of Rb and/or topoIIα), then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy post resection or biopsy. After every 3 cycles, repeat brain MRI’s will be obtained to evaluate treatment response and disease progression. Exploratory aims include catheter stability testing, tissue genomic sequencing and PDX modeling. CONCLUSION We propose a trial using clinical microdialysis, placed in diffuse midline glioma tissue post biopsy, as an experimental research tool, to assess CNS drug entry and targeted inhibition with abemaciclib. These studies will be the first of their kind focused on the dynamic nature of CNS drug delivery with the overall intent to inform future clinical therapies.

e15075 Background: Nearly all patients who develop large and/or symptomatic brain metastases receive corticosteroids such as dexamethasone (Dex) to treat or prevent symptoms like nausea, headaches, or focal neurologic deficits. Dex has immunosuppressive effects such as induction of T cell apoptosis, so it’s possible that this treatment may impair the anti-tumor immune response. To address this question, we performed a secondary analysis of our in-press data describing the phenotype of brain metastasis-infiltrating CD8+ T cells to determine whether the duration of Dex therapy prior to surgical resection correlated with phenotypes we described our cohort. Methods: Fresh brain metastases specimens were weighed, and immune cells were isolated. CD45+ and CD8+ lymphocytes were counted via flow cytometry from 35 and 34 samples, respectively. A subset of samples were analyzed by high-parameter spectral flow cytometry to gain phenotypic information. Dex treatment was later extracted from the electronic medical record, and Spearman’s correlation coefficients (CC) were calculated to evaluate the association between duration of Dex therapy and brain metastasis-infiltrating lymphocyte density or phenotype. Results: Patients were on Dex for a median of 3 days (4mg q6 hours) prior to surgery. On univariate analysis, the CC between CD45+ lymphocytes or CD8+ T cells per gram of tumor and duration of Dex treatment was -0.185 (P=0.288) and -0.122 (P=0.49), respectively. The CC between frequency of PD-1+ CD8+ T cells and duration of Dex was -0.064 (p=0.784, 21 patients). In our previous work, we used the FLOWSOM algorithm to identify distinct populations of CD8+ T cells that were enriched in brain metastases compared to blood. We described two such populations, one with a tissue residence phenotype, and the other with terminally-differentiated phenotype. The CC between frequency of these populations and duration of Dex was 0.043 (p=0.889) and 0.238 (p=0.433), respectively (13 patients). We also tested for correlation between frequency of individual PD-1+ CD8+ T cell populations and duration of Dex treatment (13-18 patients). The CC for Tim3+, CD39+, CTLA4+, CD127+, Tcf-1+, CD28+, and GZMB+ populations of PD-1+ CD8+ T cells were 0.037 (p=0.891), 0.096 (p=0.705), -0.094 (p=0.738), 0.011 (p=0.971), -0.026 (p=0.918), 0.384 (p=0.128), and 0.236 (p=0.358), respectively. Conclusions: Within this cohort of patients who were on Dex for a median of 3 days prior to surgery, duration of pre-surgery Dex did not significantly affect density of brain metastasis-infiltrating CD45+ lymphocytes or CD8+ T cells or frequency of PD-1+ CD8+ T cells.

Additional file 1. Pharmacokinetics of plasma and brain dialysate sampling post temozolomide and regadenoson.

Additional file 2. Individual temozolomide concentrations within non-contrast enhancing brain interstitium on a log based scale (A). Contrast-enhancing brain interstitium values in patients 1 and 3 (B). Solid line demonstrates treatment with temozolomide alone. Dashed line demonstrates combined treatment with regadenoson.

Additional file 1. Pharmacokinetics of plasma and brain dialysate sampling post temozolomide and regadenoson.