Recurrent Glioblastoma Patients Research Articles

Abstract CT125: A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma

Abstract Background: This Phase 0/2 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of newly-diagnosed and recurrent glioblastoma (GBM) patients to the PARP1/2 selective inhibitors, pamiparib and olaparib, in combination with radiotherapy. Materials/Methods: In this study, newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID) prior to resection. In the Phase 0 component of the study total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in Gd-nonenhancing tumor, determined eligibility for Phase 2. PARP inhibition was assessed via ex vivo tumor tissue radiation and quantification of PAR levels compared to non-irradiated control. When demonstrating a PK response, newly-diagnosed, MGMT-unmethylated GBM or recurrent GBM patients were eligible for Phase 2 dosing of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. Results: A total of 41 patients (Arm A, n=16; Arm B, n=19; Arm C, n=6) were enrolled in the Phase 0 component of the study. In Arms A and B, mean unbound concentrations of pamiparib in Gd-nonenhancing tumor were 167.3 nM and 104.3 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n=35) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.82 in Arm B (p<0.01) and 1.11 in Arm C patients. In Arm A, 7 of 11 MGMT-unmethylated GBM patients advanced to Phase 2. Two patients were ineligible due to clinical status, 1 patient was ineligible per physician decision, and 1 patient declined to participate. In Arm B, 11 of 19 patients advanced to Phase 2. Eight patients were ineligible due to clinical status. At a mean follow-up of 5.8 months, median progression-free survival (PFS) was 5.8, 6.0, and 3.8 months for Arms A (n=7), B (n=11), and C (n=1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulted in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Conclusions: Pamiparib achieved pharmacologically-relevant concentrations in Gd-nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of newly-diagnosed patients with MGMT-unmethylated GBM and recurrent GBM patients advanced to therapeutic dosing in this trial, and pamiparib was generally well-tolerated in these patients. Citation Format: Nader Sanai, Yu-Wei Chang, Jun Jiang, Jennifer Molloy, Chelsea Pennington-Krygier, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Jing Li, Shwetal Mehta. A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT125.

Abstract CT019: Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial

Abstract Background: Glioblastoma (GBM) has dismal prognosis, where median survival is approximately 12 months for patients harboring unmethylated O6−methylguanine DNA methyltransferase (MGMT) promoter (uMGMT) due to temozolomide (TMZ) chemotherapy resistance. In preclinical studies, we showed that sequential administration of bortezomib (BTZ) prior to TMZ depleted MGMT protein, abrogated autophagic flux and sensitized uMGMT GBM cells to TMZ. Thus, a phase I/II was launched to investigate clinical benefit. An interim analysis based on Simon´s MinMax design (where at least 2 patients should show clinical benefit amongst the first 15 evaluable patients) would allow the study to continue to full recruitment. Clinical benefit, was defined by progression free survival and or objective radiological complete (CR), partial (PR) responses or stable disease (SD) based on RANO criteria at 6 months and 1-year follow-up. This study aimed to identify the biological mechanisms underlying the objective responses in the initial 15 recurrent GBM patients treated in this trial. Methods: Adult recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, Karnofsky performance status (KPS) ≥70 and with measurable lesions were enrolled. They received BTZ 1.3mg/m2 IV on days 1,4,7, during each 4-week cycle starting on day 3 with per oral TMZ at 200mg/m2 5 days/week. The sample size was powered for n=63 patients. Quantitative LC-MS/MS was used to identify novel biomarkers that correlate with objective treatment responses by determining proteomic changes in plasma collected on days 1,4,7,11,15 and 22 during first cycle of treatment. Targeted sequencing of 360 cancer genes and whole exome sequencing (WES) of tumor DNA were conducted to identify associated molecular genetic changes. Results: The 15 patients had median age 52 yrs (range 25-62 yrs), 10 male and 5 female treated at Haukeland University Hospital in Norway. Median KPS was 90 (70-100) and median NANO score was 1 (0-7). 27% (n=4/15) of patients obtained objective radiological responses, where 2/4 (50%) obtained PR and 2/4 (50%) had SD. LC-MS/MS revealed significantly increased (p<0.05) levels of proteins important for regulation of cell death and apoptosis (ADAMTS13, HPR, HBD, CLU and APOE) in objective responders compared to the rest of the patients. Sequential BTZ+ TMZ therapy was safe, tolerated and platelet nadirs consistently normalized by day 22 of each cycle. Proteins associated with platelet activation, aggregation and degranulation (ACTN1, ITGB3, PLEK, PPBP, THBS1, TF, TAGLN2, TLN1, PFN1, VCL and FERMT3) were significantly upregulated (1.6-4.8 fold, p<0.05) on day 15 and 22 compared to baseline in patient plasma. Preliminary analysis of sequencing data identified EGFR gain-of-function mutation in 3 of the 4 responder patients; potentially distinguishing this as a molecular biomarker for the objective treatment responders. Conclusion: Sequential BTZ+TMZ therapy is safe and effective as indicated by objective radiological response. Activation of tumor cell death and apoptosis pathways was observed specifically in objective responders. The interim criteria were fulfilled as 4 amongst the first 15 patients showed clinical benefit. The study is currently recruiting. Citation Format: Mohummad Aminur Rahman, Dorota Goplen, Andreas Waha, Leif Oltedal, Judit Haasz, Surendra Kumar, Even Birkeland, Hrvoje Miletic, Frode Selheim, Martha Chekenya. Biological mechanisms underlying objective responses in recurrent GBM patients treated with sequential bortezomib and temozolomide: An interim analysis of NCT03643549 Phase IB/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT019.

494 Evaluating ERK1 2 Phosphorylation as a Predictive Biomarker for Survival in Recurrent Glioblastoma Patients: A REMARK Criteria-guided Analysis of a Clinical Trial Cohort Treated With Intracerebral PD-1 and CTLA-4 Blockade

INTRODUCTION: Glioblastoma patients exhibit variable clinical responses to anti-PD-1 immunotherapy. Our previous work identified ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples as a predictive biomarker of overall survival in two independent cohorts of recurrent glioblastoma patients undergoing adjuvant anti-PD-1 therapy (Arrieta et al, Nat Cancer, 2021). This biomarker, however, has not yet been explored with alternative immune checkpoint blockade strategies nor assessed using REMARK criteria. METHODS: Adhering to REMARK criteria for biomarker validation, we investigated p-ERK as a predictor of survival in 24 evaluable recurrent glioblastoma patients from a clinical trial (NCT03233152; Duerinck J, et al, JITC, 2021). Patients underwent intracerebral administration of immune checkpoint inhibitors within a phase I clinical trial, receiving either ipilimumab (10 mg), or a combination of ipilimumab (5 mg) and nivolumab (10 mg), followed by postsurgical intravenous nivolumab (10 mg). We quantified p-ERK+ cell density in tumor regions and conducted a double-blinded statistical analysis of p-ERK’s association with survival outcomes, performed by an independent statistical team. RESULTS: Although analysis of the entire cohort revealed no statistically significant survival difference between patients with high and low p-ERK tumors (p = 0.29), a focused examination of wild-type IDH GBM patients demonstrated a significantly prolonged survival for those with high p-ERK tumors (median survival = 55.6 weeks, 95% CI 33.86-NA) compared to those with low p-ERK tumors (median OS of 30 weeks, 95% CI 16.14-NA; p = 0.036). CONCLUSIONS: Despite the limited sample size, this study highlights the promising predictive potential of p-ERK as a biomarker in a third independent prospective glioblastoma cohort treated with a novel immune checkpoint blockade administration approach, emphasizing the need for further investigation and validation in larger cohorts.

Real-Time MRI Stereotaxis Aided Smartflow Convection Delivery of DNX-2401

INTRODUCTION: The Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) study is a phase II clinical trial testing the efficacy of a recombinant adenovirus DNX-2401 combined with the immune checkpoint inhibitor pembrolizumab. METHODS: Prospective case series. RESULTS: Precise catheter placement was achieved in all patients treated, and no adverse events were noted. Average radial error from target was 0.9 mm. The average procedural time was 3 hours and 16 minutes, and comparable to other CED techniques. In two patients, delivery of DNX-2401 was visualized as T1-hypointensity using an MRI taken within 30 minutes of procedure completion. These patients exhibited partial response based on RANO assessment. Infusion associated T1-hypointensity in tumor core was not seen in the other patients, who showed no evidence of therapeutic response. CONCLUSIONS: Our pilot study supports the safety of MRI guided SmartFlow convection delivery of the DNX-2401 adenovirus in recurrent glioblastoma patients. Visualization of drug delivery may serve as an imaging biomarker for therapeutic response.

Innovative approaches to enhance high-LETd tumor targeting in carbon ion radiotherapy

Abstract Purpose To present novel approaches in particle therapy that could result in an improvement of patient outcome. Methods Technological/planning and biological innovations could bring particle therapy into a new area of precision medicine. However, several hurdles have to be overcome in order to transform these R&D opportunities into clinical advantages. In this contribution, we summarize the potential advantages of novel tumor targeting, through high-LETd boosting strategies with carbon ions, over standard IMPT: LETd-optimization for IMPT plan, IMPTLET, and spot-scanning hadron arc (SHArc) therapy. Two patient cases are presented to showcase the benefit: a pancreatic cancer patient (PATA) and a recurrent glioblastoma patient (PATB). Results For both patients, the prescription dose and target/organs at risk (OARs) optimization goals were reached for the three techniques. In standard IMPT, the maximum LETd is placed outside of the target volume and extends into normal tissues. For the gross target volume (GTV), mean LETd values were, on average, around ∼40–60 keV/µm. IMPTLET allowed an increase in the GTV minimum LETd from 38.4 keV/µm to 48.6 keV/µm, and from 55.1 to 87.1 keV/µm, for PATA and PATB, respectively. SHArc led to an enhancement of the maximum LETd in the GTV up to at least 125 keV/µm, while the minimum GTV LETd were 47.2 keV/µm and 46.1 keV/µm, respectively. For PATA, SHArc lowers the maximum LETd in the gastrointestinal tract to 47.5 keV/µm compared to 88.0 keV/µm and 83.0 keV/µm found for the IMPT and IMPTLET plans, respectively. Conclusions Many technological and biological innovations could enhance our current clinical approach. Following the current success of the IMPTLET introduction in clinic, SHARc will represent an interesting clinical option in carbon ion therapy.

Abstract 2119: Translational research to facilitate development of novel therapeutic combinations of letrozole for the treatment of glioblastoma

Abstract Letrozole (LTZ), a third-generation aromatase inhibitor, appears to be a promising novel therapeutic for the treatment of glioblastoma (GBM). It synergistically enhances the efficacy of the DNA alkylating agent temozolomide, one of the few approved chemotherapeutics for GBM, against patient-derived GBM cells. RNA-seq analysis of tumor from recurrent GBM patients treated with LTZ prior to surgery in a “window of opportunity” phase 0/1 dose escalation clinical trial revealed that LTZ downregulates genes encoding for DNA-damage repair proteins (BRCA2) in a dose dependent manner. Our central hypothesis for this project is that combination of LTZ with targeted therapeutic agents that promote DNA damage results in synergistic effects against GBM. The objective of this study is to evaluate the effects of poly-ADP ribose polymerase (PARP) inhibitors in combination with LTZ against patient-derived GBM cells. Our secondary aim for this project is to delineate the blood-brain barrier (BBB) permeability of PARP inhibitors. Employing patient-derived G43, G75 and JHH-136 GBM lines we assessed the influence of PARP inhibitors (olaparib, pamiparib, veliparib and niraparib) in combination with LTZ on cell viability and neurosphere growth. We then utilized male CD-IGS rats (n=6; body wt., 250g) to assess plasma and brain extracellular fluid (ECF) pharmacokinetics (PK) of PARP inhibitors using cerebral microdialysis. The IC50 values for PARP inhibitors in these assays ranged from 0.06 to 11.31 µM. Treatment in combination with LTZ (0.05 µM), a non-cytotoxic concentration of LTZ in these lines, significantly decreased the IC50 values for PARP inhibitors (0.012 to 0.51 µM). Combination Index analysis indicated that this combination was strongly synergistic. Furthermore, the plasma and brain ECF PK analyses suggested that PARP inhibitors such as pamiparib and niraparib exhibit facile transport across the BBB barrier as reflected in Kp,uu,brain (ratio of AUCecf/AUCplasma, unbound) values of 0.98 and 0.45, respectively. Overall, these results provide a strong foundation for pursuing further development of combination therapy of GBM with LTZ and PARP inhibitors. A careful assessment of the clinical efficacy and safety profile of these agents will further guide shortlisting combination of LTZ for pre-clinical and clinical development. Citation Format: Aniruddha Sunil Karve, Bhavesh Babulal Gabani, Sidharth Nitin Gadgil, Shravani Parag Kulkarni, Gary A. Gudelsky, Pankaj B. Desai. Translational research to facilitate development of novel therapeutic combinations of letrozole for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2119.

Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

Single-cell atlas reveals the immunosuppressive microenvironment and Treg cells landscapes in recurrent Glioblastoma.

Patients diagnosed with glioblastoma (GBM) have the most aggressive tumor progression and lethal recurrence. Research on the immune microenvironment landscape of tumor and cerebrospinal fluid (CSF) is limited. At the single-cell level, we aim to reveal the recurrent immune microenvironment of GBM and the potential CSF biomarkers and compare tumor locations. We collected four clinical samples from two patients: malignant samples from one recurrent GBM patient and non-malignant samples from a patient with brain tumor. We performed single-cell RNA sequencing (scRNA-seq) to reveal the immune landscape of recurrent GBM and CSF. T cells were enriched in the malignant tumors, while Treg cells were predominately found in malignant CSF, which indicated an inhibitory microenvironment in recurrent GBM. Moreover, macrophages and neutrophils were significantly enriched in malignant CSF. This indicates that they an important role in GBM progression. S100A9, extensively expressed in malignant CSF, is a promising biomarker for GBM diagnosis and recurrence. Our study reveals GBM's recurrent immune microenvironment after chemoradiotherapy and compares malignant and non-malignant CSF samples. We provide novel targets and confirm the promise of liquid CSF biopsy for patients with GBM.

Intranasal Delivery of Perillyl Alcohol (NEO100) as a New Treatment Strategy for Glioma

Background: Perillyl alcohol (POH) is a naturally occurring monoterpene that is being developed as an intranasally delivered agent for the treatment of brain-localized malignancies. Clinical trials with glioma patients in Brazil have yielded preliminary evidence that this approach might be able to achieve therapeutic activity and result in prolonged survival of patients. Methods: NEO100, a highly pure, current good manufacturing practice-produced version of POH, is being evaluated in a Phase I/IIa clinical trial with recurrent glioblastoma patients in the United States. Patients self-administer POH/NEO100 as a mist with a nasal mask over the course of 15 minutes, four times a day, every day. Results: The treatment regimen is well tolerated, even if maintained over several years. It correlated with improved survival when compared to historical controls. Conclusion: There is human data demonstrating that this novel approach could become useful for the treatment of malignant glioma. Clinical Trial Registration Number:: NCT02704858

Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.

Metabolomic characterization of human glioblastomas and patient plasma: a pilot study

Background Glioblastoma (GBM) is a clinically challenging primary brain tumor with poor survival outcome despite surgical resection and intensive chemoradiation. The metabolic heterogeneity of GBM can become biomarkers for treatment response, resistance, and outcome prediction. The aim of the study is to investigate metabolic distinctions between primary and recurrent GBM tissue and patient plasma to establish feasibility for metabolic profiling. Methods A single-center cohort study analyzed tissue and blood samples from 15 patients with GBM using untargeted metabolomic/lipidomic assays. Metabolomic, lipidomic, and biogenic amine analyses were conducted on GBM tissue and patient plasma at diagnosis and recurrence using untargeted mass spectrometry. The study utilized a small but longitudinally collected cohort to evaluate alteration in metabolites, lipids, and biogenic amines between specimens at diagnosis and recurrence. Results Exploratory analysis revealed significant alteration in metabolites, lipids, and biogenic amines between diagnostic and recurrent states in both tumor and plasma specimens. Notable metabolites differed at recurrence, including N-alpha-methylhistamine, glycerol-3-phosphate, phosphocholine, and succinic acid in tissue, and indole-3-acetate, and urea in plasma. Principal component analysis revealed distinct metabolomic profiles between tumor tissue and patient plasma. Distinct metabolic profiles were observed in GBM tissue and patient plasma at recurrence, demonstrating the feasibility of using metabolomic methodologies for longitudinal studies. One patient exhibited a unique tumor resistance signature at diagnosis, possibly indicating a high-risk metabolomic phenotype. Conclusions In this small cohort, the findings suggest the potential of metabolomic signatures of GBM tissue and patient plasma for risk stratification, outcome prediction, and the development of novel adjuvant metabolic-targeting therapies. The findings suggest metabolic discrepancies at diagnosis and recurrence in tissue and plasma, highlighting potential implications for evaluation of clinical response. The identification of significant changes in metabolite abundance emphasizes the need for larger studies using targeted metabolomics to validate and further explore these profiles.

GammaTile® (GT) as a brachytherapy platform for rapidly proliferating glioblastomas: from case series to clinical trials.

Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 (131Cs) brachytherapy platform for such aggressive tumors. We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement. There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2days (range: 1-5days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347days (11.6months), median progression free survival of ≥ 320days (10.6months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively. Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design.

Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = −0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

Intraoperative radiotherapy in recurrent IDH-wildtype glioblastoma with gross total resection: A single-center retrospective study

BackgroundIsocitrate dehydrogenase-wildtype (IDHwt) glioblastoma (GBM) is one of the most aggressive primary brain tumors. The recurrence of GBM is almost inevitable. As an adjuvant option to surgery, intraoperative radiotherapy (IORT) is gaining increasing attention in the treatment of glioma. This study is aimed to evaluate the therapeutic efficacy of IORT on recurrent IDHwt GBM. MethodsIn total, 34 recurrent IDHwt GBM patients who received a second surgery were included in the analysis (17 in the surgery group and 17 in the surgery + IORT group). ResultsThe progression-free survival and overall survival after the second surgery were defined as PFS2 and OS2, respectively. The median PFS2 was 7.3 months (95% CI: 6.3–10.5) and 10.6 months (95% CI: 9.3–14.6) for those patients who received surgery and surgery + IORT, respectively. Patients in the surgery + IORT group also had a longer OS2 (12.8 months, 95% CI: 11.4–17.2) than those in the surgery group (9.3 months, 95% CI: 8.9–12.9). The Kaplan–Meier survival curves, analyzed by log-rank test, revealed a statistically significant difference in PFS2 and OS2 between both groups, suggesting that IORT plays an active role in the observed benefits for PFS2 and OS2. The effects of IORT on PFS2 and OS2 were further confirmed by multivariate Cox hazards regression analysis. Two patients in the surgery group developed distant glioma metastases, and no radiation-related complications were observed in the IORT group. ConclusionsThis study suggests that low-dose IORT may improve the prognosis of recurrent IDHwt GBM patients. Future prospective large-scale studies are needed to validate the efficacy and safety of IORT.

A Systematic Review of Nanomedicine in Glioblastoma Treatment: Clinical Efficacy, Safety, and Future Directions.

(1) Background: Glioblastoma (GBM) is categorized as a grade IV astrocytoma by the World Health Organization (WHO), representing the most aggressive and prevalent form of glioma. It presents a significant clinical challenge, with limited treatment options and poor prognosis. This systematic review evaluates the efficacy and safety of various nanotherapy approaches for GBM and explores future directions in tumor management. Nanomedicine, which involves nanoparticles in the 1-100 nm range, shows promise in improving drug delivery and targeting tumor cells. (2) Methods: Following PRISMA guidelines, a systematic search of databases including Google Scholar, NCBI PubMed, Cochrane Library, and ClinicalTrials.gov was conducted to identify clinical trials on GBM and nanomedicine. The primary outcome measures were median overall survival, progression-free survival, and quality of life assessed through Karnofsky performance scores. The safety profile was assessed by adverse events. (3) Results: The analysis included 225 GBM patients, divided into primary and recurrent sub-populations. Primary GBM patients had a median overall survival of 6.75 months, while recurrent GBM patients had a median overall survival of 9.7 months. The mean PFS period was 2.3 months and 3.92 months in primary GBM and recurrent GBM patients, respectively. Nanotherapy showed an improvement in quality of life, with KPS scores increasing after treatment in recurrent GBM patients. Adverse events were observed in 14.2% of patients. Notably, Bevacizumab therapy exhibited better survival outcomes but with a higher incidence of adverse events. (4) Conclusions: Nanotherapy offers a modest increase in survival with fewer severe side effects. It shows promise in improving the quality of life, especially in recurrent GBM patients. However, it falls short in terms of overall survival compared to Bevacizumab. The heterogeneous nature of treatment protocols and reporting methods highlights the need for standardized multicenter trials to further evaluate the potential of nanomedicine in GBM management.

Abstract B038: Clinical and biological activity of ST101, a peptide antagonist of C/EBPβ, in recurrent Glioblastoma (rGBM) patients. Results from the rGBM cohort of a multi-cohort Phase 2 Study

Abstract Background: CCAAT/enhancer-binding protein β (C/EBPβ) is a master regulator of mesenchymal transformation in GBM (Carro, 2010) and has been proposed as a master regulator of the immunosuppressive M2 program in macrophages. ST101 is a first-in-class peptide antagonist of C/EBPβ, that promotes selective tumor cell death in multiple cancers without impacting normal cell viability (Darvishi, 2022). Additionally, we have shown in vitro that ST101 induces a shift in PBMC-derived M2 macrophages and human iPS-derived microglia, resident macrophage of the CNS, from an M2-like immunosuppressive phenotype toward an immune-active M1-like identity. Methods: In an ongoing Phase 1-2 study (NCT04478279), we enrolled a cohort of patients (pts) with rGBM. The primary objective was to evaluate the safety/tolerability of ST101 and assess efficacy parameters. Patients with progressive disease (PD) after standard first-line treatment (surgery, radiation, and temozolomide) were enrolled and treated with monotherapy ST101 500 mg, IV, QW. Disease assessment by MRI was performed every 9 weeks, and response assessed by mRANO. Results: As of 05 July 2023, 33 pts were enrolled, and 30 were evaluable for efficacy. Clinical activity was observed in 9 pts, with 30% disease control rate (DCR) composed of 1 patient with a PR (for 54 weeks) and 8 patients with stable disease (SD) (median of 5 months (~3 – 8 months)). Two pts with SD remain on treatment, 16 pts are still alive, and evaluation of survival is still ongoing. Current median OS (95% CI) is 9.8 months (7.3-NE), with a 6-month OS of 74%. Analysis of tumor tissue from a pt with pseudo-PD and who was clinically stable for >22 weeks and underwent tumor resection 21 days after discontinuation of ST101, showed significant geographical necrosis within the tumor. The tumor also stained positive for ST101 by immunohistochemistry (IHC), demonstrating blood-brain-barrier penetration as well as long-standing retention. Tissue samples assessment from a sub-study in rGBM patients are currently under evaluation. The assessment will include gene expression and IHC analysis and aim to determine whether ST101 restricts glioblastoma growth by direct suppression of glioblastoma cells, reprogramming of macrophages and microglia toward an immune-promoting and cancer-suppressive phenotype, or both. ST101 was shown to be safe and well tolerated, with infusion-related reactions (IRR) being the most commonly reported AE. IRRs are managed by pre-medication (antihistamines and leukotriene antagonist) and infusion rate adjustment, and show tolerance over time, with 79% of patients having IRRs on the first infusion with 21% on the eighth infusion. Conclusion: ST101 as a single agent demonstrated clinical activity and tissue treatment effect. Assessment of tissue samples from a sub-study in rGBM pts is ongoing and aiming to determine the MOA of ST101 directly on tumors and within the tumor microenvironment. Encouraging response and survival data warrants further assessment of ST101 in combination therapy for the treatment of pts with GBM. Citation Format: Fabio Iwamoto, Robin Buerki, Nicholas Butowski, Katherine B. Peters, Anja Williams, Gerald Falchook, Jim Rotolo, Rob Michel, Stephen Kaesshaefer, Claudio Scuoppo, Abi Vainstein-Haras. Clinical and biological activity of ST101, a peptide antagonist of C/EBPβ, in recurrent Glioblastoma (rGBM) patients. Results from the rGBM cohort of a multi-cohort Phase 2 Study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B038.

Comparison between [68Ga]Ga-PSMA-617 and [18F]FET PET as Imaging Biomarkers in Adult Recurrent Glioblastoma.

The aim of this prospective clinical study was to evaluate the potential of the prostate specific membrane antigen (PSMA) targeting ligand, [68Ga]-PSMA-Glu-NH-CO-NH-Lys-2-naphthyl-L-Ala-cyclohexane-DOTA ([68Ga]Ga-PSMA-617) as a positron emission tomography (PET) imaging biomarker in recurrent glioblastoma patients. Patients underwent [68Ga]Ga-PSMA-617 and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET scans on two separate days. [68Ga]Ga-PSMA-617 tumour selectivity was assessed by comparing tumour volume delineation and by assessing the intra-patient correlation between tumour uptake on [68Ga]Ga-PSMA-617 and [18F]FET PET images. [68Ga]Ga-PSMA-617 tumour specificity was evaluated by comparing its tumour-to-brain ratio (TBR) with [18F]FET TBR and its tumour volume with the magnetic resonance imaging (MRI) contrast-enhancing (CE) tumour volume. Ten patients were recruited in this study. [68Ga]Ga-PSMA-617-avid tumour volume was larger than the [18F]FET tumour volume (p = 0.063). There was a positive intra-patient correlation (median Pearson r = 0.51; p < 0.0001) between [68Ga]Ga-PSMA-617 and [18F]FET in the tumour volume. [68Ga]Ga-PSMA-617 had significantly higher TBR (p = 0.002) than [18F]FET. The [68Ga]Ga-PSMA-617-avid tumour volume was larger than the CE tumour volume (p = 0.0039). Overall, accumulation of [68Ga]-Ga-PSMA-617 beyond [18F]FET-avid tumour regions suggests the presence of neoangiogenesis in tumour regions that are not overly metabolically active yet. Higher tumour specificity suggests that [68Ga]-Ga-PSMA-617 could be a better imaging biomarker for recurrent tumour delineation and secondary treatment planning than [18F]FET and CE MRI.

CTNI-39. REGOMA-OS: A LARGE ITALIAN MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY ANALYZING REGORAFENIB EFFICACY AND SAFETY IN RECURRENT GLIOBLASTOMA PATIENTS

Abstract BACKGROUND in the randomized phase 2 REGOMA trial, regorafenib (REG) showed promising activity in recurrent glioblastoma (GBM) patients (PTS); subsequently, in Italy the National Health System has permitted the reimbursement of the REG as second-line therapy. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting. Materials and METHODS major inclusion criteria were: histologically confirmed diagnosis of GBM according to WHO 2016 and relapse after Stupp treatment, good performance status (ECOG PS 0-1), good liver function. REG was administered at standard dose of 160mg/die for 3 weeks on/1 week off. Brain MRI was performed within 14 days before starting REG and every 8-12 weeks, subsequently. Primary endpoint was overall survival. RANO criteria were used for response evaluation, CTACAE v. 5 for adverse events. RESULTS from Sept 2020 to Oct 2022, 192 recurrent GBM PTS were enrolled from 29 Cancer Centres in Italy: median age was 58ys (IQR 52.8-67.0), 68% male, ECOG PS was 0 in 85 (44%), 115 PTS (60%) undertook steroids at baseline. MGMT was methylated in 43%, IDHwt in 92%. Median follow-up was 16.6 months (IQR 12.6-19.6). Median OS was 8.2ms (95% CI 6.5-9.6), 12ms-OS 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS 14.3%. Radiological response was PR and SD in 12 (8%) and 25 (16%) PTS. 77 (44%) PTS received third-line therapy. The median of REG cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 adverse events (AE) were reported in 53 (28%) PTS; reduction/delay and permanent discontinuation due to AE in 36% and 8% of PTS. No death was considered as treatment-related AE. CONCLUSIONS compared to the REGOMA trial, this large Italian multicenter, prospective and observational trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.

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

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.

CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS

Abstract STUDY DESIGN MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons. METHODS Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ. RESULTS Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated. CONCLUSION CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.