bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-23. NEOANTIGEN-DIRECTED CELLULAR THERAPY IN A PRECLINICAL MOUSE MODEL OF MALIGNANT GLIOMA
Authors: Schaettler Max , Dunn Gavin 
Published: November 2021

Abstract
Adoptive cellular therapy in the form of CAR T cells or TCR engineered T cells has emerged as a novel approach in the treatment of both solid and hematologic malignancies. Neoantigens generated by tumor somatic mutations represent potentially attractive therapeutic targets in this context owing to their tumor-specific expression and circumvention of immunological tolerance. However, existing cell therapy systems generally target self-proteins or virally overexpressed antigens that fail to recapitulate the features of endogenous tumor neoantigens. Thus, there exists a need for a model in which tumor-specific neoantigens can be targeted via adoptive cellular therapy. Prior work from our lab identified the Imp3D81N mutation (mImp3) within GL261 as a neoantigen recognized by CD8 T cells in both intracranial tumors and draining cervical lymph nodes. To generate a system for targeting this neoantigen, we isolated and cloned mImp3-specific TCRs through a single-cell sort followed by a nested multiplexed PCR reaction. The specificity and functionality of these isolated TCRs was determined through introduction into a T cell hybridoma, identifying a top candidate based upon a high degree of cytokine production and specificity for the mutant epitope. A TCR transgenic mouse was then generated in which more than 90% of all T cells were CD8 T cells bearing this mImp3-specific TCR. T cells isolated from this mouse display specificity for the mImp3 peptide and display in vitro reactivity to GL261 and other cell lines in a mImp3-dependent manner. Therefore, this model represents the first TCR transgenic targeting a brain tumor neoantigen, opening the door for further investigation into cell therapy against this class of antigens.
IMMU-33. NEOANTIGEN-SPECIFIC T CELLS CAN INFILTRATE IDH-MUTANT LOWER GRADE GLIOMAS AND PERSIST IN THE PERIPHERAL BLOOD
Authors: Zhang Michael , Wang Cliff , Pan Zheng , Yuen Benjamin , Peng Songming , Kwok Darwin , Nejo Takahide , Martin Michael , Hong Chibo , Hilz Stephanie , Phillips Joanna , Shai Anny , Oberheim-Bush Nancy Ann , Hervey-Jumper Shawn , McDermott Michael , Mandl Stefanie , Okada Hideho , Costello Joseph 
Published: November 2021

Abstract
The prospect of using immunotherapy for IDH-mutant LGGs has been daunting given the immune-poor microenvironment and low mutational burden. We hypothesized that LGG-targeting T cells might still be present at low frequency and with limited regional infiltration into the tumor. To improve sensitivity, we combined high-density multi-region tumor sampling with high-throughput neoantigen-T cell screening for a patient with WHO Grade II diffuse astrocytoma who eventually progressed, at second recurrence, to anaplastic astrocytoma. We performed maximal-anatomic sampling from 10 distinct regions of the tumor at the initial resection, as well as single sampling at first recurrence, for exome-based prediction of clonal and subclonal expressed neoantigens, RNAseq-based estimation of regional immune cell composition, and T cell receptor (TCR) beta deep sequencing. Based on our predictions, we then generated a barcoded library of patient-specific peptide-HLA multimers loaded with predicted neopeptides. Using this library, neoantigen-specific CD8 T cells were captured and isolated from patient peripheral blood and subjected to single cell TCR sequencing. We screened patient-derived peripheral blood drawn two years after initial resection and identified five T cell clones recognizing three LGG neoepitopes. Two neoepitopes were derived from truncal, tumor-wide mutations, including a truncating splice-site mutation in TP53 and a missense mutation in MRPL46. Each of these neoepitopes were recognized by two distinct TCRs, consistent with TCR convergence. A third neoepitope was derived from a subclonal MRPL46 mutation. Using the TCR beta sequence as a molecular barcode, TCRs specific to the 2 clonal neoepitopes, but not the subclonal neoepitope, were detectable in the glioma and blood at initial resection, as well as in the recurrent glioma. In summary, we demonstrate the existence and persistence of neoantigen-targeting T cells within the blood and tumor of an IDH-mutant LGG patient. These findings suggest a feasible methodology to develop personalized T cell-based immunotherapies for IDH-mutant LGGs.
IMMU-53. STING-ING GLIOBLASTOMA WITH SPHERICAL NUCLEIC ACIDS
Authors: Mahajan Akanksha , Hurley Lisa , Tommasini-Ghelfi Serena , Dussold Corey , Stegh Alexander , Mirkin Chad 
Published: November 2021

Abstract
The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that are amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e.,the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently completed early clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway in vitro and in vivo. In a poorly immunogenic and highly aggressive syngeneic mouse glioma model, in which tumours were well-established, only one dose of intranasal treatment with STING-SNAs decelerated tumour growth, improved survival and importantly, was well-tolerated. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites via intranasal route, exploits the binding of dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.
INNV-02. ACCELERATING RESEARCH FOR BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL DISEASE THROUGH PATIENT-LED COLLABORATIONS
Authors: Hodgdon Christine 
Published: November 2021

Abstract

PATIENT-DRIVEN INITIATIVE OF THE METASTATIC BREAST CANCER (MBC) ALLIANCE
The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The project has grown to include 35 members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or LMD.

DISPARITIES FOR PATIENTS LIVING WITH BCBM & LMD
In the US, approximately 200,000 new cases of brain metastases are diagnosed each year.1 Approximately 10-15% of patients with MBC will develop brain metastases, and may be as high as 30-50% for certain subtypes.2 A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research.

VALUES & OBJECTIVES
The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (1) Increase the quality and quantity of basic research; (2) increase the number of clinical trials in areas where research is lacking; (3) diversify the type of clinical trial interventions; (4) eliminate restrictive eligibility criteria in clinical trials; (5) Incorporate clinically meaningful trial endpoints.

References
Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nat Rev. Clinical oncology vol. 8,6 (2011): 344-56. doi: 10.1038/nrclinonc.2011.58
Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35
INNV-14. PREDICTIVE UTILITY OF TEMOZOLOMIDE RESPONSE AS DETERMINED BY 3D EX-VIVO CELL CULTURE ASSAYS IN NEWLY DIAGNOSED GLIOBLASTOMA: A SINGLE INSTITUTION CASE SERIES EVALUATING PROGRESSION FREE SURVIVAL
Authors: Lipinski Lindsay J , Abad Ajay , Fenstermaker Robert A , Fabiano Andrew J , Prasad Dheerendra , Smith Ashley M , Gevaert Matthew , DesRochers Teresa M , Vibat Cecile Rose T 
Published: November 2021

Abstract
Glioblastoma is an aggressive tumor that is clinically and pathologically heterogeneous, and as such, remains challenging to treat. Response to initial standard treatment is widely variable and patient specific. We describe a cohort of 11 newly diagnosed patients enrolled in the 3D-PREDICT study at a single institution who underwent maximal safe surgical resection with tumor tissue collected prospectively for ex vivo cell culture assays against a panel of commonly used agents, including temozolomide. Nine of eleven patients received concurrent radiation + temozolomide followed by adjuvant temozolomide as per current standard of care. Two patients progressed immediately following concurrent chemoradiation; pseudoprogression was ruled out with short interval repeat imaging and clinical deterioration with pathology confirming recurrent tumor on re-resection in one patient. Median follow-up was 10 months (range 2-18). Outcomes were assessed retrospectively using Kaplan-Meier time-to-event curves, separating into two groups the temozolomide responders (n=4) and temozolomide nonresponders (n=7), as defined by the previously validated assay. The event was reached when radiographic tumor recurrence/progression occurred. Due to limited sample size, statistical significance was not reached, but a trend toward longer time to recurrence was noted among the temozolomide responder group. Continued experience with this tool may help clinicians predict which patients with newly diagnosed glioblastoma will respond well to initial treatment with temozolomide and those that may be more appropriate for clinical trial enrollment, independent of MGMT promoter methylation status. Longer term studies with a larger number of patients will help to determine the true significance of this drug response prediction assay.
INNV-20. RADIOGRAPHIC RESPONSE AND SEIZURE CONTROL IN IDH1 MUTANT GLIOMA PATIENTS USING IVOSIDENIB
Authors: Peters Katherine , Patel Mallika , Alford Candice , Chavez Gerardo , Kim Jung-Young , Durling Jennifer , Novack Tracy , Batich Kristen , Shoaf Madison , Hanzlik Emily , Affronti Mary , Johnson Margaret , Landi Daniel , Khasraw Mustafa , Desjardins Annick , Friedman Henry , Ashley David M 
Published: November 2021

Abstract
Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in grade II-III gliomas, and the mutant enzyme leads to the production of the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG is responsible for the gliomagenesis associated with these tumors and the promotion of seizures via glutamate receptors. Ivosidenib, a small molecule oral mIDH1 inhibitor, has shown promise in clinical trials to treat IDH1 mutant gliomas, and providers can utilize this agent in IDH1 mutant glioma patients. We evaluated our IDH1 mutant glioma patients treated off-label with ivosidenib and described the radiographic response and seizure control in this cohort when ivosidenib was initiated between October 2020 to February 2021. Radiographic response was determined using RANO criteria, and seizure control was determined by comparing seizures per month before and after initiation of ivosidenib. All patients represented received single-agent ivosidenib dosed at 500 mg orally once a day. One patient required a dose reduction to 250 mg orally once a day because of drug-induced diarrhea. In our cohort of six patients, patient age range was 31 to 74 years with four female patients and two male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=3) oligodendroglioma (WHO), IDH1 mutant, 1p19q co-deleted (n=2), and anaplastic astrocytoma IDH1 mutant (n=1). Three patients experienced a reduction of seizure frequency, two patients did not have seizures before or after therapy, and one patient remained with the same level of seizures (1 seizure/month). Radiographic responses recorded included three patients with stable disease, two patients with minor responses, and one patient with a partial response. Treatment with ivosidenib is ongoing for this cohort of mIDH1 glioma patients. Updated information on prolonged disease control and seizure control in this cohort of IDH1 mutant glioma patients will be presented. Therapeutics, such as ivosidenib, can lead to improved seizure control and radiographic outcomes in IDH1 mutant glioma patients.
PATH-18. INTEGRATING TUMOR MICROENVIRONMENT WITH GENOMIC ABERRATIONS AND TUMOR CLASS IN ADULT GLIAL/GLIONEURONAL TUMORS BY DECONVOLUTION OF BULK METHYLATION DATA
Authors: Singh Omkar , Aldape Kenneth , Pratt Drew 
Published: November 2021

Abstract
It is increasingly recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of non-neoplastic immune cellular components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data using methylCIBERSORT on 450k/850k methylation data from a set (n= 4057) of high- and low-grade glial and glioneuronal tumors. Using the cell type proportion data as input, we used dimension reduction (UMAP) to visualize sample-wise patterns of that emerge from the cell type proportion estimations. In glioblastomas (n= 2076) we identified distinct tumor clusters based on immune cell proportion and, interestingly, TME-based cluster groups demonstrated an association with specific genetic alterations such as EGFR amplification and/or CDKN2A/B homozygous deletion. Among 1178 IDH-mutant gliomas, clustering of tumors according to immune cell proportions led to 2 major subgroups, which largely aligned with 1p/19q co-deletion status. Among the non-codeleted tumors (IDH-mutant astrocytomas, N=734), clustering of immune cell decomposition revealed clusters which showed distinct proportions of a key genomic aberration in these tumors (CDKN2A/B loss). To investigate the possible role of monocyte proportion-relative gene expression and promoter methylation of the immune checkpoint PD-L1 and PD-L2 genes, we used a data subset (n=594) samples with matched gene expression profiles. We observed significantly high positive correlations (R=0.54 and 0.68, respectively) between monocyte proportion and expression of PD-L1 and PD-L2, in line with prior reports that monocytic cells can express these immune markers. Consistent with this, we found high negative correlations (R= -0.51 and -0.61, respectively) between monocytes and promoter methylation of PD-L1 and PD-L2, respectively. Overall, the findings highlight specific roles of the TME in biology and classification of adult CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic aberrations.
PATH-21. THE SINGLE-CELL PATHOLOGY LANDSCAPE OF PEDIATRIC GLIOMA
Authors: Messiaen Julie , Nasari Pouya , Van Herck Yannick , Verhaaren Ben , Sebastian Ivey , Milli Giorgia , Bosisio francesca , Pey Jon , De Vleeschouwer Steven , De Vloo Philippe , Depreitere Bart , Vanden Bempt Isabelle , Sciot Raf , Antoranz Asier , Jacobs Sandra , De Smet Frederik 
Published: November 2021

Abstract
High-grade glioma are the main cause of cancer-related death in children. Despite extensive research, their prognosis remains poor with very few treatment options. This can be attributed to the highly heterogeneous and plastic nature of glioma tumor cells and their interactions with the microenvironment, although quantitative data are still largely missing. Here, we used high-dimensional, multiplexed immunohistochemistry to map the spatial, single-cell tissue architecture of 31 pediatric glioma samples covering 9 histologic diagnoses. This novel approach allowed us to map the spatial distribution of the various tumoral subtypes, which typically occur in specific tumoral niches, and how these interact with their local immune-microenvironment. Finally, by aligning these findings to the clinical data of the patients and comparing these to adult glioblastoma, we are now able to more precisely describe the heterogeneous landscape of pediatric glioma at single-cell resolution.
PATH-32. EXTENT, PATTERN, AND PROGNOSTIC VALUE OF MGMT PROMOTOR METHYLATION: DOES IT DIFFER BETWEEN GLIOBLASTOMA AND IDH-WILDTYPE/TERT-MUTATED ASTROCYTOMA?
Authors: Teske Nico , Karschnia Philipp , Weller Jonathan , Siller Sebastian , Dorostkar Mario M , Herms Jochen , von Baumgarten Louisa , Tonn Jörg-Christian , Thon Niklas 
Published: November 2021

Abstract

INTRODUCTION
The cIMPACT-NOW update 6 introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear.

METHODS
We searched the institutional database for patients with: 1.) glioblastoma defined by histopathology; and 2.) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region.

RESULTS
We identified 224 patients with glioblastoma diagnosed based on histopathology, and 71 patients with IDHwt astrocytoma with pTERTmut (32 astrocytomas WHO grade II and 39 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two groups as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two groups. Surgery was associated with improved overall survival in IDHwt astrocytoma with pTERTmut. In patients treated with radiochemotherapy or radiotherapy, higher numbers of methylated CpG sites were associated with favourable outcome in both groups.

CONCLUSION
Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both groups, higher numbers of methylated CpG sites are associated with favourable outcome when radio/chemotherapy is administered. Surgery may form the basis for favourable outcome.
PATH-35. AKT1(E17K) MUTATIONS ARE FREQUENT GENOMIC EVENTS IN CERVICAL SPINAL MENINGIOMAS
Authors: Alkhatib Majd , Schackert Gabriele , Juratli Tareq 
Published: November 2021

Abstract

INTRODUCTION
Spinal meningiomas represent about one-third of all spine tumors. To date, little is known about the molecular profile of spinal meningiomas and their clinical impact. In this study, we correlate clinical parameters with targeted sequencing findings in a well-characterized cohort of 42 patients with spinal meningiomas.

METHODS
Samples from 42 spinal meningiomas (31 females and 11 males) were collected. Targeted sequencing for AKT1 E17K hot spot mutations was performed. Furthermore, clinical and imaging data were collected and correlated with the AKT1 mutation status.

RESULTS
Gross total resection (Simpson grade I /II) was achieved in all patients. The mean follow-up period was 60 months (6 –288 months). None of the patients demonstrated a tumor recurrence. AKT1E17K mutations were detected in 8 patients (19%), in five male and three female patients (p= 0.019). Although the majority of resected meningiomas (n= 28, 66.6%) were located in the thoracic spine, meningiomas originating in the cervical spine harbored significantly more AKT1 E17K mutations (6 out of 14, p= 0.010). Notably, all AKT1 mutated meningiomas arose ventrally or ventrolaterally to the spinal cord. The histologic examination revealed a WHO Grade 1 in 36 meningiomas (85.7%): 21 meningothelial, 8 psammomatous, 5 transitional, 2 fibrous. The remaining six meningiomas were classified as atypical WHO grade 2. Remarkably, AKT1 E17K mutations were significantly related to a meningothelial subtype (p= 0.044).

CONCLUSIONS
Our molecular study demonstrates that AKT1 E17K mutations are a frequent genomic event in spinal meningiomas. The majority of AKT1 mutated meningiomas occurred in male patients, originate in the cervical spine, and exhibit meningothelial histology.