bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-48. ANALYSIS OF PROTON RADIATION THERAPY INDUCED CONTRAST ENHANCEMENT: A SINGLE INSTITUTION, RETROSPECTIVE STUDY
Authors: Puri Sushant , Huang Ellen , Li Anne , Tarui Yurika , Redmond Kristen , Kut Carmen , Page Brandi , Croog Victoria , Laterra John , Kleinberg Lawrence 
Published: November 2024

Abstract
Proton radiotherapy (PRT) has superior physical dose distribution with a lesser integral off target radiation dose exposure compared with standard photon radiotherapy resulting in reduced toxicity of uninvolved normal tissues. However, there may be toxicity in areas targeted for high dose treatment as a result of uncertainty about the relative radiobiologic effect (RBE) of proton radiotherapy compared with photon radiotherapy and the potential for localized high doses at the end of the proton beam range (Bragg peak). This may result in radiation-induced contrast enhancement (RICE) reflecting transient toxicity or permanent injury, particularly when associated with concurrent chemotherapy. We analyzed 150 consecutive adult patients, with a histopathologic diagnosis of CNS malignancy, who underwent only PRT at Johns Hopkins Hospital between 2019 – 2023 with least 1 year of follow-up imaging. RICE was defined as a new post-treatment contrast enhancement on MRI within the radiation field. The determination of disease progression or RICE was confirmed with additional follow-up MRI or pathology. RICE was identified in 14 cases (9.3%). The median age was 48 y (range 19 – 72 years), sex 50% female. Diagnosis was 5 astrocytoma, 3 meningioma, 2 glioblastoma, 1 medulloblastoma, 2 oligodendroglioma, 1 tectal glioma. 4/5 astrocytoma patients were grade 2, 2/3 meningioma was grade 1, 1/3 was grade 2, 2/2 oligodendroglioma was grade 2. The median time since completing PRT to development of RICE was 3.5 months. The median radiation dose was 52.20 Gye (range 23.40 - 60.06). Dexamethasone was used in 11 patients (78 %) and in bevacizumab was used 2. Chemotherapy with temozolomide 7 (50%), PCV 1, and none in 5. 12 (85%) patients were still alive. PRT can also be associated with radiation injury in the target, and more information is needed about the incidence, natural history, and associations with localized dosimetry.
CTIM-01. OUTCOMES AND IMMUNE RESPONSES AFTER PEPTIDE VACCINATION TARGETING HUMAN CYTOMEGALOVIRUS ANTIGEN PP65 IN CHILDREN AND YOUNG ADULTS WITH RECURRENT HIGH-GRADE GLIOMA AND MEDULLOBLASTOMA: RESULTS OF A PHASE 1 TRIAL
Authors: Thompson Eric , Ashley David , Ayasoufi Kathy , Norberg Pam , Archer Gerald , Buckley Evan , Herndon James , Walter Ashley , Archambault Bridget , Balajonda Bea , Flahiff Charlene , Jaggers Denise , Gorski Laura , Vlahovic Gordana , Reap Elizabeth , Schroeder Kristin , Desjardins Annick , Johnson Margaret , Peters Katherine , Khasraw Mustafa , Mitchell Duane , Sampson John , Landi Daniel 
Published: November 2024

Abstract

INTRODUCTION
The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG.

METHODS
PEP-CMV is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV intradermally in the groin every two weeks for 3 doses, then monthly.

RESULTS
42 patients were enrolled. The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. The median number of prior chemotherapy regimens was 4 (range 1-15). Of the 38 patients who received PEP-CMV, the maximum grade adverse events (AE) possibly, probably, or definitely related to PEP-CMV were: 17 (45%) Grade 1 AEs, 16 (42%) Grade 2 AEs, 2 (5%) Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) Grade 4 AE (cerebral edema). One patient developed cytokine release syndrome (Grade 2). The median PFS was 2.5 months (95% CI:2.2, 3.2) and median OS was 6.4 months (95% CI:3.4, 7.9). The 12-month OS was 26.6% (95% CI:14, 41.1%). Of the 21 patients with evaluable immune monitoring data (received ≥3 vaccines/known CMV status), T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median 2 vs 22, P=0.01). PFS and OS were significantly better in patients with low levels of CD56brightCD16dim phenotype NK cells: P=0.029 and P=0.047, respectively. Patients with naïve CD8+ counts over the median had significantly better PFS (P=0.006).

CONCLUSIONS
PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%.
CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS
Authors: Yim Eunji , Donovan Laura , Bargo Alicia , Nayak Lakshmi , Odia Yazmin , Wong Eric , Pring Krystelle , Malig Mervin , Genfi Yacha , Wright Nathaniel , Kesari Lakshmi , Russ Alyssa , Chang Rae , Torres Denisse , Manjrekar Kriti Bagri , Ana Sarah Sta , Sender Naomi , Mistretta Suzanne , Iwamoto Fabio 
Published: November 2024

Abstract

BACKGROUND
Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS).

METHODS
Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion.

RESULTS
Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis.

CONCLUSIONS
Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.
CTIM-11. LONG-TERM SURVIVORS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Perez-Olle Raul , Pennock Greg K , Scott Charles , Andrews Carrie , Zilberberg Jenny , Hooper D Craig , Judy Kevin D , Exley Mark A , Andrews David W 
Published: November 2024

Abstract
Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers (BDCs) implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. The Phase 1b study enrolled 33 patients in four different cohorts implanted with 10 or 20 BDCs for 24 or 48 hours. Here we report on 6 subjects with survival beyond 4 years, including 5 subjects who survived 5 years or more (15.2%). There were 4 male and 2 female subjects, with a median age of 52 years (range 32-75). At diagnosis the MGMT promoter was methylated in 4 of 5 subjects that survived 5 years or more. We also report on T cell receptor Vβ CDR3 region sequencing of peripheral blood mononuclear cells and tissue infiltrated lymphocytes that was performed in a subset of 9 patients, including 3 subjects who survived beyond 4 years. Immune correlates of IGV-001 suggest an association between peripheral T cell clonal expansion and PFS/OS outcomes. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949) has completed enrollment and results are expected to be available in 2025.
CTIM-13. D2C7-IT IN COMBINATION WITH AN FC-ENGINEERED ANTI-HUMANCD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOLLOWED BY CERVICAL PERILYMPHATIC INJECTIONS (CPLIS) OF 2141-V11 IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)
Authors: Desjardins Annick , Chandramohan Vidya , Herndon James E II , Threatt Stevie , Bullock Chevelle , Bradbury Claire , Johnson Margaret O , Khasraw Mustafa , Low Justin T , Peters Katherine B , Shoaf Madison , Landi Daniel , Batich Kristen , Friedman Allan H , Friedman Henry S , Ashley David M , Knorr David , Osorio Juan , Ravetch Jeffrey , Bigner Darell D 
Published: November 2024

Abstract

BACKGROUND
The combination of D2C7-IT, an antibody toxin conjugate, and anti-mouseCD40 via CED generates robust antitumor immunity by killing tumor cells, activating microglia, reversing glioma-associated microglia and macrophage (GAMM)-mediated immune suppression, and empowering polyfunctional tumor antigen-specific CD8 T cells in glioma models. In addition to reprogramming GAMMs, anti-CD40 also activated dendritic cells and induced glioma-specific T cell responses in tumor draining lymph nodes. After establishing the phase 2 dose of the combination of D2C7-IT+2141-V11 when infused via CED, we initiated an assessment of the safety and efficacy of the combination of D2C7-IT+2141-V11 CED followed by repeated subcutaneous CPLIs of 2141-V11 ipsilateral to the tumor in patients with rGBM, IDH wild-type (NCT04547777).

METHODS
Eligible are adult patients with solitary supratentorial rGBM; ≥4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Patients are treated with D2C7-IT (166μg) and 2141-V11 (3mg), both infused via CED, followed by CPLI of 2141-V11 at 2mg at weeks 2 and 4 post D2C7-IT+2141-V11 CED, followed by every 3 weeks for 1 year and then every 4-6 weeks.

RESULTS
As of May 22, 2024, 18 patients with rGBM (median age of 54) were treated with D2C7-IT+2141-V11 CED followed by CPLIs of 2141-V11. 83% patients remain alive (range 3.3-14.8 months from start of D2C7-IT CED infusion) with a median of 8 CPLIs of 2141-V11 received (range 3-19). No study related grade 4 or 5 adverse events (AEs) were observed. Grade 3 AEs related to D2C7-IT and/or 2141-V11 include one each of hydrocephalus, headache, seizure, and cerebral edema. AEs related exclusively to CPLIs of 2141-V11 consist of grade 1 injection site reaction (n=16).

CONCLUSIONS
The addition of CPLIs of 2141-V11 post CED of D2C7-IT+2141-V11 is feasible and has shown an acceptable toxicity profile. The safety and efficacy results will be updated.
CTIM-16. SAFETY AND PRELIMINARY EFFICACY OF AZD1390 + RADIATION THERAPY FOR GLIOBLASTOMA
Authors: Wen Patrick , Yang Jonathan T , Imber Brandon S , Drappatz Jan , Jena Rajesh , Forst Deborah , Zukas Alicia , Short Susan C , Fan Chunling , Trigg William , Milner Alvin , Polanska Urszula M , Glover Colin , Stavraka Chara , Dalal Darshan , Karanovic Djuro , Chalmers Anthony J 
Published: November 2024

Abstract

BACKGROUND
Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. AZD1390, an ataxia telangiectasia mutated kinase inhibitor, aims to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood–brain barrier penetration, confirmed in healthy volunteers (NCT03215381) and patients with glioblastoma (Phase 0; NCT05182905). This Phase 1, open-label study (NCT03423628) evaluated safety and efficacy of AZD1390 and IMRT in patients with glioblastoma.

METHODS
Adult patients received escalating once-daily AZD1390 doses with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent glioblastoma) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly-diagnosed O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma). Patients received 2 additional weeks of adjuvant AZD1390 post-IMRT. Primary objective was safety; secondary objectives included efficacy and pharmacokinetics.

RESULTS
As of Feb 6, 2024, 115 patients (Arm A=75; Arm C=40) received AZD1390 10–900 mg/day. Pharmacokinetics were linear, with a slightly more-than dose-proportional increase and mean elimination half-life ~9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE), most commonly fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 patients. The maximum tolerated dose was 400 mg (Arm A) and 300 mg (Arm C). Dose-limiting toxicities included creatinine kinase elevation (Arm A) and radiation skin injury (Arm C). AEs led to AZD1390 discontinuation in 15/115 patients. Safety profiles were mostly consistent across Arms despite different radiation schedules. At target-engaging doses, median overall survival was 12.7 months (95% CI: 10.7–18.9; Arm A) and still maturing (Arm C).

CONCLUSIONS
Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment. Clinical investigation is ongoing.
CTIM-17. INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) FOR ADULTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE HEMISPHERIC GLIOMA
Authors: Van Gool Stefaan , Kosmal Jennifer , Van de Vliet Peter , Kampers Linde , Stücker Wilfried 
Published: November 2024

Abstract
Diffuse Midline Glioma (DMG, H3K27 mutant) and Diffuse Hemispheric Glioma (DHG, H3G34 mutant) are rare malignant CNS tumors with dismal prognosis. We retrospectively searched in our database for adults (&gt;18y) with molecularly define DMG/DHG, treated between May 2015 and 2024 with IMI as part of first-line treatment. Amongst 157 IMI-treated malignant glioma patients, four patients fit these restrictions, pointing to scarce experience of IMI for DMG/DHG adult patients. HM (M, 29y) was diagnosed with a DMG in the pons. He received radiochemotherapy, and continued after 2x TMZm with BRAF-MEK-inhibition therapy. He received one IO-Vac® dendritic cell vaccine but showed fast progression thereafter. He died 9 months after diagnosis. GJE (F, 28y) had a DMG at the corpus callosum. She received radiochemotherapy and 6x TMZm, followed by 2x IO-Vac® and 3x maintenance immunogenic cell death (ICD) immunotherapy (NDV injections, sessions of modulated electrohyperthermia), combined with WT1 and H3K27M long-peptide vaccines. She progressed after 20 months, for which a new IO-Vac® and an H3K27M short- and long-peptide vaccine were given. She died 5 months later. Overall Survival (OS) was 26 months after initial diagnosis. JD (F, 27y) was diagnosed with a DMG in C2-C6. She received radiochemotherapy followed by IMI alone, including 2x IO-Vac®, one ICD immunotherapy, and four doses of anti-PD1. She died 17 months later, making OS 27 months after diagnosis. VJ (F, 21y) had a DHG in the left cerebrum. She received radiochemotherapy and 12 cycles of maintenance TMZ (TMZm), between which ICD immunotherapy was inserted each time. Afterwards, she received two IO-Vac®. Finally, she received ICD immunotherapy (6x) combined with checkpoint inhibitors (4x anti-CTLA4, 10x anti-PD1). Thirty months after diagnosis, she is in remission with a stable Health Utility Index of 0.72. IMI might have contributed to a better OS in three out of four DMG/DHG patients, and should be explored further as part of the treatment for these patients.
CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA
Authors: Derek Li Yuping , Luo Jingqin Rosy , Grote Cierra , Nehring Leslie , Katumba Ruth , Etter Kelsey , Barozinsky Kaiden , Ferrando-Martinez Sara , Stermer Kristina , Lee Byung Ha , Johanns Tanner , Butt Omar , Huang Jiayi , Campian Jian L , Chheda Milan G 
Published: November 2024

Abstract

BACKGROUND
Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG.

METHODS
We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS).

RESULTS
We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference.

CONCLUSIONS
rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.
CTIM-28. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT
Authors: Ricardo McFaline-Figueroa J , Sun Lu , Youssef Gilbert , Huang Raymond , Li Gang , Kim Jiyoon , Lee Eudocia , Nayak Lakshmi , Chukwueke Ugonma , Beroukhim Rameen , Batchelor Tracy , Chiocca E Antonio , Everson Richard , Doherty Lisa , Stefanik Jennifer , Partridge Kathryn , Spearman Amanda , Myers Alexa , Westergaard Catharina , Russ Alyssa , Lavallee Maria , Smokovich Anna , LaForest-Roys Corey , Fox Rachel Garcia , McCluskey Christine , Bi Wenya Linda , Arnaout Omar , Peruzzi PierPaolo , Cosgrove G Rees , Ligon Keith , Romany Isabel Arrillaga , Clarke Jennifer , Reardon David , Cloughesy Timothy , Prins Robert , Wen Patrick 
Published: November 2024

Abstract
Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue from an additional 25 patients with recurrent glioblastoma treated with neoadjuvant pembrolizumab. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. PF6 for the stage 2 expansion cohort was 0%, while overall survival and progression-free survival were similar to historical controls at 6.8 months and 2.5 months, respectively. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not observe a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma in our expansion cohort. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.