bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-03. LONG TERM FOLLOW-UP OF A PROSPECTIVE SAFETY AND TOXICITY STUDY OF IMMUNE CHECKPOINT INHIBITOR THERAPY INITIATED 8 DAYS PRIOR TO RADIOSURGERY FOR MELANOMA BRAIN OR SPINE METASTASIS
Authors: Kleinberg Lawrence , Ye Xiaobu , Sharfman William , Jackson Christopher , Redmond Kristin , Bettegowda Chetan , Szajna Kelly , Isennock Whitney , Wollett Jessica , Lipson Evan , Lim Michael 
Published: November 2023

Abstract
We conducted a pilot study of checkpoint inhibitor (ICI) therapy followed in eight days(+/- 2) by initiation of SRS for brain or spine metastasis based on murine experiments of pre-SRS initiation of ICI. Alternative time intervals would be tested If there was &gt;33% dose limiting toxicity(DLT) &gt;Gr3 by CTCAE 4.0 within 12 weeks of treatment initiation (excluding Gr3 tumor flare, rash, immune reaction resolving to gr1 in &lt;28 days). Initially ipilimumab was used, with protocol change to nivolumab as standard of care evolved. Treatment continued until DLT, progression, or clinical decision to end therapy. Dosing and timing of subsequent cycles were by institutional preference. Eligibility included melanoma with newly diagnosed unirradiated brain or spine metastasis, at least one &gt;3 mm, no autoimmune diseases. Twenty-one patients enrolled, 17(81%) treated with nivolumab, 20(95%) had brain metastasis. The median baseline number of brain metastasis was 2(1-9). 7 subjects (33%) had only one brain met. Seven subjects(33%) were free of extra-CNS metastasis at baseline; 5(23%) had 1-5 systemic metastasis (oligometaststic), and 9 subjects(43%) had 6 or more systemic metastasis. Median number of cycles of checkpoint inhibitor therapy was 3 (1-37). The grade 3 toxicities (no grade 4 and 5) with possible, probable, or definite attribution to ipilimumab were colitis(4.8%), diarrhea(9.5%), fatigue(4.8%), muscle weakness (4.8%), and headache(4.8%). One subject had colitis as a DLT. No toxicity &gt;3 or above was associated with nivolumab. Estimated median overall survival was 37.4 months, within minimum f/u of 8 surviving patients of 40 months (40-68). Three-year OS rate was 52%. Checkpoint inhibitor therapy initiated 8 days prior to SRS was safe and survival outcome is favorable. Peripheral blood Immune correlative studies are pending. Prospective data is needed to define optimal safety, timing, and outcome of concurrent checkpoint inhibitor therapy and radiosurgery for melanoma metastatic to the brain.
CTIM-11. MRNA AGGREGATES ELICIT RAPID IMMUNOLOGIC RESPONSE AND PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Ghiaseddin Ashley , Mendez-Gomez Hector , Rahman Maryam , DeVries Anna , Zhang Dingpeng , Zhao Chong , Hodik Marcia , Kresak Jesse , Massini Tara , Gatica Sebastian , Ligon John , Castillo Paul , Huang Jianping , Silver Natalie , Hwang Eugene , Kline Cassie , Mueller Sabine , Prados Michael , Mitchell Duane , Sayour Elias 
Published: November 2023

Abstract

BACKGROUND
Glioblastoma immunotherapy trials remain limited by heterogeneity and the immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed a novel cancer immunotherapy that leverages use of mRNA lamellar aggregates (RNA-LPA) encoding for personalized glioblastoma antigens to simultaneously reprogram the GBM TME while inducing tumor specific immunity in the periphery.

METHODS
In a Phase I trial (PNOC020) with an embedded acceleration titration design (ATD) for patients with newly-diagnosed MGMT unmethylated glioblastoma, we sought to assess whether intravenous administration of RNA-LPAs encoding for pp65 mRNA (tumor associated antigen) mixed with personalized tumor mRNA (extracted and amplified from patient specific biopsies) could activate peripheral immunity while simultaneously reprogramming the GBM TME. All patients received surgical resection with adjuvant chemoradiation followed by escalating doses of RNA-LPA (0.625-1.5 µg/kg).

RESULTS
We have treated 3 patients on the ATD and one patient on the expanded Phase I trial. In all patients treated to date, RNA-LPAs elicited a rapid response (within hours) characterized by release of cytokines (IL-12, TNF-α, IFN-α), chemokines (CCL2, CCL4, CXCL9-10), increase in plasmacytoid dendritic cells and recruitment of peripheral blood mononuclear cells. Over time there was expansion of antigen specific T cells; T cell receptor (TCR) sequencing pre- and post-infusion demonstrated changes to the most prevalent clonotypes by ~10-20%. In the first subject treated on the expanded phase I trial, we observed significant immunologic response after the fourth vaccine, including 20-fold increase in IFN-γ inducible protein-10. One month after vaccine administration, there was marked increase in the enhancing areas on MRI, which on biopsy demonstrated no viable tumor cells and only reactive gliosis, necrosis, and lymphocytic infiltrates.

CONCLUSION
RNA-LPAs elicit rapid immune activation in the periphery and reprogram the GBM TME into a proinflammatory milieu as evidenced by tissue confirmed pseudoprogression.
CTIM-13. PHASE I CLINICAL TRIAL OF ONCOLYTIC HSV-1 M032, A SECOND-GENERATION VIRUS ARMED TO EXPRESSED IL-12, FOR THE TREATMENT OF ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE MALIGNANT GLIOMA
Authors: Estevez-Ordonez Dagoberto , Stein John , Maleknia Pedram , Gallegos Carlos , Atchley Travis , Laskay Nicholas , Clements Jennifer , Lobbous Mina , Leavenworth Jianmei , Riley Kristen , Aban Inmaculada , Sorace Anna , Chkheidze Rati , Nabors Burt , Markert James 
Published: November 2023

Abstract

BACKGROUND
Effective treatment options are limited for patients diagnosed with malignant glioma, and outcomes remain very poor. Recurrence and progression rates are universal. Preclinical data showed that a second-generation oncolytic herpes virus (oHSV) with selective replication and armed to induce IL-12 expression was a more effective anti-glioma agent than the first-generation oHSV.

METHODS
We conducted an open-label, dose-escalating phase I trial designed to determine the safety and tolerability of intratumoral injection of the M032 virus in patients with recurrent or progressive MG. Patients underwent stereotactic placement of intratumoral catheters. The following day, M032 was infused over a period of 6 hours. Primary endpoint was to determine safety and maximum tolerated dose (maximal planned dose of 109 PFU). Dose elevations were made using a modified Continual Reassessment Method.

RESULTS
Twenty-one patients with recurrent MG ages 19 to 71 received M032 (16 Males, 5 Females). Fourteen patients had IDH wild-type tumors, and eighteen patients had unmethylated MGMT status. Four grade 1, two grade 2, two grade 3, and two grade 4 adverse events were identified as possibly related to M032. Both grade 3 and grade 4 adverse events possibly related to M032 occurred in a single patient on the 108 PFU cohort. No serious adverse events at the maximal plan dose were attributed to M032. Median post-treatment survival was 9.38 months (95% CI, 7.57 to 12.95). 2 participants were still alive following treatment.

CONCLUSIONS
Intratumoral M032 had an acceptable adverse-event profile. We observed two grade 3 and two grade 4 adverse events in a patient with a large tumor prompting an amendment to tumor size inclusion criteria. No dose-limiting toxicity occurred at the maximum dose. Preliminary evidence suggests favorable response in some patients with recurrent or progressive MG. Careful selection of patients is needed when considering treatment with M032 (ClinicalTrials.gov number, NCT02062827).
CTIM-24. REPEATED PERIPHERAL INFUSIONS OF ANTI-EGFRVIII CAR T CELLS IN COMBINATION WITH PEMBROLIZUMAB REMODELS THE TUMOR MICROENVIRONMENT IN DE NOVO GLIOBLASTOMA
Authors: Binder Zev , Bagley Stephen J , Lamrani Lamia , Marinari Eliana , Desai Arati , Nasrallah MacLean P , Maloney Eileen , Brem Steven , Lustig Robert A , Kurtz Goldie , Alonso-Basanta Michelle , Bonte Pierre-Emmanuel , Goudot Christel , Richer Wilfrid , Piaggio Eliane , Kothari Shawn , Guyonnet Lea , Guerin Coralie , Waterfall Joshua , Mohan Suyash , Hwang Wei-Ting , Tang Oliver , Logun Meghan , Bhattacharyya Meghna , Markowitz Kelly , Delman Devora , Marshall Amy , Wherry E John , Amigorena Sebastian , Beatty Gregory , Brogdon Jennifer , Hexner Elizabeth , Migliorini Denis , Alanio Cecile , O'Rourke Donald M 
Published: November 2023

Abstract
Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n = 7). Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in one patient in the tumor. However, shared TCRs were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CART. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNAseq, and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.
CTIM-27. PERIPHERAL BIOMARKER ANALYSIS OF T CELL-MEDIATED COLLAGEN REMODELING CORRELATES WITH TUMOR RESPONSES IN A PHASE IIA TRIAL OF VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901)
Authors: Iwamoto Fabio , Nissen Neel , Reardon David , Forst Deborah , Lee Eudocia , Berthoud Tamara , Soare Catalina , Diaz-Mitoma Francisco , Anderson David , Wen Patrick , Willumsen Nicholas , Karsdal Morten , Lassman Andrew 
Published: November 2023

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 with KPS³70 received VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF intradermally (NCT03382977). Patients received VBI-1901 q4w, with serologic immune-monitoring q2w after each vaccination and surveillance brain MRI scans q6w. Among 16 patients treated with the highest (10µg dose) of VBI-1901, the mOS was 12.9 months with a 12-month OS rate of 62.5%. T cell-mediated collagen remodeling is necessary for T cell migration and activity. The peripheral C4G biomarker targets granzyme-B-cleaved type IV collagen, which is associated with T cell infiltration and has previously been shown to potentially identify recurrent GBM patients responding to nivolumab and bevacizumab. Here, C4G was measured in available plasma samples from patients with progressive disease (PD) (n = 9), stable disease (SD) (n = 5) or partial tumor responses (PR) (n = 2) prior to (baseline) and after (cycle 1-4) treatment with VBI-1901. Although numerically lower in patients with PD, there were no differences in baseline levels of C4G among the groups. However, there were statistically significant increases in C4G levels in the 2 patients with PR both after 1st/2nd doses (p = 0.0324) and after 3rd/4th doses (p = 0.0027) of treatment (1st/2nd doses; PD: 7.6ng/mL, SD: 10.0ng/mL, PR: 21.0ng/mL. 3rd/4th doses; PD: 6.1ng/mL, SD: 8.5ng/mL, PR: 16.8ng/mL). On-going analyses are evaluating additional peripheral markers of tumor microenvironment (TME) remodeling. Evaluating the balance of immune infiltration vs. tumor cell growth in patients with brain tumors is challenging and these data suggest a means of assessing this dynamic using a peripheral biomarker. These data may be particularly useful in discerning pseudoprogression associated with T cell infiltration from tumor progression.
CTIM-35. INB-400 PHASE 1B/2 DRUG RESISTANT IMMUNOTHERAPY WITH ACTIVATED, GENE MODIFIED ALLOGENEIC OR AUTOLOGOUS ΓΔ T CELLS IN COMBINATION WITH MAINTENANCE TEMOZOLOMIDE RECURRENT OR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Goswami Trishna , Lamb Lawrence , Rochlin Kate , Nabors Burt 
Published: November 2023

Abstract
Gamma delta (gd) T cells are innate immune cells that synergistically target cancer cells via NKG2D ligands (NKG2D-L) upregulated by chemotherapy. INB-200, a Phase 1 trial, demonstrated the safety and efficacy of autologously (auto) derived genetically modified drug resistant immunotherapy (DRI) gd T cells combined with maintenance temozolomide (TMZ) to treat newly diagnosed (ND) patients with GBM. Initiation of , a 3-arm phase 1b/2 study confirming the efficacy of the auto product in ND GBM and the safety and efficacy of an allogeneic (allo) product in both ND and relapsed GBM has begun. Arm A assesses the auto product in ND GBM patients with 1x107 cells delivered on Day 1 of cycles 1-6 along with TMZ maintenance therapy per the Stupp regimen. In the Phase 1b arm, the haploidentical allo product, will be assessed for safety in 6 relapsed GBM patients who will receive 1x107 cells in combination with 150mg/m2 of TMZ on Day 1 of every six 28-day cycles. Arm B will continue enrollment of relapsed patients following the Phase 1b and Arm C will test the safety of the allo derived product in ND, GBM patients. In Arm C, patients will receive 1x107 allo DeltEx DRI cells on Day 1 of cycles 1-6 in combination with TMZ maintenance. Cells are administered through a Rickham catheter in all arms. Primary endpoints for the Phase 1b define the RP2D and subject/ product characteristics to optimize manufacturing, while Phase 2 endpoints will determine the 12 mos OS rate for Arms A & C and 9 mos OS rate for Arm B. Eligible patients are adults with IDH-wt ND or relapsed GBM with no concurrent TTF or immunotherapy, willing to place an indwelling Rickham catheter. Allo arm patients must have a haploidentical donor. Fifteen US centers will conduct study.
CTNI-11. THE VALUE OF STEREOTACTIC BIOPSY OF PRIMARY AND RECURRENT BRAIN METASTASES IN THE ERA OFPRECISION MEDICINE
Authors: Katzendobler Sophie , Do Anna , Weller Jonathan , Rejeski Kai , Dorostkar Mario , Albert Nathalie , Forbrig Robert , Niyazi Maximilian , Egensperger Rupert , Tonn Joerg-Christian , von Baumgarten Louisa , Quach Stefanie , Thon Niklas 
Published: November 2023

Abstract
BACKGROUND: Brain metastases (BM) represent the most frequent intracranial tumors with increasing incidence. Many primary tumors are currently treated in protocols that incorporate targeted therapies either upfront or for progressive metastatic disease. In cases with diagnostic uncertainty, both in newly diagnosed or recurrent BM, stereotactic biopsy serves as an alternative to microsurgical resection particularly whenever resection is not deemed to be safe or feasible. This retrospective study aimed to analyze both diagnostic yield and safety of an image-guided frame based stereotactic biopsy technique (STX).
CTNI-30. MESENCHYMAL STEM CELL (MSC11FCD) BASED THERAPY ELICITED A FAVORABLE RESPONSE WITH EFFICIENT 5-FU CONVERSION IN PATIENTS WITH RECURRENT GLIOBLASTOMA: AN OPEN LABEL, PHASE I/IIA TRIAL
Authors: Lim Jaejoon , Chang Da-Young , Sim Jeongmin , Jung Jin-Hwa , Park JeongMan , Kim Yu Jin , Kim Dongkil , Hwang Sojung , Kim Sung-Soo , Cho Hea-Young , Suh-Kim Haeyoung , Cho Kyunggi 
Published: November 2023

Abstract
Mesenchymal stem cells (MSC) are being developed as therapeutic agents for treatment of various diseases due to their high tropism to damaged sites and cancers, and low immunogenicity. We are developing technologies to efficiently transfer therapeutic genes including suicide genes that will be used to suppress tumor growth or to ensure safety against possible adverse events and to develop off-the-shelf formulations for allogeneic uses. MSCs were engineered to express a suicide gene encoding non-human cytosine deaminase (CD) enzymes. We aimed to conduct a phase I/IIa clinical trial to investigate the maximum tolerated dose, safety, and efficiency of MSC11FCD in recurrent glioblastoma (GBM) patients. This study was a single-arm, open label, investigator-initiated trial on 10 patients recruited between 2021. The MSCs were administered via intra-tumoral injection after surgical resection. No severe adverse events and dose-dependent toxicities were observed. Median overall survival was not reached, and the median progression-free survival was over 4 months. We identified efficient 5-FU production and specific gene signature as biomarkers that predict response to MSC11FCD therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor. In conclusion, MSC11FCD therapy was safe and showed clinical efficiency in recurrent GBM patients. Specific gene signature can be used to screen individuals who might benefit from MSC11FCD therapy.
CTNI-33. TARGET TRIAL: A PHASE I/II OPEN-LABEL MULTICENTER STUDY TO ASSESS SAFETY, TOLERABILITY, AND CLINICAL EFFICACY OF AZD4547 IN PATIENTS WITH RELAPSED/REFRACTORY FGFR FUSION POSITIVE GLIOMA
Authors: Picca Alberto , Stefano Anna Luisa Di , Savatovsky Julien , Ducray Francois , Chinot Olivier , Moyal Elisabeth Cohen-Jonathan , Augereau Paule , Schmitt Yohann , Lerond Julie , Rousseaux Nabila , Fardeau Christine , Mokhtari Karima , Bielle Franck , Meyronet David , Iavarone Antonio , Sanson Marc 
Published: November 2023

Abstract

BACKGROUND
AZD4547 is a potent oral FGFR1-3 inhibitor. We tested its safety, tolerability, and efficacy in patients presenting relapsed/refractory (r/r) high-grade gliomas (HGGs) with FGFR fusion in a phase I/II open label multicenter study (NCT02824133).

METHODS
the study was based on a two-stage design and included adult patients with HGG expressing a FGFR-TACC gene fusion (as centrally confirmed by RT-PCR sequencing) relapsing after at least one line of standard chemoradiation. Patients received AZD4547 (AstraZeneca) at a dose of 80mg bd on a continuous schedule, until disease progression or inacceptable toxicity. The primary endpoint was the 6-months progression-free survival rate (PFS6). This research was conducted with support from AstraZeneca.

RESULTS
12 patients with r/r isocitrate dehydrogenase wildtype HGGs positive for FGFR-TACC fusions (all FGFR3-TACC3) were included in the efficacy analysis cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first tumor relapse. The PFS6 was 25% (95% confidence interval [CI] 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n = 3) were at the first tumor recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was stable disease in six patients and progressive disease in six. Median OS was 17.5 months. Grade 3 toxicities included hematological, metabolic, nail changes, stomatitis, or other disorder (n = 1 each). No grade 4 toxicities were seen.

CONCLUSION
overall, tolerance was acceptable. The study did not meet the predetermined objective of PFS6 ≥ 35% and was stopped. A molecular characterization is ongoing to identify potential markers associated with prolonged stabilizations.
CTNI-40. A MULTICENTER, RETROSPECTIVE ANALYSIS OF PROGNOSTIC FACTORS IN INTRACRANIAL H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA IN ADULTS
Authors: Ryba Alice , Özdemir Zeynep , Nissimov Nitzan , Hönikl Lisa , Neidert Nicolas Noel , Jakobs Martin , Kalasauskas Darius , Krigers Aleksandrs , Freyschlag Christian , Ringel Florian , Trong Philip Dao , Heiland Dieter Henrik , Gempt Jens , Onken Julia , Molina Eric Suero , Westphal Manfred , Schüller Ulrich , Mohme Malte 
Published: November 2023

Abstract
H3 K27M-mutant glioma were first described as a new grade IV entity in the 2016 WHO classification. Current studies have focused on its common pediatric appearance, increasing the need to better understand this entity in adults. Here we report a multicentric, retrospective analysis of 70 diffuse midline glioma in adults. We included molecularly confirmed H3K27M-mutant glioma in patients &gt;18 years of age between 2015-2022. Clinical-, radiological- and surgical features were analyzed. Univariate and multivariate analyses were then performed to identify prognostic factors. The study was approved by the ethics committee (PV4904). Overall, 70 patients were identified, with a mean age of 36.13 years at the initial diagnosis. Median overall survival was 13.62 + 14 months. H3K27M-mutated glioma showed a midline involvement in 61.4%. Clinically, obstructive hydrocephalus was observed in almost half of the patients (46.3%). Gross total resection (GTR) was achieved in 14.5% of all patients. 30.4% had a subtotal resection (STR), and 55.1% received a biopsy. Intraoperative cryo-section resulted in low-grade glioma in 25%, high-grade glioma in 63.9% and no tumor in 11.1%. Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location site in the mesencephalon/metencephalon showed a significantly longer survival (8.3 vs. 16.2 months, p = 0.009). Preoperative Karnofsky Performance Score (KPS) below 80 showed a reduced OS (6 vs. 11.24 months, p = 0.03). Patients, who received resection (GTR/STR) showed no significant survival benefit compared with biopsied patients (9.6 vs. 8 months, p = 0.4817). The present study describes surgical features of DMG with H3K27M mutation in one of the most extensive multicentric studies to date in adult patients. Our data show that location and preoperative KPS impact OS significantly in DMG. Furthermore, in our dataset resection of K27M-mutated glioma provided no significant survival benefit compared with biopsy.