bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-22. MEDIAN AND 2 YEARS SURVIVAL OF NEWLY DIAGNOSED UNMETHYLATED MGMT GLIOBLASTOMA PATIENTS TREATED WITH TEMFERON IMMUNO-GENE THERAPY
Authors: Eoli Marica , Farina Francesca , Cuccarini Valeria , Gentner Bernhard , Barcella Matteo , Anghileri Elena , Bruzzone Maria Grazia , Carrabba Matteo , D’Alessandris Quintino Giorgio , DiMeco Francesco , Ferla Valeria , Franzin Alberto , Ferroli Paolo , Gagliardi Filippo , Legnani Francesco , Capotondo Alessia , Mazzoleni Stefania , Mortini Pietro , Olivi Alessandro , Pallini Roberto , Patanè Monica , Paterra Rosina , Pollo Bianca , Saini Marco , Snider Silvia , Naldini Luigi , Russo Carlo , Ciceri Fabio , Finocchiaro Gaetano 
Published: November 2024

Abstract
TEM-GBM is an open-label, Phase 1/2a dose-escalation study aimed to evaluate the safety and efficacy of a myeloid cell-targeted therapy (Temferon) in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). Temferon, consists of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. As of 21st May 2024, 24 GBM patients in 8 cohorts received incremental doses of Temferon and 6 are still alive. For all patients, median overall survival (OS) and median progression free survival reach 17 months and 8.3 months from first surgery, respectively. The interim survival rate at 2 years in Temferon-treated patients is 30% (6 of 20 patients; 3 patients excluded as follow-up is below 1 year). The mOS and the % of patients surviving up to 2 years are currently higher than previously reported for uMGMT patients treated as per standard practice (12.7 months and 14,8%, respectively). Two out of the six patients did not receive any additional treatment lines up to two years after 1st surgery. The other four patients instead received a 2nd treatment line (bevacizumab, regorafenib, Gamma-Knife, metronomic Temozolomide, Lomustine) as per the PI judgment, on average after 443 days from 1st surgery (333 days from Temefron - range 223-1030 days from first surgery). Specifically, Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. The data further confirms the initial evidence on safety and tolerability of Temferon and highlight the potential to prolong the survival of patients affected by uMGMT GBM.
CTIM-27. DOC1021 CELL-BASED VACCINATION AS ADJUVANT THERAPY FOR GLIOBLASTOMA: PHASE I CLINICAL TRIAL ANALYSIS
Authors: Esquenazi Yoshua , Zhu Jay , Hsu Sigmund , Zvavanjanja Rodrick , Vu Mia , Highberg Eva , Akshar Trivedi , Liu Wei , Namekar Madhuri , Hofferek Colby , Ernste James , Mossop Corey , Christina Clay , Amin Sabina , Benjamin Musher , Ravi Vinod , Jan Kemnade , Aguilar Laura , Turtz Alan , Tandon Nitin , Konduri Vanaja , Georges Joseph , Decker William 
Published: November 2024

Abstract
Glioblastoma is an aggressive tumor for which median survival remains 14-18 months despite aggressive standard of care. Cellular immunotherapy approaches have recently shown promise. Homologous antigenic loading is an ex-vivo technique that leverages p38MAPK and mTORC1 signaling cascades to initiate powerful cDC1-like skewing in monocyte-derived dendritic cells, leading to downstream induction of tissue-infiltrating, cytolytic effector memory T-cells. This open-label phase I clinical trial evaluated the autologous dendritic cell vaccine DOC1021 prepared through homologous antigenic loading and administered bilaterally near the deep cervical lymph nodes. Three courses of vaccine were administered every 2 weeks after completion of chemoradiation, adjuvanted concurrently with six weeks of weekly type I interferon. Four dose levels from 3.5x106 to 3.6x107 total vaccine cells were tested. Tumor progression prior to vaccination was not an exclusion criterion. Sixteen newly diagnosed IDH-WT patients completed treatment, median age 63 years and 94% MGMTp unmethylated. The most common related AEs were grade 1 injection-site reactions and grade 1-3 fatigue and urticaria. No DLTs were observed. Immunohistochemistry of tumors derived from early post-vaccination second resections showed enhanced CD8+ T-cell infiltration and pathologic findings consistent with residual rather than relapsed GBM in 2/3 patients. Analysis of post-vaccination PBMC in dose level cohorts 2-4 indicated expansion of both CD4+ (13/13) and CD8+ (11/13) central memory T-cell compartments (p&lt;0.002 and p&lt;0.05, respectively) as well as expansion of CD8+CD127+ T-cells (12/13; p&lt;0.001). Among three patients for whom tissue was obtained pre- and post-vaccination, clinical outcomes correlated with Visium spatial transcriptomic analysis. Median survival for the MGMTp unmethylated cohort (n=15) has not yet been reached but is statistically greater (p&lt;0.05) than that of matched historic controls. The results indicate that DOC1021 is safe, can be effectively integrated within existing standards of care and is potentially efficacious in a challenging patient population.
CTIM-29. TUMOR RESPONSES IN A RANDOMIZED PHASE IIB TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901) IN RECURRENT GLIOBLASTOMAS
Authors: Merrell Ryan , Wen Patrick , Forst Deborah , Schulte Jessica , Odia Yazmin , Bota Daniela , Nagpal Seema , Bonm Alipi , Diaz-Mitoma Francisco , Anderson David , Lassman Andrew , Iwamoto Fabio 
Published: November 2024

Abstract
Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. First-recurrent GBM patients were enrolled, with Karnofsky Performance Status of at least 70, to receive VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF and given intradermally (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with surveillance brain MRI scans every 6 weeks. Among 16 subjects receiving the highest dose of VBI-1901 in the Phase I/IIa portion of the study, the disease control rate was 44%, including 2 durable partial responses, which translated into a mOS of 12.9 months. Based on these results, the study was amended into a randomized study. Approximately 60 adult subjects (18 years or older) with first recurrence of WHO 2016 grade IV Glioblastoma, IDH-wildtype will be randomized at a 1:1 ratio to two open-label cohorts to receive: VBI-1901 or standard of care (SOC) treatment with lomustine or carmustine. Only subjects with a CD4/CD8 ratio ≥1 or a CD4 count of ≥ 400/uL at screening are eligible, as people with a preserved immune system are more likely to respond to immunization with VBI-1901 based on the initial phases of the study. As of May 15, 2024, 23 patients have been randomized across 6 sites. Among evaluable patients (n=13), disease control rates of 43% and 0% have been observed in the VBI-1901 and SOC arms, respectively, including 1 partial response in the VBI-1901 arm. Full enrollment (n=60) is anticipated by the end of the year across 11 sites, and updated tumor response data and select biomarkers associated previously with tumor responses will be presented.
CTIM-31. PRELIMINARY RESULTS OF A PHASE II STUDY OF STEREOTACTIC RADIOSURGERY IN CONJUNCTION WITH THE PD-1 INHIBITOR PEMBROLIZUMAB FOR THE TREATMENT OF RECURRENT HIGH-GRADE MENINGIOMA
Authors: Oberheim Bush Nancy Ann , Kumar Karishma , Rabbitt Jane , Daras Mariza , Sneed Penny , Boreta Lauren , Nakamura Jean , Butowski Nicolas , DeGroot John , Raleigh David , Braunstein Steve 
Published: November 2024

Abstract
Recurrence of higher-grade meningioma after initial resection and radiotherapy is frequent and associated with high rates of morbidity and mortality. Salvage therapies have limited efficacy and average survival after recurrence is approximately 5-10 years. We report here preliminary data from a phase 2 study combining immunotherapy with checkpoint inhibition with stereotactic radiosurgery for treatment of recurrent high-grade meningioma (NCT04659811). Adult patients with either grade 2 or 3 meningioma who have recurred despite treatment with surgery and radiation and who meet eligibility criteria received stereotactic radiosurgery, in 1 to 5 fractions, in conjunction with pembrolizumab 200mg on the first day of radiation and then every 3 weeks until progression, unacceptable toxicity or for 2 years. Primary objective is PFS12, and secondary objectives include safety of the combined treatment in recurrent meningioma, mOS, mPFS, and neurocognitive function and QOL metrics. To date we have enrolled 18 of planned 37 patients, 33% female, 39% grade 2 and 61% grade 3. Safety lead in was completed without any dose limiting toxicity. There have been 4 SAEs, only one of which was related to study treatment (cerebral edema). 29% of patients had at least one AE, the most common were GI disorders (23%), skin disorders (23%) and headache (17%). Preliminary data from 12 patients shows PFS12 to be 50%, which suggests that the combination of stereotactic radiosurgery may be more beneficial than treatment of Pembrolizumab alone (mPFS 7.6 months). One patient was found to have a homozygous focal deletion of the MLH1 gene and had a dramatic reduction in size of her meningioma with a durable response for over one year. These preliminary data suggest that the combination of stereotactic radiosurgery and pembrolizumab is safe, well tolerated and may be beneficial to patients with recurrent higher-grade meningioma.
CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)
Authors: Shen Colette , Abdou Yara , Chen Linda , Tan Xianming , Gupta Gaorav , Lynce Filipa , Lobbous Mina , Stringer-Reasor Erica , Anders Carey 
Published: November 2024

Abstract

BACKGROUND
Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response.

METHODS
We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.
CTIM-35. PD-1 BLOCKADE WITH CAMRELIZUMAB IN RELAPSED/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Ge Jing-Jing , Li Cheng , Qi Shao-Pei , Kong Chen-Chen , Zhao Chi , Xue Feng-Jun , Zhang Jun-Ping 
Published: November 2024

Abstract
Primary central nervous system lymphoma (PCNSL) are rare extranodal large B-cell lymphomas. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and the overall prognosis is poor. We conducted a phase 2 clinical trial to evaluate the efficacy and adverse events of PD-1 antibody camrelizumab in relapsed/refractory PCNSL. Enrolled patients received camrelizumab 200mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR). Here we present results of 20 relapsed PCNSL patients who treated with camrelizumab. Among them,12 were male and 8 were female. The median age was 57 years (range 25-67 years). Fourteen patients were available to evaluate efficacy. After camrelizumab treatment, 4 got complete response (CR), 3 got partial response (PR), 1 got stable disease, and 6 got progressed disease (PD). The ORR was 50%. The median progression-free survival (PFS) was 19.3 weeks (95% CI, 3.1-35.5). 24 week PFS rate was 40%. For the 7 patients who got CR/PR, got a long sustained response, with a median PFS of 93.6 weeks (range 17-211.6+ weeks). One patient developed pseudoprogression 2 months after initiation of treatment. By the last follow-up, 18 patients discontinued treatment (10 PD, 4 complete treatment, 3 withdrawal of informed consent, 1 lost follow-up). Eleven patient got PD. Nine patients received chemotherapy and 5 received radiotherapy after PD. PD-L1 expression, microsatellite stability and mutation burden of the tumors were detected in 9 patients, and all the three factors were not correlated with efficacy. The main drug-related adverse reaction was cutaneous capillary hyperplasia. None of the patients dropped out of the study due to adverse reactions. Our data suggest that camrelizumab is active in relapsed/refractory PCNSL and support further investigation of PD-1 blockade in PCNSL.
CTIM-36. IN-SITU VACCINATION OF BIOPSY-ONLY GBM TUMORS BY TUMOR TREATING FIELDS PLUS ANTI-PD-1 IMMUNOTHERAPY RESULTS IN ROBUST ANTIGEN-SPECIFIC T CELL SELECTION AND EXPANSION, HIGH RESPONSE RATE, AND SIGNIFICANTLY EXTENDED SURVIVAL
Authors: Chen Dongjiang , Le Son , Ghiaseddin Ashley , Manektalia Harshit , Li Ming , O’Dell Adam , Rahman Maryam , Tran David 
Published: November 2024

Abstract
We have recently described a complete in-situ immunizing protocol against GBM using Tumor Treating Fields (TTFields) to activate the DNA sensor-dependent inflammasomes and immunogenic cell death. Here, we report successful in-situ vaccination of patients with newly diagnosed GBM, especially in those with bulky, biopsy-only tumors as compared to those with maximally resected disease, using TTFields together with pembrolizumab, an anti-PD-1 immunotherapy. Patients with biopsy-only tumors displayed a marked improvement in both progression-free survival (27.2m vs 9.6m; HR 0.37, 95%CI 0.16-0.85; P=0.014), overall survival (31.6m vs 18.8m; HR 0.4, 95%CI 0.17-0.92; P=0.023), and response rates (66.6% vs 25%) when compared to those with maximally resected tumors. Using a combination of bulk RNA-seq of enriched T cells and single-cell RNA-seq and TCR clonotyping of tumors and PBMC, we tracked clonal evolution of T cells and confirmed that TTFields’ adaptive immune activation followed a type 1 interferon trajectory (T1IFN) specifically through the DC compartment in patients with biopsy-only tumor. From DC, the T1IFN pathway engaged the adaptive immune system, highly correlated with T cell activation (Pearson r=0.81; P=0.000027), and strongly predicted for extended survival (HR 0.3; P=0.034). Importantly, we discovered the adaptive replacement of expanded T cell clones induced by TTFields and enhanced by pembrolizumab predicted for prolonged survival (P=0.031), leading to sustained T cell activation (Pearson r=0.72; P=0.0018) and robust generation of central memory CD4+ and CD8+ T cells, especially in responders with biopsy-only tumors. In recurrent tumors, the PD-1/PD-L1 axis was suppressed, while concurrent upregulation of alternative immune checkpoints was observed in the periphery and TME. This was coupled with ineffective compensatory T cell activation, suggesting potential mechanisms of resistance. These findings highlight the potent in-situ vaccination effects of TTFields and support its co-application with immune checkpoint inhibitors as a promising strategy for GBM, especially in patients with substantial residual tumor.
CTNI-11. A PHASE 1 OPEN-LABEL STUDY OF BRAF INHIBITOR ABM-1310 IN PATIENTS (PTS) WITH RECURRENT BRAF V600-MUTATED PRIMARY CNS TUMORS
Authors: Li Wenbin , Kang Zhuang , Li Shenglan , Chen Feng , Zhang Botao , Huang Mengqian , Yang Zhongyuan , Chen Chen , Yang Zane 
Published: November 2024

Abstract

BACKGROUND
ABM-1310 is a blood-brain barrier penetrant BRAF inhibitor. Here we report interim results from our phase 1 study of ABM-1310.

METHODS
This is a dose-escalation plus expansions trial for adult pts with BRAF V600-mutated primary CNS tumors. In the dose-escalation, ABM-1310 is given at 150 or 200 mg twice a day (bid). In the expansion, ABM-1310 150 mg bid is administered. Study objectives include patient safety, maximum tolerated dose (MTD), preliminary efficacy and pharmacokinetics (PK). Clinical trial information: NCT05892653.

RESULTS
By May 6, 2024, 15 pts (7 male; median age 39 years old) have been treated. In the dose escalation: 4 pts received ABM-1310 150 mg bid, and another 7-pts received ABM-1310 200 mg bid. In the expansion, all 4 pts were given ABM-1310 at 150 mg bid. Among 14 efficacy evaluable pts, 3 had partial response (PR) (including one each of glioblastoma, WHO grade 2 and 3 pleomorphic xanthoastrocytoma) and 9 pts had stable disease as their best responses. Two pts have PR response for &gt; 8 months and continue study treatment. All pts experienced treatment-related AEs. Common AEs were asymptomatic QT prolongation (n=11) and rash (n=10). Seven pts had grade 3 QT prolongation. There was no drug-related SAE. There was no ABM-1310 related dose limiting toxicity although a few pts had study treatment interruption or dose reduction. One patient discontinued prematurely due to asymptomatic Grade 3 QT prolongation. There were no drug-related deaths. The MTD for ABM-1310 was 200 mg bid, the recommended dose was 150 mg bid. In PK assessment, ABM-1310 drug exposure vs. dosage showed a linear proportional relationship. This trial is ongoing.

CONCLUSIONS
ABM-1310 was generally safe and tolerated. There were no new safety signals. Preliminary efficacy data demonstrate favorable anti-cancer activity in patients with recurrent BRAF V600-mutated primary CNS tumors.
CTNI-19. MYCOPHENOLATE MOFETIL TARGETS GLIOBLASTOMA DE-NOVO PURINE METABOLISM TO OVERCOME CHEMORADIATION RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Umemura Yoshie , Clarke Nathan , Al-Holou Wajd , Elaimy Ameer , Scott Andrew , Leung Denise , Kim Michelle , Ferris Sean , Thomas Jennifer , Heth Jason , Schipper Matthew , Suresh Krithika , Lawrence Theodore , Wahl Daniel 
Published: November 2024

Abstract
Glioblastoma prefer de-novo purine synthesis while normal brain prefers resource-efficient salvage pathway. Mycophenolate mofetil (MMF) disrupts de-novo purine metabolism by inhibiting a key enzyme, IMPDH. The pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma models led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. Tissues from eight phase 0 recurrent glioblastoma subjects, receiving MMF ranging 500-2000mg BID one-week pre-operatively, were analyzed using mass spectrometry. Both enhancing and non-enhancing tumor yielded &gt;1µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p=0.009). In phase 1 study, adult patients were given MMF ranging 1000-2000mg PO BID using TITE-CRM dosing. Twenty-one recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy) with no dose-limiting toxicities (DLTs). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles. In the newly diagnosed cohort, there was no DLT with temozolomide and MMF, however, with both temozolomide and radiation, there were five DLT instances noted at 2000mg BID (G3 hemiparesis, G3 cognitive disturbance, G3 fatigue, G4 thrombocytopenia x2): all were reversible. Interim phase 1 median overall-survival in recurrent MGMT-methylated and unmethylated subjects were 16.1 (N=10) and 6.1 (N=11) months, and in newly diagnosed subjects, 27.2 (N=8) and 14.2 months (N=22) respectively. Median follow ups were 7.4 (recurrent) and 23.2 months (new diagnosis). MMF combined with chemoradiation is reasonably well tolerated in glioblastoma patients with promising evidence of drug accumulation in glioblastoma, effective target engagement and inhibition of purine synthesis, leading to a recommended phase 2 dose of MMF 1500mg BID.
CTNI-25. TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM). RESULTS OF PHASE II CLINICAL STUDY
Authors: Grossman Rachel 
Published: November 2024

Abstract

INTRODUCTION
Tumor-Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cancer cell function and tumor progression via a multimodal mechanism of action. Following the phase 3 pivotal EF-14 study, TTFields therapy concomitant with temozolomide (TMZ) maintenance therapy became approved for newly-diagnosed glioblastoma (ndGBM). Pre-clinical data and pilot clinical studies suggests synergistic effect of concomitant TTFields treatment with radiotherapy (RT).

OBJECTIVE
To assess the efficacy and safety of first line TTFields therapy concomitant with RT/TMZ vs RT/TMZ alone in adult patients with ndGBM. Design: 69 patients with ndGBM and KPS≥70 stratified by MGMT status, extent of resection, and age, were randomized 1:1. The experimental arm received TTFields therapy from the first day of chemoradiation, the control arm started 4 weeks after completion of chemoradiation. Patients continued TTFields therapy until second disease progression or 24months. The primary endpoint was 1-year PFS rate, and secondary endpoints included PFS, OS, and safety. Kaplan-Meier estimates were used to assess whether PFS and OS were improved with first line TTFields therapy/RT/TMZ vs RT/TMZ with delayed TTFields therapy.

RESULTS
Overall, 46 patients received maintenance chemotherapy and TTFields therapy. Mean age was 62 years (range:27–77). One-year PFS rate was 36% and 19% in the experimental and control arms, respectively (p-value=0.10). Median PFS was 9.9 and 5.6 months (HR 0.53, p-value 0.049). Median OS was 25.9 and 17 months (HR 0.85, p-value=0.6). Two-year OS rates were 52% and 31% (p-value 0.07). Among patients with high TTFields usage (≥75%) 2-year OS rates were 78% and 34% (p=0.01).

CONCLUSIONS
The addition of concomitant TTFields to standard treatment with temozolomide and RT for patients with ndGBM appears to be another step in improving the outcome of this patients population. This is further investigated in the large-scale TRIDENT study.