Convection-enhanced Delivery Research Articles

EXTH-68. SYSTEMIC NEUTRALIZATION OF IL6 SENSITIZES IDH-WILDTYPE GLIOBLASTOMA PRECLINICAL MODELS TO IMMUNE CHECKPOINT INHIBITION

Abstract IDH-wildtype glioblastomas are resistant to immune checkpoint inhibition (ICI). Here we integrate spatial and single-cell approaches across paired human glioblastomas before or after ICI with functional studies in immunocompetent intracranial mouse glioblastoma models to reveal mechanisms and therapeutic vulnerabilities underlying glioblastoma resistance to ICI. Spatial proteomic and transcriptomic approaches were used to identify biochemical and gene expression programs underlying ICI response or resistance in paired human glioblastoma samples (n = 7). Intracranial SB28 glioblastoma allografts were implanted in C57BL/6J mice and treated with (1) convection enhanced delivery (CED) of AAV9 gene therapy vectors encoding cytokines that reprogram the tumor immune microenvironment (TIME) in other cancers (Il1b, Ccl4, Apoa1), (2) systemic anti-PD1, (3) local anti-IL6, (4) systemic anti-IL6, or (5) combination systemic treatment with anti-PD1 and anti-IL6. Histological, mass cytometry (CyTOF), and multiplexed cytokine assays were used to assess the glioblastoma TIME in response to treatment over time. Mice were monitored for survival and tumor growth was measured using intracranial bioluminescence. Human glioblastomas with radiographic responses to ICI had lower pre-treatment IL6 levels on spatial profiling than glioblastomas resistant to ICI. Intratumor IL6 was suppressed by all AAV9 cytokine conditions compared to AAV9-GFP in mice. Mouse survival was improved by combination systemic treatment with anti-PD1 and anti-IL6, but was not improved by either antibody alone, or by anti-IL6 CED. CyTOF revealed combination systemic therapy reprogrammed the glioblastoma TIME by increasing activated immune cell types such as MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and by decreasing immunosuppressive Tregs. In summary, systemic anti-IL6 in combination with systemic anti-PD1 reprograms the glioblastoma TIME to sensitize preclinical models to ICI. These results provide mechanistic validation of findings from human glioblastomas that respond to ICI and shed light on a therapeutic vulnerability underlying the glioblastoma TIME.

EXTH-49. A NOVEL MULTIVALENT DRUG CONJUGATE FOR HIGH-GRADE GLIOMA TREATMENT

Abstract Interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed collectively in almost all patients with glioblastoma (GBM), and also in spontaneous canine gliomas, the most faithful model of human disease. The four receptors are widely present in various compartments of GBM tumors, including tumor core, infiltrating cells, tumor neovasculature and tumor-associated macrophages. Thus, the four receptors are expressed in several GBM compartments involved in tumor progression and/or resistance to therapies, covering almost 100% of the tumor microenvironment. In first-of-a-kind approach, we performed Phase I clinical trial in dogs with gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The cocktail was administered loco-regionally through convection-enhanced delivery, using anti-reflux catheters and real-time MRI monitoring of drugs distribution. We observed prominent anti-tumor responses, including several near complete regressions, prolongation of survival and excellent quality of life, although we did not achieve dose-limiting toxicity (Neuro-Oncol 2021;23(3):422-434). Encouraged by these exceptional results, we pursued the novel idea of targeting the four GBM-associated receptors with one pharmaceutical compound. To this end, we designed, produced, and tested a multivalent ligand binding to all four receptors of our interest, termed QUAD, including murine and canine receptors. However, we found that a conjugate of QUAD with DM1, a microtubule-disrupting agent, demonstrated an extremely high (in low picomolar range) and specific killing potency on GBM cells. The IC50s of QUAD-DM1 are ~50 times higher than that for all other QUAD-based drug conjugates tested thus far, having a favorable toxicity profile in rodents when injected either intracranially or intravenously. QUAD-DM1 has already produced up to 95% tumor reduction in dogs with spontaneous brain tumors. QUAD-DM1 is a highly promising agent for the treatment of human and canine high-grade gliomas.

EXTH-20. A MOUSE MODEL REVEALS VULNERABILITY OF IDH1-MUTATED GLIOMA TO FERROPTOSIS

Abstract The molecular classification of gliomas is currently based on the presence of IDH1 mutation, which is associated with better prognosis and longer survival. The hallmark of the IDH1 mutation is the production of D-2-Hydroxyglutarate with subsequent effects that are not fully understood. Ferroptosis, an iron-dependent mechanism of non-apoptotic cell death, is mostly triggered through blocking system Xc- or suppressing the antioxidant enzyme glutathione peroxidase 4 (GPX-4). In this study, we generated a mouse model of glioma harboring the IDH1(R132H) mutation in heterozygous condition, in combination with p53-deletion induced by the expression of PDGFA. We show that IDH1(R132H)-expressing mice survive longer compared to their wild-type counterparts, while histological analysis reveals characteristics of low-grade diffuse gliomas. We generated cell lines from primary tumors and analyzed their metabolic profile and response to mitochondrial stress and Ferroptosis. We treated them in vitro with RSL3, a GPX-4 inhibitor, alone or in combination with Cysteine and Methionine restriction. We show that IDH1(R132H)-expressing cells are far more sensitive to Ferroptosis in vitro. Finally, we show that convection-enhanced delivery of RSL3 in combination with dietary Cysteine and Methionine restriction in vivo, significantly prolongs survival of the IDH1(R132H)-expressing mice. Our findings suggest that Ferroptosis provides promising therapeutic potential worth exploring further and our mouse model could be used to test the efficacy of different treatments for IDH1(R132H) gliomas.

CTNI-52. SURVIVAL OUTCOMES IN RECURRENT GLIOBLASTOMA (RGBM) PATIENTS TREATED WITH A SINGLE INTRA-TUMORAL ADMINISTRATION OF BIZAXOFUSP, AN IL-4R-TARGETING TOXIN, IN A PHASE IIB TRIAL

Abstract BACKGROUND Bizaxofusp (MDNA55) is an IL4R-targeting toxin in development for recurrent (r)GBM, a universally fatal disease with mOS of 6-9 months. IL-4R is overexpressed in GBM and surrounding tumor microenvironment, with high expression associated with poor clinical outcome. Method: Efficacy and safety were evaluated in a single-arm, open-label, multi-center Ph2 study using convection-enhanced delivery of Bizaxofusp. The primary endpoint of mOS was compared to results from a blinded eligibility-matched external control arm (ECA). OS was defined as time from relapse to death/censor. IL-4R expression was determined by immunohistochemistry of available archival tumor tissues from both arms. RESULTS Bizaxofusp showed an acceptable safety profile at doses of up to 240 μg. Forty-four subjects were treated with Bizaxofusp per protocol; 81 ECA subjects met the eligibility criteria of the study. The Bizaxofusp group had a significantly longer mOS (12.85 months compared to 7.7 months for ECA; HR, 0.62; 95% CI, 0.42-0.89). Amongst the unmethylated MGMT and high IL-4R sub-groups, subjects treated with Bizaxofusp had significantly longer mOS when compared to the ECA. Eleven patients (25%) treated with Bizaxofusp survived >24 months; 3 patients were still alive (29.9, 32.8 and 40.1 months) at last follow-up. High IL-4R expression was associated with improved survival (mOS, 15.8 versus 9.8 months; HR, 0.7; 95% CI, 0.39-1.46) at all doses. However at high doses (180 μg) subjects with low IL-4R expression had significantly longer survival versus low dose Bizaxofusp (mOS, 15.4 versus 9.1 months; HR, 0.28; 95% CI, 0.09-0.91). CONCLUSION In patients with rGBM, a single treatment of Bizaxofusp resulted in significantly improved OS compared to eligibility-matched ECA. High-dose Bizaxofusp was equally effective irrespective of IL4R expression. A Phase 3 registration trial will use a novel hybrid design with a propensity-matched ECA comprising two-thirds of the control arm, setting a new precedent for GBM clinical trials.

Magnetic Resonance Imaging–Aided SmartFlow Convection Delivery of DNX-2401: A Pilot, Prospective Case Series

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. Here, we report the first patients in this study who underwent viral delivery through real-time magnetic resonance imaging (MRI) stereotaxis-guided SmartFlow convection delivery of DNX-2401. Patients who underwent real-time MRI-guided DNX-2401 delivery through the SmartFlow convection catheter were prospectively followed. Precise catheter placement was achieved in all patients treated, and no adverse events were noted. Average radial error from target was 0.9 mm. Average procedural time was 3 hours 16 minutes and was comparable to other convection-enhanced delivery techniques. In 2 patients, delivery of DNX-2401 was visualized as >1 cm maximal diameter of T1 hypointensity infusate on MRI obtained immediately after completion of viral infusion. These patients exhibited partial response based on Response Assessment in Neuro-Oncology assessment. The remaining patient showed <1 cm maximal diameter of infusate on immediate postinfusion MRI and showed disease progression on subsequent MRI. Our pilot case series supports compatibility of the SmartFlow system with oncolytic adenovirus delivery and provides the basis for future validation studies.

A Biphasic Fluid-Structure Interaction Model of Backflow During Infusion Into Agarose Gel.

The efficacy of convection-enhanced delivery as a technique to treat disorders of the central nervous system is limited by backflow, in which the infused fluid flows backwards along surface of the catheter rather than towards the targeted area. In order to improve treatment protocols, finite element models of backflow have been developed to understand the underlying physics. Garcia et al. (Journal of Computational and Nonlinear Dynamics, 8:011017, 2013) presented a finite element model that accounted for the flow in the annular gap that develops between the tissue and the outer surface of the catheter by using a layer of biphasic elements with a formula for the axial hydraulic conductivity to represent annular Poiseuille flow. In this study, we present a generalization of that model using fluid-FSI and biphasic-FSI elements that are recently available in FEBio. We demonstrate that our model of a 0.98-mm-radius catheter is able to reproduce experimental backflow lengths and maximum fluid pressures for infusions into a brain tissue surrogate and that it agrees well with the previous model by Garcia et al. (2013). The model predicts that the backflow length and the total amount of flow into the hemispherical region forward of the catheter tip is comparable for two different catheter sizes, albeit at a higher fluid pressure for the smaller catheter. This biphasic-FSI model has the potential to be extended to a stepped catheter geometry, which has been shown in experiments to be successful in controlling backflow.

Harnessing Nuclear Energy to Gold Nanoparticles for the Concurrent Chemoradiotherapy of Glioblastoma

Nuclear fission reactions can release massive amounts of energy accompanied by neutrons and γ photons, which create a mixed radiation field and enable a series of reactions in nuclear reactors. This study demonstrates a one-pot/one-step approach to synthesizing radioactive gold nanoparticles (RGNP) without using radioactive precursors and reducing agents. Trivalent gold ions are reduced into gold nanoparticles (8.6–146 nm), and a particular portion of 197Au atoms is simultaneously converted to 198Au atoms, rendering the nanoparticles radioactive. We suggest that harnessing nuclear energy to gold nanoparticles is feasible in the interests of advancing nanotechnology for cancer therapy. A combination of RGNP applied through convection-enhanced delivery (CED) and temozolomide (TMZ) through oral administration demonstrates the synergistic effect in treating glioblastoma-bearing mice. The mean survival for RGNP/TMZ treatment was 68.9 ± 9.7 days compared to that for standalone RGNP (38.4 ± 2.2 days) or TMZ (42.8 ± 2.5 days) therapies. Based on the verification of bioluminescence images, positron emission tomography, and immunohistochemistry inspection, the combination treatment can inhibit the proliferation of glioblastoma, highlighting the niche of concurrent chemoradiotherapy (CCRT) attributed to RGNP and TMZ.

Long-lasting antiseizure effects of chronic intrasubthalamic convection-enhanced delivery of valproate

Intracerebral drug delivery is an experimental approach for the treatment of drug-resistant epilepsies that allows for pharmacological intervention in targeted brain regions. Previous studies have shown that targeted pharmacological inhibition of the subthalamic nucleus (STN) via modulators of the GABAergic system produces antiseizure effects. However, with chronic treatment, antiseizure effects are lost as tolerance develops. Here, we report that chronic intrasubthalamic microinfusion of valproate (VPA), an antiseizure medication known for its wide range of mechanisms of action, can produce long-lasting antiseizure effects over three weeks in rats. In the intravenous pentylenetetrazole seizure-threshold test, seizure thresholds were determined before and during chronic VPA application (480 μg/d, 720 μg/d, 960 μg/d) to the bilateral STN. Results indicate a dose-dependent variation in VPA-induced antiseizure effects with mean increases in seizure threshold of up to 33%, and individual increases of up to 150%. The lowest VPA dose showed a complete lack of tolerance development with long-lasting antiseizure effects. Behavioral testing with all doses revealed few, acceptable adverse effects. VPA concentrations were high in STN and low in plasma and liver. In vitro electrophysiology with bath applied VPA revealed a reduction in spontaneous firing rate, increased background membrane potential, decreased input resistance and a significant reduction in peak NMDA, but not AMPA, receptor currents in STN neurons. Our results suggest an advantage of VPA over purely GABAergic modulators in preventing tolerance development with chronic intrasubthalamic drug delivery and provide first mechanistic insights in intracerebral pharmacotherapy targeting the STN.

Identifying Gene-Treatment Interactions and Targetable Radiation Vulnerabilities in Glioblastoma through Coupling of In Vivo CRISPR Perturbation and Single Cell Transcriptomics

Glioblastoma (GBM) is an incurable brain tumor comprised of dynamic malignant cell states and microenvironment components that underlie treatment resistance. Here we use genome-wide CRISPR/Cas9 functional genomics to define biological drivers and therapeutic vulnerabilities across human and mouse GBM models. To interrogate these mechanisms in the context of the tumor microenvironment and in vivo physiology, we established in vivo Perturb-seq intracranially, a technique coupling functional genomics with single cell transcriptomics, where each cell is an individual experiment. Orthotopic intracranial tumor models were established using human (GBM6, GBM43) or mouse (GL261, SB28) GBM cells stably expressing CRISPR interference (CRISPRi) machinery. Perturb-seq target selection for phenotyping of gene-treatment interactions was performed using genome-wide CRISPRi screens ± radiotherapy in cell cultures. Dual sgRNA lentivirus libraries were transduced either ex vivo prior to intracranial GBM cell transplantation or in vivo using intratumor convection enhanced delivery (CED). Transcriptional phenotyping was performed using single-cell RNA-seq with CRISPR direct capture following focal brain radiotherapy (2 Gy x 5) or mock treatment. GBM cell states were validated using single-nucleus RNA-seq data from 86 primary-recurrent patient-matched GBMs. Mechanistic and functional validation was performed using small molecule inhibitors, immunohistochemistry, clonogenic assays, and in vivo survival experiments. In vivo Perturb-seq ± radiotherapy of 48 genes underlying GBM radiotherapy responses, which were enriched for DNA damage response and metabolic pathways, was performed in > 425,000 single cells. Radiotherapy induced 16 distinct GBM cell states, and genetic perturbations reprogrammed these cell states in a treatment-dependent fashion. Quantitative modeling of gene/radiotherapy interactions using high dimensional manifolds revealed in vivo-specific genetic dependencies. We revealed a critical role for Prkdc, the catalytic subunit of DNA-dependent protein kinase (DNA-PK), as a radiotherapy sensitizer through regulation of cell intrinsic growth and oxidative stress pathways, and cell extrinsic interferon and signaling pathways that altered cell-cell interactions in vivo. These pathways were also disrupted in single-nucleus RNA-seq analysis of post-radiotherapy human GBM tumors. Inhibition of Prkdc using a Food and Drug Administration approved small molecule sensitized GBM cells to radiotherapy and extended survival in mice harboring human intracranial xenografts. We establish in vivo Perturb-seq in orthotopic GBM models as a platform for simultaneous functional genomic discovery and characterization of therapeutic targets, revealing an underappreciated role for Prkdc in GBM tumors in vivo that is targetable using small molecules. These tools are adaptable for a wide range of disease models and treatment modalities.

Influence of focused ultrasound on locoregional drug delivery to the brain: Potential implications for brain tumor therapy

IntroductionEfficient delivery of therapeutics across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Locoregional drug delivery platforms offer an improved therapeutic index by achieving high drug concentrations in the target tissue with negligible systemic exposure. Intrathecal (intraventricular) [IT] and convection-enhanced delivery [CED] are two clinically relevant methods being employed for various CNS malignancies. Both of these standalone platforms suffer from passive post-administration distribution forces, sometimes limiting the desired distribution for tumor therapy. Focused ultrasound and microbubble-mediated blood-brain barrier opening (FUS-BBBO) is a recent modality used for enhanced drug delivery. It is postulated that coupling of FUS with these alternative delivery routes may provide benefits. Multimodality FUS may provide the desired ability to increase the depth of parenchymal delivery following IT administration and provide a means for contour directionality with CED. Further, the transient enhanced permeability achieved with FUS-BBBO is well established, but drug residence and transit times, important to clinical dose scheduling, have not yet been defined. The present investigation comprises two discrete studies: 1. Conduct a comprehensive quantitative evaluation to elucidate the effect of FUS-BBBO as it relates to varying routes of administration (IT and IV) in its capacity to facilitate drug penetration within the striatal-thalamic region. 2. Investigate the impact of combining FUS-BBBO with CED on drug distribution, with a specific focus on the temporal dynamics of drug retention within the target region. MethodsFirstly, we quantitatively assessed how FUS-BBBO coupled with IT and IV altered fluorescent dye (Dextran 2000 kDa and 70 kDa) distribution and concentration in a predetermined striatal-thalamic region in naïve mice. Secondly, we analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye. ResultsOur results indicate that IV administration coupled with FUS-BBBO successfully enhances delivery of dye into the pre-defined sonication targets. Conversely, measurable dye in the sonication target was consistently less after IT administration. FUS enhances the distribution volume of dye after CED. Furthermore, a shorter time of residence was observed when CED was coupled with FUS-BBBO application when compared to CED alone. Conclusion1. Based on our findings, IV delivery coupled with FUS-BBBO is a more efficient means for delivery to deep targets (i.e. striatal-thalamic region) within a predefined spatial conformation compared to IT administration. 2. FUS-BBBO increases the volume of distribution (Vd) of dye after CED administration, but results in a shorter time of residence. Whether this finding is reproducible with other classes of agents (e.g., cytotoxic agents, antibodies, viral particles, cellular therapies) needs to be studied.

P17.03.A MAGIC-G1: A PHASE 1 DOSE-ESCALATION TRIAL OF WEEKLY INTRATUMORAL ADMINISTRATION OF THE SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)

Abstract BACKGROUND One of the biggest challenges in treating rGBM is achieving high local drug concentration. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming the blood-brain barrier, while also limiting systemic toxicity. MTX110 (Midatech Ltd), a water-soluble formulation of panobinostat, has demonstrated cytotoxic activity in GBM cell lines, as well as safety and efficacy in two pediatric diffuse pontine glioma trials. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumor, thus avoiding systemic administration and therefore toxicity. MATERIAL AND METHODS Eligibility includes adult rGBM patients with a single enhancing lesion ≤3cm in maximal diameter; ≥4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥60%. MTX110 is continuously infused over 48hrs weekly at a rate of 0.5mL/h, via a CED catheter implanted into the enhancing disease recurrence connected to a fully internalized pump system. After safety of a single patient treated at 60μM has been established, 3-6 patients will be treated with MTX110 at 90μM as a single agent (Cohort 1). Patients in cohort 2 will receive MTX110 in combination with lomustine at a starting MTX110 dose of 60 μM and following the same dose-escalation approach. RESULTS As of March 30, 2023, the 1st patient was treated in monotherapy at 60μM and has received 12 weekly infusions of MTX110. No dose-limiting toxicities were observed. Observed study related adverse events (AEs) included: grade 1 cognitive disturbance, headache, and seizure; grade 2 candida wound infection, erythema of the scalp, bruising, and hemiparesis; and grade 3 abdominal seroma at pump insertion site. Enrolment is ongoing and the next patient will receive the 90 μM dose. CONCLUSION Weekly intratumoral administration of MTX110 via a fully internally implanted CED pump system is feasible. Updated results will be presented.

TIPS-23 SAFETY AND FEASIBILITY RESULTS FROM A PHASE 1/2 CLINICAL TRIAL OF RHENIUM (186RE) OBISBEMEDA (186RNL) IN RECURRENT GLIOMA: THE RESPECT-GBM TRIAL

Abstract OBJECTIVES 186RNL is BMEDA-chelated 186Re encapsulated in nanoliposomes. 186Re’s ~2 mm beta emission path length provides direct delivery of radiation therapy while sparing surrounding healthy tissue. 186RNL is delivered via convection enhanced delivery (CED) to achieve durable, localized tumor retention with high absorbed radiation doses. We present results from our ongoing ReSPECT-GBM trials (NCT01906385). METHODS ReSPECT-GBM is a multi-center, sequential cohort, open-label, dose escalation, Phase 1/2 clinical trial in adults with recurrent glioma to evaluate the safety, tolerability, and activity of a single dose of 186RNL administered by CED. Following computer-assisted MRI guidance treatment planning for CED catheter placement, patients received a single administration of 186RNL before whole body planar and SPECT/CT imaging for dosimetry and distribution. Patients were followed for safety, progression, and survival. RESULTS 25 patients across 8 dosing cohorts including 23 with recurrent GBM were treated with a single dose of 186RNL ranging from 1.0-41.5mCi. Average absorbed radiation dose (AARD) to the tumor was ~300 Gy over a wide range. Exposure outside the brain was negligible. A single dose of 186RNL was well-tolerated, with no dose limiting toxicities. No patient had treatment-related death or withdrawals and most AEs mild or moderate (Grade 1 or 2) and non-serious. 5 patients remain alive. mOS for all patients was &amp;gt;12 months, with an OS30 of 25% overall and 50% for those receiving &amp;gt;100Gy. Cox Proportional Hazards Ratio and Accelerated Failure Time modeling both demonstrate absorbed dose and percent tumor treated to significantly correlate with overall survival (p&amp;lt;0.003-0.0001). Five patients have subsequently enrolled in Phase 2 and all are alive. CONCLUSION A single dose of 186RNL in recurrent glioma patients achieves high absorbed doses without significant toxicity, is well tolerated, and shows favorable OS. Cohort 8 and Phase 2 continue enrolling. Development progress and data will be reported.

Efficient neutron capture therapy of glioblastoma with pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl)butyric acid (PBC-IP).

Boron neutron capture therapy (BNCT) has been applied for clinical trials on glioblastoma patients since 1950s, however, the low survival rate under the treatments has hampered the widespread use of BNCT. In this study, we developed a novel boron agent, PBC-IP, which consists of three functional groups: FRα-targeting, 10B resource (twelve 10B atoms in the molecule), and albumin-binding moieties. PBC-IP was selectively taken up by glioma cell lines such as C6, F98, and U87MG cells and accumulated 10- to 20-fold higher than L-4‑boronophenylalanine (BPA). PBC-IP administrated intravenously to the human glioblastoma (U87MG) xenograft model showed higher boron accumulation in tumors (29.8 μg [10B]/g at 6 h) than BPA (9.6 μg [10B]/g at 3 h) at a 25 mg [10B]/kg dose, effectively suppressing tumor growth after thermal neutron irradiation. PBC-IP administrated via convection-enhanced delivery (CED) accumulated in the F98 glioma orthotopic rat model, achieving 26.5 μg [10B]/g in tumors with tumor/normal (T/N) brain and tumor/blood (T/B) boron ratios of 37.8 and 94.6, respectively, 3 h after CED. Survival at 180 days after BNCT was 50% in the PBC-IP group and 70% in the combined BPA and PBC-IP groups, with no residual brain tumors.

The efficacy of boron neutron capture therapy with folate receptor targeted novel boron carrier in F98 rat brain tumor models.

21 Background: Boron neutron capture therapy (BNCT) is a particle therapy that can be targeted at the cellular level. The most commonly used boron carrier in clinical BNCT is boronophenylalanine (BPA), which is taken up into the tumor cell via L type amino acid transporter (LAT-1). The development of new boron carrier is an important issue, because BNCT using BPA is sometimes ineffective. Focusing on folate receptors that are highly expressed in malignant gliomas, PBC-IP which contained the pteroyl group was developed. The efficacy of BNCT with this drug was evaluated. The efficacy of BNCT using PBC-IP in the F98 rat brain tumor model has been evaluated. Methods: F98 rat glioma cells were used in the in vitro cellular uptake experiment.F98 rat glioma cells were exposed to BPA, sodium borocaptate (BSH), and PBC-IP. F98 rat brain tumor models were used in biodistribution experiment and neutron irradiation experiment. PBC-IP was administered by Convection enhanced delivery (CED). Results: In vitro cellular uptake experiment showed the boron concentration of PBC-IP was much higher than that of BPA and BSH. In vivo biodistribution experiment showed that boron concentration in the tumor using PBC-IP CED was the highest at 3 hours after the termination of 24 h administration. In the in vivo neutron irradiation experiment, significantly difference was observed between BNCT BPA group and combination BNCT (BPA + PBC-IP) group. In addition, long time survivors were observed in BNCT using PBC-IP groups, which were not observed in BNCT BPA groups. Conclusions: This study showed that PBC-IP in combination with BPA may provide the multi-targeted neutron capture therapy, this is because the mechanism of tumor accumulation of PBC-IP is different from that of BPA. In addition, therapeutic strategies targeting folate receptors may be useful, and further research is warranted.

Bioreducible Gene Delivery Platform that Promotes Intracellular Payload Release and Widespread Brain Dispersion.

We here introduce a novel bioreducible polymer-based gene delivery platform enabling widespread transgene expression in multiple brain regions with therapeutic relevance following intracranial convection-enhanced delivery. Our bioreducible nanoparticles provide markedly enhanced gene delivery efficacy in vitro and in vivo compared to nonbiodegradable nanoparticles primarily due to the ability to release gene payloads preferentially inside cells. Remarkably, our platform exhibits competitive gene delivery efficacy in a neuron-rich brain region compared to a viral vector under previous and current clinical investigations with demonstrated positive outcomes. Thus, our platform may serve as an attractive alternative for the intracranial gene therapy of neurological disorders.

Radiofluorination of an Anionic, Azide-Functionalized Teroligomer by Copper-Catalyzed Azide-Alkyne Cycloaddition.

This study describes the synthesis, radiofluorination and purification of an anionic amphiphilic teroligomer developed as a stabilizer for siRNA-loaded calcium phosphate nanoparticles (CaP-NPs). As the stabilizing amphiphile accumulates on nanoparticle surfaces, the fluorine-18-labeled polymer should enable to track the distribution of the CaP-NPs in brain tumors by positron emission tomography after application by convection-enhanced delivery. At first, an unmodified teroligomer was synthesized with a number average molecular weight of 4550 ± 20 Da by free radical polymerization of a defined composition of methoxy-PEG-monomethacrylate, tetradecyl acrylate and maleic anhydride. Subsequent derivatization of anhydrides with azido-TEG-amine provided an azido-functionalized polymer precursor (o14PEGMA-N3) for radiofluorination. The 18F-labeling was accomplished through the copper-catalyzed cycloaddition of o14PEGMA-N3 with diethylene glycol-alkyne-substituted heteroaromatic prosthetic group [18F]2, which was synthesized with a radiochemical yield (RCY) of about 38% within 60 min using a radiosynthesis module. The 18F-labeled polymer [18F]fluoro-o14PEGMA was obtained after a short reaction time of 2-3 min by using CuSO4/sodium ascorbate at 90 °C. Purification was performed by solid-phase extraction on an anion-exchange cartridge followed by size-exclusion chromatography to obtain [18F]fluoro-o14PEGMA with a high radiochemical purity and an RCY of about 15%.

Towards a Procedure-Optimised Steerable Catheter for Deep-Seated Neurosurgery.

In recent years, steerable needles have attracted significant interest in relation to minimally invasive surgery (MIS). Specifically, the flexible, programmable bevel-tip needle (PBN) concept was successfully demonstrated in vivo in an evaluation of the feasibility of convection-enhanced delivery (CED) for chemotherapeutics within the ovine model with a 2.5 mm PBN prototype. However, further size reductions are necessary for other diagnostic and therapeutic procedures and drug delivery operations involving deep-seated tissue structures. Since PBNs have a complex cross-section geometry, standard production methods, such as extrusion, fail, as the outer diameter is reduced further. This paper presents our first attempt to demonstrate a new manufacturing method for PBNs that employs thermal drawing technology. Experimental characterisation tests were performed for the 2.5 mm PBN and the new 1.3 mm thermally drawn (TD) PBN prototype described here. The results show that thermal drawing presents a significant advantage in miniaturising complex needle structures. However, the steering behaviour was affected due to the choice of material in this first attempt, a limitation which will be addressed in future work.

Application of chemotherapeutic drugs and convection-enhanced delivery technology in glioma.

Gliomas are the most common primary intracranial malignant tumors of the central nervous system. The most popular clinical strategy for glioma treatment is maximum surgical resection combined with radiotherapy and chemotherapy. However, the therapeutic effect of this strategy is suboptimal; the prognosis remains poor, and relapse is common. Moreover, this strategy does not significantly improve the duration of patient survival, and a complete cure remains elusive. In preclinical studies, it is necessary to establish a stable and reliable glioma model in order to develop new treatments and chemotherapeutic drugs for glioma. Different cell lines have different biological characteristics. Thus, it is essential to select the most suitable glioma cell line for model development based on the purpose of the study. Understanding the different chemotherapeutic agents used in glioma treatment can provide a drug reference for convection-enhanced delivery and help in the development of new drugs for this tumor. Convection-enhanced delivery technology enables drug transport across the blood-brain barrier, enhances drug targeting, and reduces systemic toxicity. Therefore, it has great potential in the chemotherapeutic treatment of glioma. This review summarizes the advantages and disadvantages of different glioma cell lines as well as the current progress in different chemotherapeutic drugs and convection-enhanced delivery for gliomas. It lays the foundation for new treatment strategies and provides a theoretical basis for the clinical application of these chemotherapeutic agents and convection-enhanced delivery techniques in glioma treatment.

Efficacy of convection enhanced delivery of MTX110 (soluble panobinostat) in preclinical Diffuse Intrinsic Pontine Glioma models using metabolic hyperpolarized 13C imaging

BackgroundDiffuse intrinsic pontine glioma (DIPG) usually occurs in children and has poor outcomes despite treatment. Large drug screens have identified the pan-histone deacetylate inhibitor panobinostat as a promising agent, however clinical response might be hampered by limited blood brain barrier penetration. Hyperpolarized 13C magnetic resonance (MR) metabolic imaging has successfully been applied to non-invasively assess metabolic activity of cancer therapies. Here, we use in vitro and in vivo DIPG models to validate the therapeutic efficacy of MTX110, an aqueous form of panobinostat delivered by convection enhanced delivery (CED) and apply metabolic imaging. MethodsMTX110 inhibitory effect was assessed in 11 DIPG cell lines. Caspase 3/7 levels were measured to assess mode of cell death. FACS analysis was utilized to determine impact on cell cycle. Hyperpolarized 13C imaging determined changes in pyruvate and lactate levels after treatment. In vivo activity of CED of MTX110 was assessed in a patient-derived xenograft rat model and tissue half-life of MTX110 was determined using mass spectrometry. ResultsMTX110 showed similar IC50 to panobinostat ranging from 5.34 nM and 47.96 nM. Anti-proliferative effects of MTX110 are mediated by G1 cell cycle arrest and subsequent apoptosis. Drug treatment led to reduced pyruvate to lactate conversion. CED of MTX110 significantly prolonged survival of tumor-bearing rats (p = 0.0372) with no signs of systemic toxicity. Tissue half-life after single CED of MTX110 is 2 h. ConclusionsOur results demonstrate that CED of MTX110, has potent antitumor activity with limited systemic toxicity and that hyperpolarized 13C imaging is able to assess metabolic impact.

Clinical characterization of patients with recurrent glioblastoma in trials involving CED and non-CED treatment.

e18845 Background: Glioblastoma (GBM) is the most common and aggressive of the primary malignant brain tumors in adults. Bevacizumab (beva) remains the only currently approved therapeutic for recurrent GBM (rGBM) patients who progress on prior therapy. Despite advances in care, rGBM has a median expected progression-free survival (PFS) of &lt; 4 months and overall survival (OS) of ~8 months. NCCN guidelines [Version 2.2022], and other oncology medical societies unanimously recommend patients seek treatment by entering a clinical trial. Since the late 1990’s a number of studies have explored the use of convection-enhanced delivery (CED) of drugs, a well-accepted and widely published delivery option for the treatment of rGBM. This analysis compares the demographics, medical history and survival outcome of patients enrolled into recently completed clinical trials with beva monotherapy to those entered into CED studies. Methods: Data for this analysis was sourced from the Medidata Enterprise Data Store (MEDS), comprised of over 28,000 historical clinical trials for de-identified aggregate patient-level analyses and from the study and patient-level data in the CED studies referenced in D’Amico [J Neurooncol 2021]. Aggregate summary statistics comparing beva and CED patients were based on combined study- and patient-level data using weighted (by sample size) means, incidence and overall survival (OS) rates and median of medians. Results: 163 rGBM beva patients were identified from MEDS. The CED cohort included 636 patients from MEDS and studies referenced in D’Amico. Cohort comparisons (beva vs CED) found median age: 56 vs 55 years; Caucasian race: 91% vs 93%; male sex: 68% vs 65%; not Hispanic or Latino ethnicity: 90% vs 94%; median OS: 7.9 vs 8.4 months. Over the last 2 decades there was a 23% increase in patients with ECOG Performance Status = 0 and 25% decrease in tumor area size at study enrollment, whereas there was no clear temporal OS trend. Conclusions: Patient demographics and most tumor attribute variables were similarly distributed between the beva and CED cohorts. While there is some indication that recent CED studies have enrolled healthier patients with smaller tumors; as expected, this does not appear to have translated to a consistent survival benefit.