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Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Supplementary Figure from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Data from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Correlation between multi-parametric MR-PET imaging changes before and after GDC-0084. A) Pearson's correlation coefficient (R) and B) resulting p-values describing the association between all imaging measurements. No significant correlations (P

Examples of metabolic responders to GDC-0084 as indicated by a decrease in 18F-FDG PET uptake. A-B) Examples of a clear reduction in focal 18F-FDG uptake within the tumor. C-E) Example of more subtle reduction in 18F-FDG uptake after GDC-0084. C and E) demonstrate both focal (tumor) and global (gray matter) reductions in 18F-FDG uptake.

Post-treatment multi-parametric MR-PET imaging measurements and responses for each oral dose of GDC-0084. Post-treatment measurements of A) contrast enhancing tumor volume, B) median 18F-FDG uptake relative to white matter, C) median ADC, D) median FA, E) median Ktrans, F) median vp¬, and G) median rCBV and change in measurements of H) contrast enhancing tumor volume, I) median 18F-FDG uptake relative to white matter, J) median ADC, K) median FA, L) median Ktrans, M) median vp¬, and N) median rCBV for dose levels of 2, 4, 8, 15, 20, 30, 45, and 65mg.

Correlation between Cmax and AUC.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

INTRODUCTION Cranial irradiation with protons (PRT) as compared with photons (PHT) reduces radiation exposure to healthy brain tissue and may mitigate early- and late-delayed complications. Prior work in our group has demonstrated that PRT results in less brain atrophy over 2 years post-treatment as compared with PHT. It is unknown whether individual factors, such as cerebrovascular disease risk (CVDR; known to be important in post-RT brain changes), interacts with treatment type to affect brain volume change. METHODS Patients treated with PRT for grade 2 or 3 gliomas were meticulously matched to patients treated with PHT using an eleven-tiered criterion (i.e., age, sex, tumor type, tumor location, laterality, IDH mutation status, 1p19q deletion status, concurrent chemotherapy, adjuvant chemotherapy, total Gy dose, and number of fractions). Brain volume changes were evaluated by measuring changes in ventricular size in the contralesional hemisphere (to reduce impact of tumor-related changes on volumetric measurements). A CVDR score was created, incorporating history of hypertension, hyperlipidemia, smoking, and diabetes. Correlation and multiple regression analyses examined the relationship between CVDR and brain volume loss over 2 years. RESULTS Mann-Whitney tests of independence showed no significant differences in CDVR between PHT and PRT treatment groups. Cerebral volume loss correlated significantly with CVDR (r =.404, p =0.02) and treatment type (r=-.366, p =0.036). Age and gender were unrelated to volume loss. A multiple regression analysis that included treatment type (PHT, PRT) and CVDR accounted for 23% of the variance in volume loss, F(2, 32) = 4.383, p < .021. CONCLUSION The current study demonstrates that neurotoxicity of radiation therapy is related to both CVDR and radiation treatment type. Longitudinal data, including a larger sample size, are warranted to confirm these preliminary findings. Inclusion of routine neuropsychological outcome data will be critical to understand the functional significance of these results.

Background Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

BACKGROUND We sought to compare the Response Assessment in Neuro-Oncology (RANO), modified RANO (mRANO), and immunotherapy RANO (iRANO) in a large population of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma. METHODS Bidimensional measurements of enhancing disease and FLAIR sequence evaluation were performed by two independent readers on brain MRIs of consecutive patients with IDH-wildtype nGBM and rGBM treated at a single institution. Discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using iterative multiple imputations for censored observations. RESULTS 526 nGBM and 580 rGBM cases were included. Spearman’s correlations were not significantly different between RANO and mRANO in nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.48 [0.40, 0.55] vs. 0.50 [0.42, 0.57]). Evaluation of FLAIR did not improve the correlation in patients who received antiangiogenic therapy. Acquisition of confirmation scans was associated with increased correlation only when PD was identified within 12 weeks of completion of radiation in nGBM. The use of the post-radiation MRI as a baseline was associated with increased correlation compared to use of the pre-radiation MRI in nGBM (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). The correlation with iRANO was similar to RANO and mRANO among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy. CONCLUSIONS RANO and mRANO demonstrated similar correlations between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans were only beneficial in nGBM in the first 12 weeks after completion of radiation. There was a trend in favor of the post-radiation MRI as the baseline scan in nGBM. The use of iRANO criteria did not add a significant benefit in patients who received immunotherapy.

BACKGROUND The clinical trial NRG/RTOG 0825 sought to determine if the addition of bevacizumab to temozolomide and radiation improves survival in patients with newly diagnosed glioblastomas. Tertiary objectives included measuring the effect of the addition of bevacizumab to standard chemoradiation on neurocognitive function and quality of life. In this study, we describe brain atrophy changes as measured by ventricular volume expansion. METHODS We analyzed longitudinal MRI brain studies obtained from NRG/RTOG-0825. Volume changes in the contralesional (non-tumor) lateral ventricle were measured. Patients were included if they had either a scan at post operative (week 0) or post radiation baseline (week 10). Patients were also required to have at least one follow-up MRI brain scan 6 months or more from their baseline scans (at Week 0 or Week 10). Volumes were delineated using tissue segmentation in Slicer software. RESULTS 177 patients were identified with eligible baseline scans at Week 0 and 162 patients at Week 10. For participants analyzed at 6 months from the Week 0 scan, mean ventricular volume increased by 54.70% (SEM: 3.21%, t = 6.41, p < 0.001, N = 135). For patients analyzed at 6 months from the Week 10 scan, mean ventricular volume increased by 31.89% (SEM: 2.52%, t = 3.96, p < 0.001, Nf117). CONCLUSIONS This study presents evidence of progressive brain volume loss in patients with glioblastoma treated with standard chemoradiation with or without anti-VEGF therapy. This is one of the largest sample sizes of volumetric analysis in real world patients with glioblastoma. These volume changes begin early in the disease course and may precede treatment. Next directions include correlating these volumetric changes with neurocognitive score changes, quality of life scores and analyzing these changes by treatment arm.

PURPOSE Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues. METHODS Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed. RESULTS We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group. CONCLUSION No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.

Ependymoma can arise throughout the whole neuraxis. In children, tumors predominantly occur intracranially, whereas the spine is the most prevalent location in adults. Significant variance in the grade II versus grade III distinction of ependymomas has led to the acknowledgment that the clinical utility of histopathological classification is limited. Epigenomic profiling efforts have identified molecularly distinct groups of ependymomas that adequately reflect the biological, clinical, and histopathological heterogeneities across anatomical compartments, age groups, and grades. The recent update of the World Health Organization classification of central nervous system tumors has already integrated one of these groups, and molecular classification will be part of future clinical trials to improve risk stratification. Clinical management of this rare disease is challenging, making professional experience and intensified multidisciplinary cooperation pivotal factors for treatment success. Novel research strategies are currently applied for target discovery in ependymomas since for most molecular groups, genetic drivers are unknown.

Abstract 959 Background: We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS non-Hodgkin lymphoma (NHL) (JCO 2007 25: 1350–1356). Rapid dissemination throughout the craniospinal axis was demonstrated and cytologic responses were detected in six out of ten patients. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. The major goals of this current trial are to perform the first study of intraventricular immuno-chemotherapy in humans and to evaluate the safety of two dose levels of intraventricular rituximab as well as its pharmacokinetics in combination with intraventricular methotrexate (MTX). Secondary goals are to obtain information regarding the efficacy of this approach in the treatment of patients with recurrent CNS lymphoma, (brain parenchyma, intraocular or the leptomeningeal compartment). Methods: Thirteen patients with recurrent/refractory CD20+ CNS NHL were treated at UCSF, Dana Farber Cancer Institute and Massachusetts General Hospital on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned four week schedule. Rituximab is combined with MTX (12 mg) during the second intraventricular injection each week. Patients achieving partial response or better were eligible for a second month of combination intraventricular rituximab plus MTX. Results: No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. The most common treatment-related toxicity was paresthesias (grade 1). One patient exhibited NHL progression outside of the CNS at three weeks and thus was not evaluable for CNS response, and one patient exhibited stable disease. Complete cytologic responses were detected in ten out of thirteen patients at the one-month restaging. Parenchymal responses were detected in three out of six subjects with one partial response within the corpus callosum, and two complete regressions of lesions within temporal lobe and cerebral cortex. One patient with leptomeningeal lymphoma non-responsive to intravenous rituximab and refractory to high-dose intravenous and intrathecal methotrexate, oral temozolomide and intrathecal liposomal cytarabine, obtained a sustained complete response with the intraventricular rituximab/MTX protocol and subsequently was approved for consolidative autologous stem cell transplant. Two patients have participated in extended dosing on protocol without progression for five and eight months respectively. Thus far, there is no evidence for a relationship between FcGR3A polymorphism and therapeutic resistance in a preliminary analysis (n=8 patients). The maximum tolerated dose of intraventricular rituximab with this combination was established as 25 mg. The mean maximum intraventricular rituximab concentration after intraventricular injection of rituximab was 285 microgram/ml at the 10 mg dose level (N=3) and 882 microgram/ml at the 25 mg dose level (N=10); (p Conclusions: Intraventricular rituximab/MTX appears to be safe in recurrent CNS NHL. Twelve of thirteen patients completed at least one month of therapy, without any treatment-associated serious adverse events at any of the institutions. Intraventricular administration of methotrexate may significantly attenuate rituximab clearance from the leptomeningeal compartment. There is encouraging evidence for significant activity of intraventricular immuno-chemotherapy in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. These results provide strong support for further investigation of this novel therapeutic approach. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: Off Label Use: We will discuss the off-label use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.