bluuebunny/crossref_metadata_2025 huggingface dataset:
DDRE-33. PRECLINICAL THERAPEUTIC EFFICACY OF THE NOVEL BLOOD BRAIN BARRIER PENETRANT ATR INHIBITOR LR02 IN GLIOBLASTOMA
Authors: Koul Dimpy , Balasubramaniyan Veerakumar , Li Xiaolong , Khan Sabbir , Guggi Davide , Mehrling Thomas , DeGroot John
Published: November 2021

Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months despite radiation and alkylating temozolomide (TMZ) chemotherapy. DNA damage response (DDR) pathways are among the most important key players of oncogenic mutations associated with resistance to both chemotherapy and radiation in GBM. The high frequency of alterations in DDR pathways in GBM suggests that its inhibition by DDR inhibitors may render GBM cells more susceptible to DNA damaging interventions. Here, we report the preclinical in vitro and in vivo activity of a novel, orally bioavailable Ataxia-telangiectasia mutated serine/threonine protein kinase and Rad3-related (ATR) inhibitor LR02 (Laevoroc Oncology) in a panel of 15 well-characterized glioma stem-like cells (GSCs). Effects on cell proliferation, survival and tumor formation were analyzed following treatment with LR02. Growth inhibition was time- and dose-dependent with a 3-day exposure resulting in a growth inhibitory IC50 (gIC50) in the low nM range in all the glioblastoma cell lines tested. LR02 inhibited growth of GSCs at IC50 values ranging from 500nmol/L to-~2umol/L. Additional studies showed that temozolomide sensitized GSC to LR02. Importantly, we demonstrate that MGMT promotor methylation status was associated with cellular response to LR02 treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. LR02 showed efficacy and survival benefit in a GSC262 (MGMT methylated) orthotopic model of GBM. Further administration of LR02 further enhanced the in vivo antitumor efficacy of temozolomide (TMZ) against GBM using the GSC262 model demonstrating that ATR inhibitor LR02 may enhance alkylating agent-mediated cytotoxicity and provide a novel treatment combination for GBM patients. Our present findings establish that the ATR inhibitor LR02 can specifically be used in tumors with MGMT deficiency when combined with alkylating chemotherapy. Further studies are ongoing to evaluate the potential of LR02 to overcome radiation and chemotherapy resistance in glioblastoma.
DDRE-40. BIOINFORMATICS ANALYSIS OF GRADE I AND III MENINGIOMA GENE EXPRESSION SUGGESTS MMP28 AS A POSSIBLE POSITIVE PROGNOSTIC INDICATOR
Authors: Michelhaugh Sharon , Dyson Gregory , Ali-Fehmi Rouba , Bollig-Fischer Aliccia , Mittal Sandeep , Degen Katherine
Published: November 2021

Meningiomas are the most common primary brain tumor. Grade I meningiomas are slow growing with a good prognosis following surgical resection. High grade meningiomas (II and III) are more aggressive with greater rates of recurrence and poor prognosis despite surgical resection and radiotherapy. This study sought to identify key pathways and genes that contribute to the molecular mechanisms that separate these distinct meningioma phenotypes. FFPE specimens were evaluated and graded by a pathologist. Total RNA was extracted from tissue curls and RNA samples were measured with the Illumina DASL whole genome gene expression assay (n = 29,374 probes). A log2 transformation was applied to all of the data and quantile normalization using 21 samples. A t-test of the log2 expression of the 10 grade III samples and 11 grade I samples resulted in 1505 differentially expressed genes. The GeneCard Suite’s GeneAnalytics tool was used to perform pathway enrichment analysis. Similar to other comparable data sets, DNA Damage, Cell Cycle, EGF/EGFR Signaling, TGF-Beta Signaling, and PI3K-AKT Signaling pathways were among the 20 enriched pathways. Notably, matrix metalloprotease 28 (MMP28, also known as epilysin) was down regulated in grade III meningiomas compared to grade I (III/I expression ratio 0.315; P=0.015). MMP28 is expressed in numerous tissues including the nervous system during development and regeneration. In cancer, MMP28 is thought to enhance epithelial to mesenchymal transition by altering the TGF-B signaling pathways. MMP28 is an indicator of poor prognosis for pancreatic, lung, gastric and hepatic cancers as well as glioblastoma. However, MMP28 has also been reported as down regulated during malignant transformation in colon cancer. Our data suggest that MMP28 may have an alternative role in meningioma and serve as a positive prognostic indicator.
DDRE-42. TOWARDS PRECISION MEDICINE: AUTOMATED DRUG SCREENING PLATFORM UTILIZING TUMOR-ORGANOIDS TO IDENTIFY PATIENT-SPECIFIC DRUG-RESPONSES IN MENINGIOMA
Authors: Jungwirth Gerhard , Paul Adrian , Junguo Cao , Unterberg Andreas , Abdollahi Amir , Herold-Mende Christel
Published: November 2021

Tumor-organoids (TO) are mini-tumors generated from tumor tissue preserving its genotype and phenotype by maintaining the cellular heterogeneity and important components of the tumor microenvironment. We recently developed a protocol to reliably establish TOs from meningioma (MGM) in large quantities. The use of TOs in combination with lab automation holds great promise for drug discovery and screening of comprehensive drug libraries. This might help to tailor patient-specific therapy in the future. The aim of our study was to establish an automated drug screening platform utilizing TOs. For this purpose, we established TOs by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples in the high-throughput format of 384-well plates. The drug screening was performed fully automated by utilizing the robotic liquid handler Hamilton Microlab STAR and a drug library containing 166 FDA-approved oncology agents. Viability was assessed with CellTiterGlo3D. In total, we performed the drug screening with 166 drugs on TOs from 11 patients suffering from MGM (n=8 WHO°I, n=2 WHO°II, n=1 WHO°III). The top five most effective drugs resulted in a decrease of TO viability ranging from 84.6–63.3%. K-means clustering analysis resulted in groupings of drugs with similar modes of action. One cluster consisted of epigenetic drugs while another cluster consisted of several proteasome inhibitors. However, when looking at a patient-individual level, in 11 patients 44 of 166 drugs, were among the top 10 most effective drugs, providing strong evidence for heterogeneous drug-responses in MGM patients. Taken together, we successfully developed an automated drug screening platform pipeline utilizing TOs from MGM to identify patient-specific drug-responses. The observed intra-individual differences of drug responses mandate for a personalized testing of comprehensive drug libraries in TOs to tailor more effective therapies in MGM patients.
DDRE-48. COMPARTMENT LOCKED IL-12 - INCREASED TISSUE RETENTION AND MINIMAL PERIPHERAL EXPOSURE ALLOW HIGHER TREATMENT EFFICACY AND TOLERABILITY IN LOCAL GLIOBLASTOMA THERAPY
Authors: Beffinger Michal , Schellhammer Linda , Shekarian Tala , Deplazes Sereina , Zimmermann Ivan , Egloff Pascal , Buch Thorsten , Seeger Markus , Hutter Gregor , Vom Berg Johannes
Published: November 2021

Recent clinical studies in glioblastoma (GBM) highlight the potential of local IL-12 therapy, but they also bring back tolerability concerns due to leakage into the periphery. This leakage might thus hamper exploiting the full potential of local IL-12 therapy. Fusion with an IgG4 Fc portion increases the tissue retention of IL-12; but could also confer export into the blood and subsequent systemic recycling through the neonatal Fc receptor (FcRn), ultimately leading to potentially toxic IL-12 serum levels. We assessed the expression of FcRn in human and murine GBM and its role in IL-12Fc tissue retention and systemic exposure upon local delivery. Human or murine IL-12Fc was injected in GBM-bearing or naïve wt or FcRn-humanized mice continuously or as bolus via convection-enhanced delivery (CED). We screened combinations of amino-acid substitutions at the (IL-12)Fc:FcRn binding interface to abolish this interaction. Brain and blood concentrations were assessed via ELISA or cytokine bead arrays. FcRn affinity was measured by SPR/ELISA and bioactivity tested on PBMCs and human GBM explant cultures. Treatment efficacy and immunological correlates were assessed in GBM bearing mice. FcRn is upregulated in human and mouse GBM and contributes to brain export and subsequent peripheral recycling of IL-12Fc in the blood. IL-12Fc with abrogated FcRn binding due to a unique set of substitutions is fully functional and appears brain compartment locked (CL IL-12) as it exhibits enhanced tissue retention and reduced serum levels upon local injection, reaching up 100x higher brain to serum concentration ratios than regular IL-12. Compared to its non-modified counterpart, murine CL IL-12 shows significantly higher treatment efficacy at negligible systemic footprint in late stage murine GBM. In patient explant cultures, human CL IL-12 leads to successful inflammatory conditioning. Compartment locked IL-12 should thus allow a wide dosing window to fully harness its therapeutic potential for local GBM therapy.
DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?
Authors: Smith-Cohn Matthew , Burley Nicholas , Grossman Stuart
Published: November 2021

BACKGROUND

Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently.

METHODS

We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems.

RESULTS

We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions.

CONCLUSION

Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.
EPID-08. IMPORTANCE OF THE INTERSECTION OF AGE AND SEX TO UNDERSTAND VARIATION IN INCIDENCE AND SURVIVAL FOR PRIMARY MALIGNANT GLIOMAS
Authors: Wang Gi-Ming , Cioffi Gino , Patil Nirav , Waite Kristin , Lanese Robert , Ostrom Quinn , Kruchko Carol , Berens Michael , Connor James , Lathia Justin , Rubin Joshua , Barnholtz-Sloan Jill
Published: November 2021

BACKGROUND

Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States.

METHODS

Incidence data from 2000-2017 were obtained from the Central Crain Tumor Registry of the United States, which obtains data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance Epidemiology and End Results Program (SEER), and survival data from the CDC’s NPCR Registries. Age-adjusted incidence rates and rate ratios per 100,000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences.

RESULTS

Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI:1.01 - 1.07, p=0.003), increasing with age, peaking at 50-59 years (IRR:1.56, 95% CI: 1.53 - 1.59, p< 0.001). Females had worse survival for ages 0-9 (HR:0.93, 95% CI:0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR:1.36, 95% CI:1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma.

CONCLUSION

To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.
EPID-12. MITOCHONDRIAL DNA SEQUENCE VARIATION AND MENINGIOMA
Authors: Samanic Claudine , Teer Jamie , Thompson Zachary , Creed Jordan , Fridley Brooke , Nabors L Burt , Williams Sion L , Egan Kathleen
Published: November 2021

Meningiomas are the most common primary central nervous system tumors. Risk factors include female sex, African American race, a higher body mass index, and exposure to ionizing radiation. Genome-wide association studies have identified two risk loci for meningioma in the nuclear genome (rs12770228 and rs2686876). Whereas mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, research on meningioma is lacking. We examined the association of 42 common (minor allele frequency ≥ 5%) germline mtDNA variants, haplogroups, and genes with meningioma risk in 1,080 controls and 478 cases from a case-control study conducted at medical centers in the southeastern US. Participant DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for meningioma overall, WHO grade 1 (n=409) and WHO grade 2/3 (n=69) meningiomas. Overall, meningioma risk was significantly higher among women (OR=2.86; 95% CI:2.21-3.71) compared to men, higher among African Americans (OR=2.37, 95% CI:1.41-3.99) compared to Caucasians, and higher among those who were overweight (OR=1.48; 95% CI:1.11-1.98) or obese (OR= 1.73; 95% CI:1.26-2.38) compared to those of normal weight. The variant m.16362T >C (rs62581341) in the mitochondrial control region was positively associated with grade 2/3 meningiomas (OR=2.33; 95% CI: 1.14-4.79), but not with grade 1 tumors (OR=0.99; 95% CI:0.64-1.53). Haplogroup L, a marker for African ancestry, was identified among 3.6% of controls and 8.6% of cases and was associated with meningioma risk overall (OR=2.56; 95% CI:1.52-4.30). When stratifying by self-reported race, the association between haplogroup L and meningioma was only apparent among the small number of self-reported Caucasians with this haplogroup (OR=6.68; 95% CI=1.66-26.91) when compared to non-L haplogroups, combined. No other common mtDNA variant (minor allele >5%), haplogroup, or gene was associated with meningioma risk. These findings merit further study.
EPID-13. PREDICTIVE VALUE OF SERUM PROLACTIN LEVEL TO THE TUMOR SIZE RATIO FOR PREOPERATIVE DIAGNOSIS OF PROLACTIN-PRODUCING PITUITARY ADENOMA
Authors: Kim Jeong-Hwa , Choi Jung-Won , Seol Ho-Jun , Nam Do-Hyun , Lee Jung-Il , Hong Chang-Ki , Kong Doo-Sik
Published: November 2021

PURPOSE

Preoperative diagnosis of prolactinomas is critical because medication of dopamine agonists instead of surgical resection has been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating the prolactin producing adenoma or hyperprolactinemia-causing NFPAs. The author investigated the use of ratio of PRL levels to the tumor size as the optimal cutoff value for prolactin-producing tumor, comparing with the NFPA.

METHOD

We performed a retrospective review of patients who underwent the transsphenoidal surgery (TSS) for pituitary lesions in the single institute between January 2015 to May 2020. A total of 223 patients with hyperprolactinemia at the initial diagnosis were analyzed in the study, including NFPA patients (n=175) and prolactinoma patients (n=48). Receiver operating curve (ROC) analyses were performed for serum prolactin levels (PRL) and serum prolactin levels/tumor maximal diameter (PRL/MD).

RESULT

Prolactinoma group showed higher median values in serum PRL (258.6 μg/L) and smaller maximal tumor diameter (16.6 mm), compared to those of NFPA group (serum PRL 44.4 μg/L, p-value = 0.002 and MD 23.9 mm, p-value < 0.001). A moderate correlation was found between serum prolactin level and maximal diameters in prolactinomas (r=0.43, p=0.002), whereas a weak relationship was confirmed in NFPAs (r=0.17, p=0.028). The cutoff was 8.93 μg/L*mm (area under the curve [AUC] = 0.94) for PRL/MD and 99.43 μg/L for PRL (AUC = 0.91). In prolactinomas, there was no statistical difference between the PRL/MD of macroadenomas (n=36, 21.7μg/L*mm) and microadenoma (n=12, 16.8μg/L*mm) (p=0.109).

CONCLUSION

The serum PRL levels and tumor size exhibited stronger linear correlation in prolactinomas than in NFPAs. The PRL/MD ratio showed better diagnostic value for differentiating two pathologies than the serum PRL levels alone. These findings suggest PRL/MD ratio may be an alternative method to preoperative diagnosis of prolactinomas differentiating from hyperprolactinemia-causing NFPAs.
EPID-23. THE PAKISTAN BRAIN TUMOR EPIDEMIOLOGY STUDY: PAVING THE WAY FOR A NATIONAL BRAIN TUMOR REGISTRY
Authors: Shah Mashal , Baig Erum , Bajwa Mohammad Hamza , Laghari Altaf Ali , Bin-Anis Saad , Akhunzada Naveed Zaman , Gilani Jaleed , Jawed Noyan , Khalid Usman , Qadeer Namra , Lutfi Areeb , Tahir Izza , Bajwa Rameen , Rashid Huzaifa , Sadia Haleema , Ghazi Kinzah , Gillani Mishal , Azam Iqbal , Shamsi Uzma , Consortium Pakistan Brain Tumor , Siddiqi Sameen , Enam Syed Ather
Published: November 2021

INTRODUCTION

In Pakistan, brain tumor epidemiology has been examined in single-centre studies or as part of general cancer registries, which are limited by catchment area, age group, or are not specific to brain tumors. The Pakistan Society of Neuro-Oncology conducted a nationwide study to assess the distribution of brain tumor distribution and associated risk factors. This unfunded study explores data from across Pakistan and serves as a potential model for LMICs to emulate.

METHODS

A cross-sectional study was designed to include patients diagnosed with brain tumors in major neurosurgical centers in Pakistan retrospectively from January-December 2019. Patients, both alive and deceased, with a radiological diagnosis of a brain tumor were included. Data were recorded on a comprehensive online form from 35 centers, encompassing an estimated 85% of all the brain tumor patients seeking initial treatment by a neurosurgeon from the public and private sectors. Data collection was split into three regions: Sindh and Balochistan; Punjab; and Khyber Pakhtunkhwa and Islamabad. Data collection occurred between August 2020 and January 2021.

RESULTS

A total of 2750 brain tumor cases were recorded of which 1897 (69%) were diagnosed in the private sector hospitals. MRIs were a more common radiological study compared to CT scans. 2666 surgeries were performed, 174 individuals underwent chemotherapy and 479 underwent radiation therapy; approximately two-thirds of the patients that require adjuvant treatment are not able to receive it. Gliomas were the most common tumor, while pineal tumors were the least common. Findings indicate a low metastasis frequency and few females seeking care.

CONCLUSION

The study shows that brain tumors are mostly diagnosed and operated on in the private sector; the public sector should be more engaged. The study also highlights that despite inconsistencies in hospital records for brain tumor patients, reliable information can be collected in LMIC settings.
EPID-24. TRANSCRIPT: A cenTRAl NERVOUS SYSTEM CANCER CLINICAL tRIals PostmorTem
Authors: Kim Yeonju , Armstrong Terri , Gilbert Mark , Celiku Orieta
Published: November 2021

BACKGROUND

Despite the growing number of neuro-oncology clinical trials, there have been limited advances in the treatment of malignant primary central nervous system tumors. We surveyed the landscape of past, ongoing, and planned trials to assess trends in their interventions, outcomes, and design considerations to guide future studies.

METHODS

Data on interventional trials on ClinicalTrials.gov were accessed programmatically using AACT and R. Neuro-oncology trials were isolated using primary malignant brain tumor classification terms. Instrument names from PROQOLID were used to identify clinical outcome assessment (COA) use. Linear regression was used to assess chronological trends; power analyses utilized CBTRUS survival rates among trials investigating overall survival.

RESULTS

We identified 3039 interventional brain tumor trials that started between 1966 and 2025. Trials were most frequently phase II (43%), completed (40%), non-blinded (92%), single-group assignment (65%), non-randomized (51%) studies targeting glioblastoma (45%). Planned outcomes were reported by 93% of trials; this included adverse event or toxicity (54%), overall/x-year survival (44%), progression free survival (43%), maximum tolerated dose (16%), and objective response rate (14%). Evaluating the anticipated and actual trial enrollment, we estimate that only 10% and 8% of trial arms, respectively, were sufficiently powered to assess overall survival endpoints. 21% of trials mentioned the use of a COA (first trial initiated in 1992), majority of which were patient-reported outcomes. Among these, 25% and 58% reported COA as a primary or secondary outcome, respectively. The rate of COA use increased linearly over time at 1.1%/year but remained less than 5 trials per year until 2003. Ongoing work is investigating treatment mechanisms of actions and evidence of preclinical efficacy among brain tumor studies.

CONCLUSIONS

Low randomization rates and underpowered trial design may impede interpretability of efficacy. Increasing trends in COA use suggests cumulative influence of advocacy efforts to holistically evaluate net clinical benefit of interventions.
IMMU-02. GENOMIC AND TRANSCRIPTOMIC CORRELATES OF IMMUNOTHERAPY RESPONSE WITHIN THE TUMOR MICROENVIRONMENT OF LEPTOMENINGEAL METASTASES
Authors: Alvarez-Breckenridge Christopher , Prakadan Sanjay , Markson Samuel , Kim Albert , Nayyar Naema , Kuter Benjamin , Mora Joana , Shaw Brian , Lee Eudocia Quant , Chukwueke Ugonma , Cahill Daniel , Sullivan Ryan , Carter Scott , Shalek Alex , Brastianos Priscilla
Published: November 2021

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials utilizing either Pembrolizumab alone or the combination of Ipilimumab and Nivolumab. We investigated the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We isolated and sequenced 34,742 cells from both the malignant and immune compartment within CSF. Amongst the 19 patients included in the cohort, there were 13 pre-treatment and 24 post-treatment samples, and 9 patients were sampled across multiple timepoints. We detected dynamic changes in immune cell recruitment into the CSF and activation within 30 days of ICI, including increased effector T cell activation and IFN-gamma response pathways within T cells. Moreover, the overall level of IFN-gamma response and antigen processing within 30 days of ICI in malignant cells correlated with survival past clinical trial primary endpoint. Lastly, we observed evidence of longitudinal outgrowth of distinct immunogenic clones over the course of ICI. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and provides unique insights into the compartmental and temporal variation during the course of ICI. Moreover, our findings demonstrate the clinical utility of cell- free and single-cell genomic measurements for LMD research.
IMMU-08. NOVEL NANOPARTICLE-BASED DELIVERY OF H3.3K27M PEPTIDE TO TUMOR-ASSOCIATED MACROPHAGES ENHANCES THE TUMOR HOMING OF H3.3K27M-TCR TRANSDUCED T-CELLS IN HLA-A2/DR1 TRANSGENIC MICE WITH H3.3K27M+
Authors: Yamamichi Akane , Chuntova Polly , Kakihara Bunta , Chen Tiffany , Diebold David , Harada Naozumi , Akiyoshi Kazunari , Shiku Hiroshi , Okada Hideho
Published: November 2021

We have identified a novel HLA-A*02:01-restricted CD8 T-cell epitope encompassing the H3.3K27M mutation and a corresponding high-affinity T-cell receptor (TCR) that recognizes the epitope. While the development of adoptive cell transfer therapy using TCR-transduced T-cells holds a promise, we still need to overcome multiple challenges, such as suboptimal T-cell trafficking and the immunosuppressive environment of malignant glioma. For example, tumor-associated macrophages (TAMs) mediate immunosuppression but do not function as effective antigen-presenting cells. We have developed a novel cholesteryl pullulan (CHP) nanogel as a highly biocompatible and efficient vaccine delivery system targeting TAMs. In this study, we investigated whether the CHP nanogel loaded with the H3.3K27M peptide would deliver the peptide to TAMs and convert TAMs to better antigen-presenting cells that enhance the anti- H3.3K27M+ glioma activity of the TCR-transduced T-cells. As a clinically relevant mouse model, we used HLA-A2/HLA-DR1-transgenic mice and generated a syngeneic glioma cell line that expresses H3.3K27M from their astrocytes. We also generated a retroviral vector encoding the H3.3K27M-specific TCR for transduction of mouse T cells. HLA-A2/HLA-DR1-transgenic mice bearing day 16 intracerebral H3.3K27M+ glioma received an intravenous administration of the CHP nanogel along with poly-ICLC, a Toll-like receptor 3 agonist. The mice then received an intravenous infusion of TCR-transduced or control, non-transduced T-cells on the following day. The triple combination regimen with the CHP, poly-ICLC and TCR-transduced T-cells significantly suppressed the tumor growth, associated with increased levels of T-cell infiltration into the tumors compared with the dual-therapy with poly-ICLC and TCR-T-cells without the CHP. Furthermore, TAMs isolated from CHP-treated mice showed evidence of CHP-uptake, abilities to stimulate proliferation of TCR-transduced T-cells, and higher levels of HLA.A2 expression. These results suggest that the antigen-loaded CHP nanogel can promote the local antigen-presentation to T-cells and represent a promising approach for improving the efficacy of adoptive T-cell therapy for gliomas.
IMMU-32. IDENTIFICATION OF TUMOR-ANTIGEN SPECIFIC T CELLS AND THE EFFICACY OF IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA ANTIGENS DETERMINED USING CANCER IMMUNOGENOMICS APPROACH
Authors: Trivedi Vrunda , Yang Changlin , Yegorov Oleg , Dyson Kyle , Mitchell Duane
Published: November 2021

BACKGROUND

Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Owing to the heterogeneous nature and low mutation burden, identifying multiple antigens inherent to GBM that may serve as targets for immune-based therapies is attractive. Our aim is to develop a personalized immunotherapy approach using cancer immunogenomics for prospectively identifying neoantigens and uniquely expressed tumor proteins and then selectively expanding T cells against these truly tumor-specific antigens and dendritic cell vaccines to boost the T cell responses.

METHODS

RNAseq and WES was performed for murine KR158-luc GBM tumor. Using a cancer immunogenomics approach that we developed, called the O pen R eading Frame A ntigen N etwork (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer testis and developmental antigens, that are aberrantly over-expressed in KR158-luc tumor. All predicted genes were subjected to a gene enrichment strategy and an mRNA library was generated containing predominantly only the target genes but had some background non-specific genes (validated by RNAseq). KR158-luc tumor bearing animals were then treated with dendritic cells loaded with the tumor antigen specific mRNA library. Tumor volume and thus progress was determined using in vivo luciferase imaging technique. Additionally, tetramers specific to several of the predicted antigens were manufactured and the frequency of antigen specific T cells was determined using flow cytometry.

RESULTS

The dendritic cell vaccines were effective in delaying the progression of KR158-luc tumors and we identified T cells targeting several of our predicted antigens in the tumor bearing animals. The antigen specific T cells were detected in the tumor infiltrating lymphocytes as well as in the peripheral lymph organs.

CONCLUSION

We developed a dendritic cell-based vaccination approach targeting all neoantigens and TAAs identified as being tumor-specific and validated our developed immunogenomics pipeline by identifying antigen-specific T cells in the tumor bearing animals against novel GBM antigens.
IMMU-36. B CELL-VACCINE ELICITS LONG TERM IMMUNITY AGAINST GLIOBLASTOMA VIA ACTIVATION AND DIFFERENTIATION OF TUMOR-SPECIFIC CD8+ MEMORY T CELLS
Authors: Hou David , Castro Brandyn , Dapash Mark , Rashidi Aida , Zhang Peng , Han Yu , Lopez-Rosas Aurora , Lesniak Maciej , Miska Jason , Chang Catalina
Published: November 2021

While immunotherapy is used clinically to treat many cancers, its translation into brain tumors remains elusive. The importance of B cells in cancer immunity has become increasingly clear, and we previously developed a B cell-based cellular vaccine (BVax) against glioblastoma (GBM) by further activating 4-1BBL+ B cells with CD40 agonism and IFNγ. BVax were characterized as professional antigen-presenting cells (APCs) that promote CD8+ T cell migration and persistence in murine tumor-bearing brains. This study seeks to understand the mechanisms underlying BVax-induced CD8+ T cell fitness in the tumor microenvironment. Initial transcriptomic analysis highlighted that Bvax express high levels of IL15Rα, indicating their potential ability to trans-present IL15. Considering IL15 trans-presentation is fundamental in T-cell memory differentiation, we used BVax to induce T cell activation in the presence of exogenous IL15. BVax were better capable of activating antigen-specific CD8+ T cells and promoting a memory phenotype when compared to other professional APCs such as dendritic cells (DCs). T cell receptor (TCR) CDR3β sequencing showed that BVax expanded a number of TCR clones in-vitro that were found in brains of CT2A tumor-bearing mice in-vivo. These BVax-activated CD8+ T cells displayed a stronger antigen recall response and unique metabolic profile compared to DC-activated CD8+ T cells as shown by metabolomic analysis of tumor-infiltrating CD8+ T cells. When comparing the anti-tumor effects of CD8+ T cells activated by various APCs, BVax with exogenous IL15 promoted CD8+ T cells that displayed the most potent cytotoxicity against GBM cells in-vitro. Collectively, this study suggests that the IL15/IL15Rα axis and interactions with CD8+ T cell are key factors of BVax therapy in promoting a robust survival benefit and long-term immunologic memory against GBM in preclinical models. Additionally, the development of T cell therapies based on B cell licensing can be a promising future approach for glioblastoma therapy.
IMMU-47. THE ANTIGENIC PROFILE OF MURINE AND HUMAN MEDULLOBLASTOMA
Authors: Yang Changlin , Trivedi Vrunda , Dyson Kyle , Yegorov Oleg , Mitchell Duane
Published: November 2021

BACKGROUND

Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies. We performed a multi-faceted computer algorithm, the Open Reading Frame Antigen Network (O.R.A.N.), on medulloblastoma transcription profiles and predicted antigens across a broad array of antigen classes.

METHODS

Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Preclinical models- sonic hedgehog driven (Ptch1) and Group 3 MYC-driven (NSC) medulloblastoma were derived from C57BL6 murine strain with known MHC haplotypes. Only expressed mutations such as single nucleotide variations, small indels, gene fusions, and personalized TAAs were used for antigenic epitope predictions. Patient-specific or murine tumor associated antigens (TAA) were selected only if expressed >1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database (29 organs or sub-regions, n=9,141) or a mouse normal tissue database (ENCODE, n=99) was below 1 TPM, respectively. TAA sequences were passed through eight MHC class I and four MHC class II affinity algorithms. All epitopes were screened against a customized human or murine proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Immune deconvolution with single cell RNASeq integration was leveraged for teasing out medulloblastoma immunologic landscape.

RESULTS

MB patients harbor MHC-I restricted 1.9 SNV, 0.1 Indel, 0.5 gene fusions and MHC-II restricted 2.5 SNV, 0.1 Indel and 0.5 gene fusion. 79.4% patients have at least 1 neoantigen. 88.2% patients have at least one immunogenic TAA. Importantly, cancer testis antigens and previously unappreciated neurodevelopmental antigens were found expressed across all medulloblastoma subgroups. We predicted 6 neoantigens and 14 TAAs for murine NSC tumor and 19 neoantigens and 13 TAAs for Ptch1 tumor. CONCULSION: Using a custom antigen prediction pipeline, we identified potential human and murine tumor rejection antigens with important implications for development of medulloblastoma cellular therapies.
IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY
Authors: Ogando-Rivas Elizabeth , Castillo Paul , Jones Noah , Trivedi Vrunda , Drake Jeffrey , Dechkovskaia Anjelika , Candelario Kate , Yang Changlin , Mitchell Duane
Published: November 2021

BACKGROUND

Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms.

METHODS

Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides.

RESULTS

CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= < 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004).

CONCLUSION

In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.
INNV-01. THE CASE OF LEPTOMENINGEAL CARCINOMATOSIS RELATED HYDROCEPHALUS MANAGED WITH SYSTEMIC AND INTRATHECAL CHEMOTHERAPY
Authors: Hrachova Maya , Mrugala Maciej
Published: November 2021

INTRODUCTION

Leptomeningeal carcinomatosis (LC) is an end-stage sequela of metastatic cancer that commonly leads to severe neurological symptoms due to hydrocephalus and commonly treated with surgery or radiation. As these procedures are invasive and have associated risks, chemotherapy could be a great alternative. We report a case of a hydrocephalus related to LC in a patient with Stage IV breast cancer that resolved after the administration of HD-MTX and intrathecal cytarabine.

CASE

A 64-year-old right-handed woman with Stage IV ER positive, PR positive, HER2 negative invasive lobular carcinoma of the left breast on chemotherapy with palbociclib and alpelisib who presented with mild occipital headaches, diplopia and imbalance. Imaging revealed an extensive abnormal leptomeningeal enhancement withing the posterior fossa compatible with leptomeningeal carcinomatosis. CSF cytology was consistent with metastatic adenocarcinoma. Liquid biopsy detected circulating tumor cells. During the admission for the cycle 1 of systemic chemotherapy with HD-MTX and intrathecal cytarabine, neurological status deteriorated as she became stuporous due to the newly developed moderate obstructive and communicating hydrocephalus. Surgical innervation was considered but given her response to serial Ommaya taps and dexamethasone, we proceeded with observation. Symptomatic improvement was noted within few days and confirmed on imaging showing the resolution of previously seen hydrocephalus.

DISCUSSION

This case highlights the role of non-invasive combination of systemic and intrathecal chemotherapy in patients with LC-related hydrocephalus aimed to preserve patient’s quality of life. No relevant disclosures.
INNV-06. BRAF AND MEK DUAL INHIBITORS THERAPY IN RECURRENT OR ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)
Authors: Kata Karolina , Quintero Juan Carlos Rodriguez , Arevalo-Espejo Octavio , Bhattacharjee Meenakshi Bidwai , Ware Cornelius , Dono Antonio , Riascos-Castaneda Roy , Tandon Nitin , Blanco Angel , Esquenazi Yoshua , Ballester Leomar Y , Amsbaugh Mark , Day Arthur L , Zhu Jay-Jiguang
Published: November 2021

BACKGROUND AND OBJECTIVE

Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity.

METHODS

Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0.

RESULTS

Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected.

CONCLUSION

BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.
INNV-08. LOW AND INTERMEDIATE GRADE GLIOMA UMBRELLA STUDY OF MOLECULAR GUIDED THERAPIES (LUMOS) STUDY
Authors: Kong Benjamin , Sim Hao-Wen , Amanuel Benhur , Day Bryan , Buckland Michael , Verhaak Roel , Yip Sonia , Johns Terrance , Lwin Zarnie , Rosenthal Mark , Nowak Anna K , Barnes Elizabeth H , Scott Andrew M , Parkinson Jonathon , Jeffree Rosalind , Lourenco Richard De Abreu , Lau Peter , Whittle James , Hovey Elizabeth , Cher Lawrence , Kichendasse Ganessan , Hall Merryn , Robinson Cleo , Thomas Marc , Giardina Tindaro , Tu Emily , Khasraw Mustafa , Koh Eng-Siew , Gan Hui
Published: November 2021

BACKGROUND

Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space.

METHODS

LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician.

RESULTS

Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed.

CONCLUSION

LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.
INNV-19. NAVIGATING GLIOBLASTOMAS THE DIGITAL WAY: AN OBSERVATIONAL OVERVIEW OF THE USE OF A SMARTPHONE WEB APPLICATION IN A GBM PATIENT POPULATION
Authors: Fine Catherine , Brown Jon , Tozour Erin , Mason Chris , Wels Stephanie , Radick Zack , Tucker Simon , Bilstein Alex , Gottlieb Jordan , Lee Tammy , Devitte Ashley , Corbett Kevan , Scherer Stefan , Meyerrose Todd
Published: November 2021

There is limited data regarding the use of digital resources in the neuro-oncology clinic, and more specifically within the glioblastoma (GBM) patient population. Studies show that smartphone applications are feasible as a resource to improve patient-reported outcomes, produce actionable provider data, and actively engage patients in their care, leading to patients being empowered in their choices, apt to adhere to recommendations and producing quality conversations with providers. Navio, an oncology digital health company, helps patients, providers, researchers, and industry collaborators by offering personalized treatment regimens, appointment reminders, help with medication use, diagnosis education, resources, and a means to record quality of life and patient-generated health data, which can be surfaced in real-time to oncology care teams. Seventy-seven patients with a GBM, ages 25-74 years, who were beginning or receiving treatment, were invited via SMS text to access the Navio web application. Nine different GBM treatment plans and 10 different countries were represented among the patients. Patients were allowed unlimited access to all modules and encouraged by text to re-engage, at Navio-defined key moments. Of the invited patients, 58 / 77 (75 %) successfully self-onboarded to Navio’s app. Of the 58 patients onboarded, 77 % continued to engage with the application at various time points past day 1 and as far out as day 180. Engagement was seen across all age groups. Navio was able to re-engage 60 % of all patients who had 7 days of inactivity. Oncology digital resources, such as Navio’s app, are of increasing interest to gather and surface real-time data, and support patients outside of traditional clinic visits. Although early, Navio’s application represents a unique and expanding opportunity to engage and empower GBM patients, specifically during key treatment moments, to provide information for patients and their oncology care teams, and most importantly, to improve patient outcomes.
INNV-24. METASTATIC HEMANGIOPERICYTOMA TO THE LIVER: DEFINING THE IMPORTANCE OF NAB-STAT2 FUSION
Authors: Sefler Megan , Khagi Simon
Published: November 2021

BACKGROUND

Meningeal hemangiopericytoma (HPC) is a rare and aggressive vascular tumor which typically occurs in younger adults and has a tendency for local recurrence with delayed metastases outside the CNS. HPC is considered a variant of solitary fibrous tumor (SFT), and is associated with the presence of the fusion oncoprotein NAB2-STAT6. This fusion results in over-expression of the EGR1 gene and results in tumorigenesis.

CASE REPORT

We present a case of a 49 y/o female with a remote history of left occipital lobe HPC, initially treated with resection and radiotherapy in 2007, who presented with symptoms of right upper quadrant abdominal pain. She was found to have a hypervascular 7 cm mass in the right upper lobe of the liver on magnetic resonance imaging (MRI) studies and subsequently underwent hepatectomy for removal of the mass. Histopathological findings revealed metastatic HPC with features consistent with her primary meningeal tumor that was removed over 13 years agoearlier. Presence of the NAB2-STAT6 fusion was confirmed by targeted genomic analysis. MRI revealed a small focus of nodular enhancement abutting the confluence of the superior sagittal sinus and transverse sinus. This was considered her source of disease and possible dissemination. She was treated with stereotactic radiosurgery to target the lesion.

DISCUSSION

Given the rarity and often remote medical history of the primary intracranial HPC, this report suggests that 1) long term follow up of HPC is essential and 2) detection of the NAB2-STAT6 fusion can identify and confirm recurrent HPC at metastatic sites. In regards to the latter, distinguishing HPCs from other more benign spindle cell tumors that may mimic SFT (such as fibroblastic meningiomas) is also of therapeutic significance as HPCs typically require adjuvant treatment, (i.e. radiotherapy) as opposed to surgical resection alone.