bluuebunny/crossref_metadata_2025 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

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 >33% dose limiting toxicity(DLT) >Gr3 by CTCAE 4.0 within 12 weeks of treatment initiation (excluding Gr3 tumor flare, rash, immune reaction resolving to gr1 in <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 >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 >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

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

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

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

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

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

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

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

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

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 >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.
CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Majd Nazanin , Yeboa D Nana , Weathers Shiao-Pei , Yuan Ying , Robichaux Christine , Anssari Haider Al , Gachimova Evguenia , Loghin Monica , Kamiya-Matsuoka Carlos , O'Brien Barbara , Aaroe Ashley , Patel Chirag , Yung W K Alfred , Wintermark Max , Gule Maria , Ferguson Sherise , Puduvalli Vinay , de Groot John
Published: November 2023

BACKGROUND

DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles.

RESULTS

Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations.

CONCLUSION

The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).
CTNI-46. UPFRONT VERSUS DEFERRED TREATMENT IN LOWER GRADE IDH-MUTANT GLIOMAS: A SINGLE-CENTER RETROSPECTIVE ANALYSIS
Authors: Patel Anuj , Whitfield Benjamin , Ballester Leomar , Puduvalli Vinay , Kamiya-Matsuoka Carlos
Published: November 2023

BACKGROUND

IDH-mutant gliomas are a diverse group of gliomas possessing a mutation in the isocitrate dehydrogenase enzyme. The treatment for both oligodendroglioma (1p/19q co-deleted) and astrocytoma includes resection followed by radiation therapy and chemotherapy. However, there is debate over the optimal timing of adjuvant treatment after surgery. An initial observation approach is sometimes pursued, particularly after gross total resection in young adults. We sought to examine the impact of timing of treatment in order to inform clinical decision-making.

METHODS

We identified 286 biopsied or resected glial tumors treated at MD Anderson Cancer Center from July 2015 to June 2022. Tumors were categorized using available molecular data based on the WHO 2021 diagnostic criteria. Progression-free survival was analyzed using Kaplan-Meier estimates.

RESULTS

Of 286 tumors, 232 had identified IDH-mutation, of which 89 were 1p/19q co-deleted and 143 were non-co-deleted. Of oligodendroglioma patients, 71 received either upfront chemotherapy, radiation or both and 18 received treatment upon progression; of astrocytoma patients, 96 were treated upfront and 47 received treatment at progression. Among oligodendroglioma patients, there were no significant differences in PFS between treatment timing groups (75.6 vs 66.7 months, P = 0.18). There was additionally no difference between oligodendroglioma patients treated initially with PC or PCV regimens vs temozolomide (not reached vs 75.4 months, P = 0.24). Among astrocytoma patients, upfront treatment was associated with longer PFS (93.8 vs 45.2 months, P < 0.01). Patients with low-risk grade 2 gliomas (age <40 and gross total resection) also showed longer PFS with upfront treatment (138.0 vs 45.2 months, P = 0.03).

CONCLUSION

Overall, the results in this molecularly defined cohort suggest a progression-free survival benefit from upfront treatment in IDH-mutant lower grade gliomas, including in low-risk gliomas. The optimal timing and nature of adjuvant treatment for lower grade gliomas remains a matter of debate.
CTNI-56. FEASIBILITY AND EFFICACY OF AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Akbari Hamed , Mohan Suyash , Kazerooni Anahita Fathi , Bilello Michel , Sako Chiharu , Garcia Jose , Jiang Cecilia , Liu Fang , Brem Steven , Bakas Spyridon , Rathore Saima , Mamourian Elizabeth , Pepin Abigail , James Paul , Dorsey Jay F , Singh Ashish , Parker Drew , Verma Ragini , Cao Quy , Shinohara Russell T , Bagley Stephen J , Desai Arati , O'Rourke Donald M , Nasrallah MacLean P , Alonso-Basanta Michelle , Teo Boon-Keng Kevin , Kurtz Goldie , Shukla Gaurav , Lustig Robert A , Davatzikos Christos
Published: November 2023

PURPOSE

The aim of this study was to evaluate the feasibility and efficacy of AI-guided personalized precision radiation therapy (PPRT) in improving outcomes for patients with newly diagnosed glioblastoma.

METHODS

In an open-label trial conducted at the University of Pennsylvania (NCT03477513), between August 2018 and April 2021, 17 patients with IDH-wildtype glioblastoma who underwent maximal safe resection were enrolled. They were matched with a cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity Score Matching (PSM) was employed to assess the impact of the intervention on the likelihood of survival, using logistic regression to estimate the propensity score. Four patients were disqualified based on exclusion criteria. The PPRT group received personalized radiation dose escalation guided by AI-based predictive modeling of recurrence, along with concomitant and maintenance temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy between 2012 and 2020. In this study, we utilized a previously published and evaluated (retrospectively and prospectively) predictive AI model, which accurately estimated neoplastic cell infiltration and predicted future tumor recurrence using preoperative, multi-parametric MRIs.

RESULTS

Median overall survival was 24.4 months in the PPRT-temozolomide group and 17.9 months in the standard-of-care treatment group (hazard ratio, 0.34; 95% CI: 0.15-0.77; p = 0.009). PPRT was well-tolerated, with low-grade adverse events during radiation. Radiation necrosis occurred in 54% of the PPRT-temozolomide group and 36% of the standard-of-care group.

CONCLUSION

AI-guided PPRT in newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and led to a statistically significant improvement in overall survival compared to matched controls receiving standard-of-care treatment. These findings highlight the potential of personalized precision radiation therapy, with focused dose escalation, in enhancing outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
CTNI-60. TREATMENT OF RECURRENT GLIOBLASTOMA WITH APG-157 VIA EXPANDED ACCESS: PRELIMINARY RESULTS FROM SIX PATIENTS FROM A SINGLE-CENTER STUDY
Authors: Fonkem Ekokobe , Betts Colton , Bradshaw Eva , Tamini Adam , Anyanda Elizabeth , Mehta Parag
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) is the most common primary central nervous system malignancy. There is poor long-term survival with a median survival of two years and little consensus on second line therapies after progression. APG-157 is a new class of botanical drugs developed under FDA’s Botanical Drugs Guidance. The purpose of this study is to assess the safety and effect of APG-157 on the six-month survival and quality of life (QoL) of patients with recurrent GBM.

METHODS

Approval was obtained from the Baylor Scott and White IRB (# 022-230, Approval number 58100462000) and under group expanded access protocol (IND 162339). Major inclusion criteria include histologically proven GBM and unequivocal tumor progression 12 weeks after completion of standard first-line therapy. APG-157 was administered either as monotherapy or in combination with temozolomide or tumor-treating fields. Adverse events were assessed at each study visit. Patient data were collected from study conception through April 25, 2023.

RESULTS

A total of 6 patients (3 male, 3 females) were treated (median age was 54). A median of 2 treatment cycles were administered. 2 Patients withdrew from the study voluntarily, 2 patients expired while on treatment, and 2 patients continued treatment at the time of data analysis. 47.4% (9/19) of the questionnaire time points were completed, however, we saw low QoL (EORTC-QLQ-C30 and EORTC-QLQ-BN20) with a mean global health status score of 4.5. No patient saw a significant increase in their symptoms and one patient reported a 6-point decrease in their neurological symptoms. One patient who was on monotherapy of APG-157 for two months showed stable disease by MRI evaluation. There were no reported adverse events from the study medication.

CONCLUSION

Future follow-up and a larger sample size are necessary to confirm the impact of APG-157 on six-month survival and QoL.
CTNI-72. PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
Authors: Fulvio D'Angelo Hirokazu Takami , Suzuki Tomonari , Takabatake Kazuhiko , Fujimaki Takamitsu , Okamoto Michinari , Yamaguchi Shigeru , Kanamori Masayuki , Matsuda Kenichiro , Sonoda Yukihiko , Natsumeda Manabu , Ichinose Junya , Nakada Mitsutoshi , Muroi Ai , Ishikawa Eiichi , Takahashi Masamichi , Narita Yoshitaka , Higuchi Fumi , Shin Masahiro , Mineharu Yohei , Arakawa Yoshiki , Kagawa Naoki , Kawabata Shinji , Wanibuchi Masahiko , Takayasu Takeshi , Yamasaki Fumiyuki , Fujii Kentaro , Ishida Joji , Date Isao , Miyake Keisuke , Fujioka Hiroshi , Kuga Daisuke , Yamashita Shinji , Takeshima Hideo , Shinojima Naoki , Mukasa Akitake , Tanaka Shota , Asai Akio , Nishikawa Ryo , Matsutani Masao
Published: November 2023

BACKGROUND

Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results.

METHODS

Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation.

RESULTS

Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 124 germinomas, 75 intermediate-prognosis-group cases (including 37 germinomas with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year event-free survival (EFS) for germinoma, intermediate and poor-prognosis-groups were 82/73%, 76/66% and 49/49%, respectively, and overall survival (OS) for each were 97/92%, 87/70% and 61/53%, respectively. Prognosis for germinoma with or without STGC was not statistically different. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, Time from treatment to deaths was significantly shorter for deaths due to original disease (5.7 years) than complications (14.9 years) and other causes (12.7 years) (p=0.005, 0.04, respectively). Overall survival after recurrence was clearly distinct according to the original histological groups; overall survival for germinoma, intermediate prognosis group and poor prognosis group were 94, 88 and 18% at 1 year, 91, 50 and 9% at 2 years and 88, 38 and 9 % at 3 years, respectively.

CONCLUSIONS

Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
DNAR-08. BASE EXCISION REPAIR AS A THERAPEUTIC TARGET FOR DIFFUSE HEMISPHERIC GLIOMA, H3.3G34-MUTANT
Authors: Portante Alessia , Canty Laura , Patel Palak , Pajovic Sanja , Johnson Monique , Kim Byungjin , Negm Logine , Chung Jiil , Dolma Sonam , Dirks Peter , Tabori Uri , Hawkins Cynthia
Published: November 2023

Diffuse hemispheric gliomas with H3.3G34R/V mutations are primarily found in the cerebral hemisphere in adolescents and young adults, with a median age of 16-19 years. H3.3G34R frequently co-occurs with mutations in ATRX and TP53 as well as PDGFRα. We performed mutational signature analysis on a cohort of 28 cases of Diffuse hemispheric glioma, H3G34-mutant (7 WGS and 21 WES). Mutational signatures of defects in mismatch repair (MMR), homologous recombination (HR), and nucleotide excision repair (NER) pathways were found in 86% cases whereas only two (7%) had signatures of impaired base excision repair (BER). Analysis of H3.3G34R interactome data showed loss of association with MMR, HR, and NER pathways, with gains in association with proteins in the BER pathway compared to wildtype Histone H3. We thus hypothesise the Diffuse hemispheric glioma, H3G34-mutant may be dependent on BER over other DNA damage repair pathways. To test if BER could be a therapeutic vulnerability, we knocked down integral members of the BER pathway (UNG, APEX1, MPG, and XRCC1) via shRNA in 4 patient-derived H3.3G34R-mutant cell lines (two primary and two matched recurrent), and found that knockdown of XRCC1 and MPG, led to 99% (p< 0.0001) and 96% (p< 0.0001) cell death, respectively, after 8 days, compared to scrambled control. We next tested Triptolide, a BER inhibitor, and it led to cell death in vitro with IC50s of 1.1 to 1.7 nM. Taken together, these results indicate that inhibition of the BER pathway, specifically of the scaffolding-protein XRCC1, could be used as a novel therapeutic approach for diffuse hemispheric glioma, H3.3G34-mutant.
DDEL-01. UTILIZING SENSOR ARRAYS FOR INTRACRANIAL PRESSURE (ICP) RESPONSE TO CEREBROSPINAL FLUID (CSF) DRUG ADMINISTRATION, AND POTENTIAL IMPLICATIONS FOR PERSONALIZED CARE IN CNS METASTASES PATIENTS
Authors: Vanjani Nisheka , Patel Rajan , Glicksman Marcie , Lee Grace , Kumthekar Priya
Published: November 2023

BACKGROUND

Patients with leptomeningeal carcinomatosis (LC) may have elevated intracranial pressure (ICP) due to LC cancer cells having the potential to obstruct the arachnoid granulations.,Given that LC treatment may involve intrathecal (IT) drug delivery, monitoring ICP may be important for safe IT drug delivery. The EnClear device is a novel CNS drug delivery device with both intracranial and intralumbar CSF access and single-use sensing arrays that measure ICP in these dual locations.

METHODS

This is a non-human primate (NHP) study on three healthy NHP subjects undergoing IT gene therapy via intracerebroventricular (ICV). The sensor arrays measured ICP before, during, and after ICV infusion in both intracranial and lumbar locations. Our goal was to compare individual subject pressure response to drug administration as well as to compare lumbar and cranial pressure waveforms for concordance. Pressure response was quantified as change in pressure (ΔP) following volume (ΔV) administration, known as intracranial elastance (ΔP/ΔV).

RESULTS

Significant correlations were observed between ventricular and lumbar ICP waveforms with an average of 0.88 correlation coefficient. Pressure measurements between subjects demonstrated variable response to identical infusion volumes, with maximum pressures ranging from 20 mmHg to 40 mmHg. Intracranial elastance was calculated for each subject during infusions and resulted in a range of 12 to 36 mmHg/mL, a 3-fold difference in elastance between subjects.

CONCLUSION

In healthy NHPs, changes to cranial volume and pressure response can be measured in the lumbar space with good correlation between the two measurement locations. Despite this consistency between these two locations on the same subject, intersubject variability was seen despite identical drug administration. Pressure waveform sensing systems can be incorporated in the future to enable clinicians to understand individual patient brain compliance and leverage this knowledge for personalized drug delivery, particularly in patients with LC.
DDEL-11. FOCUSED ULTRASOUND-MEDIATED DELIVERY OF ANTI-PROGRAMMED CELL DEATH-LIGAND 1 ANTIBODY TO THE BRAIN OF A PORCINE MODEL
Authors: Fadera Siaka , Chukwu Chinwendu , Stark Andrew H , Yue Yimei , Yuan Jinyun , Chien Chih-Yen , Xu Lu , Albuhssin Mohammad , Chen Hong
Published: November 2023

Focused ultrasound-combined with microbubble-mediated blood-brain barrier opening (FUS-BBBO) has been established as a promising brain drug delivery technology for the treatment of brain tumors. Immune checkpoint inhibitor therapy is a form of cancer immunotherapy that has revolutionized the treatment of cancer and shown remarkable efficacy in a range of cancers. Previous studies reported successful delivery of a checkpoint inhibitor anti-PD-L1 antibody (aPD-L1) by FUS-BBBO in the mouse brain. The objective of this study was to evaluate the feasibility and safety of FUS-BBBO in the delivery of aDP-L1 to the brain of a large animal model. Pigs (4 weeks old, male, n=3) were used as the large animal model. A FUS transducer (frequency of 650 kHz, aperture of 65 mm, and a focal length of 65 mm) was used to sonicate three different brain regions in the presence of systemically injected microbubbles (Definity) for every pig. Near-infrared fluorescent dye-labeled aPD-L1 was injected intravenously to the pig after FUS sonication. Contrast-enhanced MRI was conducted to evaluate the BBB permeability. Pig brains were then harvested and imaged by the Licor Pear imaging system. Successful BBBO was confirmed by in vivo T1-weighted MR imaging. The average MR contrast enhancement volume in the FUS-targeted regions was 4.8× of that in the contralateral non-targeted regions. Ex vivo fluorescence imaging found that FUS sonication enhanced aPD-L1 delivery by 2.1× compared with the non-targeted regions. Histological analysis by hematoxylin and eosin (H&E) staining did not find evidence for tissue damage. These findings suggest that FUS-BBBO can achieve noninvasive, localized, and safe delivery of aPD-L1 to the brain of large animals, providing strong preclinical data to support the clinical translation of this promising technique for brain cancer immunotherapy.
DDEL-12. A CONFORMABLE IMPLANTABLE DEVICE - MICROMESH - FOR THE SUSTAINED DELIVERY OF CHEMOTHERAPEUTIC MOLECULES AND IMMUNE CHECK POINT INHIBITORS AGAINST HIGH-GRADE GLIOMAS
Authors: Palange Anna Lisa , Guerriero Irene , Pesce Cristiano , Mascolo Daniele Di , Decuzzi Paolo
Published: November 2023

High-grade gliomas, like glioblastoma (GBM), continue to have a poor prognosis with therapeutic options limited to maximal safe resection and adjuvant radiochemotherapy. Effective treatment is hampered by the blood-brain barrier, limiting the intratumor permeation of systemically administered agents; and biological heterogeneity of malignant cells, requiring complex therapeutic regimens. A conformable, compartmentalized polymeric implant – microMESH – has been engineered to overcome these obstacles by realizing a localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines. In the present configuration, microMESH comprises a water-soluble polyvinyl alcohol microlayer, loaded with the immune checkpoint aCD47, intercalated with a microfabricated network of poly lactic-co-glycolic acid, carrying docetaxel (DTXL). Upon deposition over the tumor margins, microMESH adheres and conforms to the local tissue releasing thereof its therapeutic cargo for several weeks, circumventing possible systemic toxicity. Gel permeation chromatography, nuclear magnetic resonance spectroscopy, weight and pH variations were measured to assess the microMESH biodegradation over time. microMESH biocompatibility and cytotoxicity were assessed on cancer cell monolayers and spheroids. The preclinical performance of microMESH was evaluated in two syngeneic mouse models of high-grade gliomas obtained via the intracranial inoculation of murine cancer cells – CT-2A, cold tumor; GL261, hot tumor. Flow cytometry was used to map the immune component in the tumor and assess the expression of immune checkpoints. Bioluminescence imaging was used to monitor tumor proliferation longitudinally. microMESH biodegraded in ~2 months with no documented toxicity. Preliminary experiments with an aCD47/DTXL–microMESH applied over the unresected margins of an orthotopic CT-2A model documented a median overall survival of 33.5 days against 18 days for untreated mice, 22 days for intravenously injected DTXL, 24 days for intraperitoneally administered aCD47 (statistically not significant difference among the control groups). microMESH allowed the sustained delivery of complex combination therapies directly at the tumor bed demonstrating superior efficacy over systemic therapies.
DDDR-13. ST-401, A BRAIN PENETRATING MICROTUBULE TARGETING AGENT THAT KILLS GLIOBLASTOMA IN INTERPHASE AND BY DISRUPTING MITOCHONDRIA FUNCTION
Authors: Khan Kainat , Sarroza Dennis , Vicente Juan , Wordeman Linda , Sancak Yasemin , Stella Nephi
Published: November 2023

The development of small molecular entities that can effectively penetrate the blood-brain barrier and kill glioblastoma (GBM) is crucial in Neuro-Oncology. ST-401, a unique microtubule depolymerizer, has shown remarkable potential as a therapeutic agent for GBM in PD-GBM isolates (nanomolar potencies) and in vivo preclinical GBM models (potencies DNA-damaging agents). This study aims to investigate the novel mechanism of action of ST-401 and its impact on GBM cell death. We recently showed that increasing concentrations of ST-401 disrupts mitochondrial function, leading to cell death initially in interphase and then in mitosis. Through single-cell RNA sequencing analysis, significant changes in mRNA related to mitochondrial functions were observed, including ribosomal proteins and OXPHOS genes. The study focuses on the role of mitochondria in GBM tumorigenesis and explores how ST-401 affects mitochondrial OXPHOS function. We identified three GBM cell lines (U251, SNB-19, and SF-539) with increasing vulnerability to ST-401, respectively, as measured by using WST-1, an index of mitochondria OXPHOS. Further investigation using the Seahorse platform demonstrated that SF-539 cells treated with ST-401 exhibited a loss of spare capacitance and significantly reduced mitochondrial function, including basal and maximal OXPHOS response, as well as ATP production. In conclusion, our results emphasize the existence of specific subtypes of GBM that show vulnerability or resistance to the antitumor effects of ST-401. Identifying these subtypes is crucial for advancing precision Neuro-Oncology and facilitating human trials. Our results also suggest that ST-401's inhibition of microtubule function and induction of cell death in interphase are associated with the loss of mitochondrial respiratory function. Given the limited treatment options for brain tumors and the challenges in delivering drugs across the blood-brain barrier, the development of brain-penetrant drugs like ST-401 holds great promise. Funded by NIH (CA244213 to NS and NS106924 to NS).