bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMIC-18. ROLE OF DISCOIDIN DOMAIN RECEPTORS (DDR1/DDR2) IN SENSITIZATION OF GLIOMAS TOWARDS RADIOTHERAPY
Authors: Syed Mohammad Faisal , Comba Andrea , Varela Maria Luisa , Argento Anna , Brumley Emily , Abel Clifford , Castro Maria , Lowenstein Pedro 
Published: November 2022

Abstract
Glioblastoma (GBM), a high-grade glial tumor, is highly aggressive and is characterized by intra-tumoral heterogeneity and widespread infiltration, impairing therapeutic success. Our laboratory discovered dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal features called “oncostreams” inside GBM tumors that facilitate invasion into the normal brain. We found that collagen 1α1 (Col1A1) is essential for oncostream structure and function. Using in vivo intravital imaging and ex vivo explant glioma models, we established that Col1A1 suppression abolishes oncostreams, reprograms the malignant histopathological phenotype, and extends median survival in mice. However, the signaling through which collagen communicates to maintain an invasion-permissive glioma tumor microenvironment remains unclear. We propose to analyze a poorly understood collagen receptor family -the discoidin domain receptors (DDRs) - which is expressed in glioma and perivascular stromal cells. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) data suggest DDR1/DDR2 overexpression correlates with tumor progression and poor prognosis in glioma patients. Our RNA-seq data further confirm overexpression of DDRs in NPA and NPD glioma compared to the normal brain. Our preliminary data suggests that inhibiting collagen receptors DDR1 or DDR2 sensitizes glioma cells to radiotherapy (IR). DDR1 inhibition completely disrupts oncostreams` structure in the ex vivo explant glioma model. Moreover, pharmacological inhibition of DDR1 combined with irradiation significantly enhances the median survival of NPA (Nras, shP53, shATRX) tumors in an orthotopic mouse glioma model. Furthermore, we are currently testing whether inhibition of DDR1 using a genetically engineered mouse model (GEMM) of glioma called NPAD1 (Nras, shP53, shATRX, shDDR1) will show an increase in overall survival. We hypothesize that blocking collagen receptors DDR1 or DDR2 will control tumor growth, invasion and mediate anti-glioma immunity. This study will eventually uncover a novel therapeutic treatment for GBM, targeting DDR1 and DDR2 in human patients.
MODL-39. CHARACTERIZING NON-ENHANCING TUMOR USING MULTI-SHELL DIFFUSION MRI
Authors: Golkar Ehsan , Parker Drew , Brem Steven , Verma Ragini 
Published: November 2022

Abstract
Characterizing infiltration in the non-enhancing tumor (NET) is clinically crucial as infiltration leads to progression, and a reduction in survival times. As voxel-wise biopsy of these regions is infeasible, a non-invasive MRI-based identification of infiltration would be a significant contribution. Diffusion MRI (dMRI), with its ability to model different levels of water restriction, as is caused by infiltration and edema, is well positioned to model the NET. This is achieved via multicomparment modeling (MCM) of the dMRI where infiltration, vasogenic edema and healthy tissue (with complex fibers) form the different compartments. Current MCM approaches are either not designed for NET or rely on advanced MRI scans currently not feasible in the clinic. The simplest ball-tensor models, including Hoy 2014 using multi-shell data and FERNET 2020 for single-shell data, consists of a free water compartment that models vasogenic edema and a tensor modeling underlying tissue. These single-tensor methods cannot model complex WM fibers. Our proposed model consists of two steps. First, two bundles are fit: an isotropic bundle with two balls that model isotropic free diffusivity and restricted diffusivity, and a bundle containing stick and zeppelin, corresponding to intra-cellular and extra-cellular diffusion of axons, respectively. Next, a fiber orientation distribution (FOD) is estimated from the fitted parameters. We applied our modeling to multi-shell data from eight patients with glioblastoma, and one patient with a metastatic brain tumor. Our method produces maps corresponding to free water (CSF), restricted diffusion, intra-cellular, and extra-cellular volume fractions. Preliminary results show that restricted diffusivity map of NET comprises 46% of vasogenic metastatic edema compare to 15% of infiltrated GBM edema. In conclusion, we demonstrate that our proposed model shows promise to characterize the NET region of various brain tumors, and distinguishing tumor types. These compartments will provide invaluable radiomic features that no other modality can capture.
CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA
Authors: Messinger Dana , Harris Micah , Cummings Jessica , Thomas Chase , Yang Tao , Sweha Stefan , Woo Rinette , Siddaway Robert , Burkert Martin , Stallard Stefanie , Qin Tingting , Mullan Brendan , Siada Ruby , Ravindran Ramya , Niculcea Michael , Dowling Abigail , Bradin Joshua , Ginn Kevin , Gener Melissa , Dorris Kathleen , Vitanza Nicholas , Schmidt Susanne , Spitzer Jasper , Li Jiang , Filbin Mariella , Cao Xuhong , Castro Maria , Lowenstein Pedro , Mody Rajen , Chinnaiyan Arul , Desprez Pierre-Yves , McAllister Sean , Dun Matthew , Hawkins Cynthia , Waszak Sebastian , Venneti Sriram , Koschmann Carl , Yadav Viveka 
Published: November 2022

Abstract
Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis. The mechanism behind tumor invasion is currently not well understood. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. Whole exome, RNA, and ChIP-sequencing were performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Additional in vitro experiments were performed to determine a potential mechanism of action for CBD-mediated effects. Self-reported CBD dosing information was collected from DMG patients. We found that increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates a similar epigenetically active state at ID1 regulatory regions in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell migration, tumor growth, and to a lesser extent invasion in both murine IUE and multiple patient-derived in vivo DMG models, improving mouse survival. ID1 knockdown significantly decreases the effect of CBD on migration, tumor growth, and invasion. CBD increases reactive oxygen species production, which also affects DMG cell proliferation in a non-ID1 mediated manner. Overall, we find that H3K27M-mediated reactivation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
RADT-05. VOLUMETRIC MODULATED ARC THERAPY CRANIOSPINAL IRRADIATION UTILIZING A VERTEBRAL BODY SPARING APPROACH: A DOSIMETRIC ANALYSIS
Authors: Matsui Jennifer , Perlow Haley , Ewing Ashlee , Cadieux Catherine , Blakaj Dukagjin , Beyer Sasha , Thomas Evan , Raval Raju , Palmer Joshua 
Published: November 2022

Abstract

BACKGROUND
Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral-body-sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. We hypothesize that VBS-CSI utilizing volumetric modulated arc therapy (VMAT) will effectively reduce vertebral body dose while minimizing dose to surrounding organs-at-risk (OAR) for adult patients with LMD.

METHODS
Ten adult patients with LMD received CSI, 30 Gy in 10 fractions. These patients were initially treated with a variety of VMAT and IMRT treatment techniques. These patients were then retrospectively replanned using VMAT VBS-CSI. For their VBS-CSI replan, full VMAT arcs for the brain fields matched to two spine isocenters for the upper and lower spine were created utilizing limited posterior arcs. The PTV was created with margins of 3mm uniformly around the brain contour and 7mm around the spinal canal. To further decrease the vertebral body dose, an avoid entry and exit contour was created. This structure was a margin on the PTV anteriorly designed to carve dose out of the vertebral bodies while still maintaining coverage to the PTV.

RESULTS
All 10 patients had a reduction in vertebral body dose with VMAT VBS-CSI when compared to their initial plan. The mean vertebral dose for the VBS-CSI plans had an average reduction of 33% compared to the initial plans. The mean dose to the small bowel and esophagus were reduced by 46% and 67%, respectively.

CONCLUSIONS
VBS-CSI may be utilized to minimize dose to surrounding OARs and vertebral bodies. In this study, VMAT VBS-CSI led to significant reductions in vertebral body dose while also minimizing dose to other OARs. VMAT VBS-CSI may be an acceptable alternative to proton-based VBS-CSI in an adult population with LMD. Prospective evaluation is warranted.
CTIM-01. TITLE: PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD): PRELIMINARY RESULTS
Authors: Pina Yolanda , Chen Ann , Arrington John A , Macaulay Rob , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Wallace Gerald , Evernden Brittany , Stewart Christine L , Khushalani Nikhil , Smalley Inna , Smalley Keiran , Vogelbaum Michael , Yu Michael , Forsyth Peter 
Published: November 2022

Abstract

BACKGROUND
LMD from systemic cancer has a dismal prognosis with median survivals of 8-10 weeks. A phase 2 trial of PD-1 inhibitor monotherapy in LMD showed median overall survival (OS) of 3.6 months (Brastianos P et al., 2020). We determined the safety/efficacy of avelumab, a PD-L1 inhibitor with WBRT in patients with LMD (NCT0371768). This combination can treat the tumor directly and increase BBB permeability (Li, 2003; Nordal, 2005) allowing the increased egress of activated T cells into the meninges/CSF.

METHODS
Patients received concurrent avelumab 800 mg IV q2 weeks for ≤ 5 cycles (unless PD or unacceptable toxicity) with WBRT 3000 cGy in 10 fractions. Primary endpoints are safety/DLTs and OS at 3 months. Secondary endpoints are CSF T-cell/cytokine profiles (scRNAseq, phosophoproteomics etc.).

RESULTS
A total of 15 patients (7 breast, 7 lung & 1 other) were enrolled (n = 13 F, ages 32-79). Pts receiving anti-PD-1/PD-1L/PD-L2/CD137,CTLA-4 therapy ≤ 6 months prior were excluded. Three of 15 patients had grade 3/4 AEs (diarrhea, lymphopenia, decreased WBC count in 3 patients). Seven patients (50%) were alive at 3 or 6 months. The estimated median follow up in 14 patients is 4.75 months (range, 0.92 – 30.05 months, 95% CI is 1.32 ~ 19.82). The median PFS is 3.75 months (95% CI = 0.85-15.16) and median OS is 6.89 months (95% CI = 1.18-14.7).

CONCLUSIONS
The combination of avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF (analysis underway) will determine mechanisms of LMD therapeutic/resistance effects.
CTIM-29. PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GBM: IDENTIFICATION OF TREATMENT-INDUCED CD8+CD107A+ CD57+ PD-1- MEMORY T-CELLS THAT ARE ASSOCIATED WITH INCREASED SURVIVAL
Authors: Peereboom David , Lindsay Ross , Badruddoja Michael , Nabors L Burt , Kumthekar Priya , Lieberman Frank , Tran David , Phuphanich Surasak , Schiff David , Sherman Jonathan , Butowski Nicholas , Dunbar Erin , Fink Karen , Iwamoto Fabio , Moertel Christopher , Schulder Michael , Walbert Tobias , Habboubi Nassir , Grzegorzewski Krzysztof , Brooks Christopher , Reardon David A 
Published: November 2022

Abstract
Recurrent glioblastoma (GBM) is an aggressive disease with poor survival and limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM antigens IL-13Rα2, ephrinA2, and survivin. Here we describe an 18-color flow cytometry analysis from stage 2 of a Ph2 clinical trial of SL-701+poly-ICLC+bevacizumab (NCT02078648), in which 12-month overall survival (OS) was 50%. Of the 27 patients in stage 2, 24 (89%) developed heterogeneous T-cell responses against 1, 2, or 3 of the SL-701 CD8 peptides. Magnitude and kinetics of peptide responses were variable among these patients with no clear relationship to OS. Therefore, a phenotypic analysis of the T-cell response in all 27 patients was conducted using terraFlow, a unique data analysis approach utilizing machine learning to identify T-cell phenotypes associated with clinical response from all possible combinations of markers. In total, 10,184 unique SL-701 induced phenotypes were measured, including 223 phenotypes (P &lt; 0.05) and 16 core phenotypes that uniquely represent differences between patients with OS above or below 12 months (P &lt; 0.05). 50% of the core phenotypes were CD8+ CD57+ CD107a+ PD-1- SL-701-specific T-cells, which are highly-differentiated memory T-cells primed for cytotoxicity. The frequency of the CD57+ core phenotypes (8%-18%) was enhanced 1.6- to 2.3-fold in patients with an OS &gt; 12 months (P &lt; 0.05). Similarly, 2 core phenotypes identified cytotoxic CD4+ and CD8+ T cells, which were enhanced 1.9- and 2.5-fold in patients with an OS &gt;12 months. The final 6 core phenotypes identified activated CD4+ CD154+ SL-701-specific T-cells (5%-19%) that were enhanced 0.3- to 0.5-fold in patients with an OS &lt; 12 months (P &lt; 0.05), suggesting helper T-cell responses in the absence of cytotoxic T-cell responses are associated with an OS &lt; 12 months. Deep sequencing of SL-701-specific T-cells using whole transcriptome-based molecular cytometry is planned.
CTIM-34. PRELIMINARY SAFETY AND EFFICACY DATA ON TWO PATIENTS WITH RELAPSED/REFRACTORY CNS LYMPHOMA TREATED WITH EMAVUSERTIB (CA-4948) AND IBRUTINIB COMBINATION: A SUBSET ANALYSIS OF TAKEAIM LYMPHOMA TRIAL
Authors: Iqbal Madiha , Tun Han , Joffe Erel , Grommes Christian , Nowakowski Grzegorz , Lunning Matthew , Ramchandren Radhakrishnan , Li Chia-Cheng , Zhao Wanying , Martinez Elizabeth , von Roemeling Reinhard , Earhart Robert , McMahon Meaghan , Isufi Iris , Leslie Lori , Rosenthal Allison 
Published: November 2022

Abstract

BACKGROUND
Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL.

METHODS
This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy.

RESULTS
Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib.

CONCLUSION
In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.
CTIM-35. A PHASE II STUDY OF GITR AGONIST INCAGN01876 AND PD-1 INHIBITOR RETIFANLIMAB IN COMBINATION WITH STEREOTACTIC RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Bagley Stephen , Shabason Jacob , Mathew Divij , Kothari Shawn , Oldridge Derek , Desai Arati , Lustig Robert , Kurtz Goldie , Alonso-Basanta Michelle , Chen Kan , Long Qi , Harsch Jessica , Salman Muhammad , Fernandez Peter , Monsour Maikel , Prior Timothy , Maloney Eileen , MacMurtrie Eileen , Angeloni Natalie , O’Neill Meghan , Albright Karen , Caturla Maria , Ignatowski Melissa , Frangos Suzanne , Blessing Caroline , Phillips Richard , Nabavizadeh Ali , Mohan Suyash , Nasrallah MacLean , Jackson Christina , Brem Steven , Amankulor Nduka , Binder Zev , O’Rourke Donald , Wherry E John 
Published: November 2022

Abstract

BACKGROUND
We evaluated the combination of retifanlimab, INCAGN01876, and FSRT in patients with recurrent GBM.

METHODS
Phase II, single-center, 2 cohort study (A: single-arm non-surgical cohort; B, two-arm neoadjuvant/surgical cohort). Cohort A patients received pre-FSRT one-time doses of retifanlimab (500mg) and INCAGN01876 (300mg), FSRT (8 Gy x 3 fractions), and post-FSRT 28-day treatment cycles (retifanlimab, day 1; INCAGN01876, days 1, 15). Cohort B patients received pre-surgery doses of retifanlimab + INCAGN01876; subsequently, patients either went directly to resection (Sub-Arm 1) or to FSRT followed by resection (Sub-Arm 2). All patients resumed immunotherapy post-operatively. Primary endpoint: ORR in Cohort A. Data cut-off for this analysis was June 30, 2022.

RESULTS
Thirty-two evaluable patients: Cohort A, n=16; Cohort B, n=16 (Sub-Arm 1, n=8, Sub-Arm 2, n=8). Median follow-up time: Cohort A, 13.6 months; Cohort B, 8.8 months. Forty-four percent women, median age 64 (IQR, 55–65), 56% MGMT unmethylated. Most common grade 3/4 treatment-related AEs included cerebral edema (25%), lymphopenia (16%), and cognitive disturbance (13%). Efficacy in Cohort A: no objective responses observed, best response of stable disease achieved in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.8 months (95% CI 8.3 months – not reached [NR]). Efficacy in Cohort B: median PFS NR, median OS 15.1 months (95% CI 8.5 months – NR). Median PFS and OS are longer in Cohort B Sub-Arm 2 compared to Cohort B Sub-Arm 1 (PFS, NR vs. 2.2 months, p = 0.009; OS, NR vs. 8.5 months, p=0.026). Results of tissue and blood-based immune correlative analyses will be presented.

CONCLUSIONS
The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without surgical resection. Survival outcomes in the neoadjuvant cohort are encouraging, largely driven by patients that received neoadjuvant FSRT.
CTNI-10. RANDOMIZED PIVOTAL STUDY OF BLOOD-BRAIN BARRIER (BBB) DISRUPTION USING EXABLATE MODEL 4000 WITH STANDARD OF CARE (SOC) THERAPY IN NON-SMALL CELL LUNG CANCER (NSCLC) BRAIN METASTASES: LIMITLESS TRIAL
Authors: Ahluwalia Manmeet , McDermott Michael , Khosla Atulya , Sahgal Arjun , Mishra Mark , Achrol Achal S , Woodworth Graeme , Lipsman Nir 
Published: November 2022

Abstract

BACKGROUND
NSCLC is the most common cause of brain metastases. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy through the skull in noninvasive manner, thereby disrupting the BBB. There is preclinical evidence of synergy of FUS-mediated BBB with immunotherapy beyond improved drug delivery due to BBB disruption (BBBD).

METHODS
LIMITLESS is a prospective, multi-center, randomized, two-arm, controlled, pivotal clinical trial to evaluate the safety and efficacy of additional targeted BBB disruption using Exablate Model 4000 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy compared to Pembrolizumab alone in 2:1 randomization. The inclusion criteria include age ≥ 18 years, KPS ≥ 70, NSCLC (EGFR and ALK negative) with up to 3 brain metastases, one of which meets the RANO-BM criteria for measurable Disease (1 cm x 1 cm) with normal organ function. The primary endpoint is to test superiority of Exablate BBBD targeted to their brain metastases over the standard of care without Exablate BBBD as determined by Objective Response Rate (ORR) based on RANO- BM by 6 months. The secondary endpoints include best objective response rate and time to response for brain metastases by treatment arm. Other end points include progression-free survival (PFS), overall survival (OS), Intracranial and extracranial PFS, quality of life assessments. The Bayesian design statistical analysis will assume superior ORR of 60% in Exablate group compared to 30% in SOC group for a total sample size of 96 subjects (64 subjects in Exablate and 32 in SOC) for 80% power using a two-sided Pearson's Chi-Square test with alpha = 0.05. For the upper-bound estimate ORR of 45% in Exablate group and 30% in SOC group will need 369 subjects (246 subjects in Exablate and 123 in SOC).