P1, N=30, Terminated, Amgen | Completed --> Terminated; Amgen business decision

P1/2, N=100, Recruiting, Wayshine Biopharm, Inc.

P1, N=200, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1, N=147, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

P1, N=51, Recruiting, Mayo Clinic | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=200, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=147, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P1, N=147, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd.

The present preclinical study evaluated the novel EGFR inhibitor WSD-0922. We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients...WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism. WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.

P1, N=51, Recruiting, Mayo Clinic | N=77 --> 51

Groups received either GNC-039 (n=5), GNC-039 with engrafted PBMC (n=5), Temozolomide(n=5), or Vehicle (n=5). However, beyond this timepoint, the level of GNC-039 in the brain region was significantly increased due to the engrafted PBMC.Collectively this data indicates the functionality of GNC-039 as a multi-specific T cell engager with the potential to target EGFRvIII+ cancer cell cytolysis in primary brain disease. The clinical phase I-b study of GNC-039 is under way and the available data exhibit strong signals of efficacy with acceptable tolerability.

CONCLUSION Lower levels of OLIG2 increase osimertinib sensitivity of EGFRvIII+ glioblastoma. We propose a schema for selecting EGFRvIII+ patients who will respond to Osimertinib.

Using CRISPR technology, we have also generated an immunocompetent mouse model tolerant to our antigens of interest, Her2 and EGFRvIII, and demonstrated the subcutaneous and intracranial growth of these antigen-expressing tumours. This model allows us to evaluate the efficacy of dual-targeting CAR T cells against heterogeneous tumours in a mouse model with an intact immune system.

Afatinib diminished AKT phosphorylation at 30 min and 6 h in the EGFR- and EGFRvIII-overexpressing cells, respectively, and decreased AR phosphorylation in EGFR-overexpressing cells at 4 h. Afatinib or MK2206 combination therapy with the AR antagonist enzalutamide in the EGFR and EGFRvIII-overexpressing cells had synergistic efficacy. Our findings suggest that EGFR signaling is involved in AR activation in glioblastoma and buttresses the concept of combining an EGFR signaling inhibitor with AR antagonists as a potential glioblastoma treatment.

Two ways of covalent AON-polymer attachments with and without disulfide bonds were explored. These MNPs bearing AONs to EGFR/EGFRvIII and c-Myc, as well as in a combination with the polymer-attached checkpoint inhibitor anti-PD-1 antibody, orchestrated a multi-pronged attack on intracranial mouse GBM to successfully block tumor growth and significantly increase survival of brain tumor-bearing animals.

To our knowledge, limited studies reported in literature expressing the EGFR vIII in meningioma tumors. Hence, Opinions regarding the role that EGFR vIII in tumorigenesis and tumor progression are clearly conflicting and, therefore, it is crucial not only to find out its mechanism of action, but also to definitely identify its role in meningioma.

We demonstrated exon deletion and splice site detection technology with an expanded RNA sequencing Oncomine panel that includes more than 1,000 gene fusion targets and assays for novel fusion detection. The approach is compatible with Ion systems, requires low input material, and retains simple workflows and fast turn-around time.

METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

Double-positive cells for PD1 and activation markers also displayed a positive correlation, suggesting PD1 highlights a population of activated CAR T cells. Further characterization of predictors of EGFRvIII-directed CART treatment efficacy may improve selection of patients and starting T cell populations for clinical expansion.

Importantly, intracranially-administered D2C7 CAR significantly prolonged survival of mice bearing orthotopic U87vIII or U87/U87vIII heterogeneous tumors compared to mock-treated controls. Altogether, these data provide evidence that D2C7 CAR T cells represent a viable therapeutic option for EGFRwt/EGFRvIII heterogeneous tumors.

Consistent with studies of systemic EGFRvIII CAR T-cell therapy, our data suggest that intratumoral EGFRvIII CAR T-cells were insufficient to eliminate BS153 tumors with homogeneous EGFRvIII expression in mice (Overall survival; EGFRvIII-treated: 20%, CD19-treated: 0%, n= 5 per group). Our current work focuses on the functional characterization of SGRP binding, SGRP-mediated phagocytosis, and on the development of a translational preclinical model of heterogeneous EGFRvIII expression to investigate an additive effect of CAR T-cell therapy and GAM modulation.

Furthermore, this data provides insight on treatment against the immunosuppressive tumor microenvironment and applications against other solid tumors. In anticipation of translating this therapy into a phase I clinical trial, we are also investigating adjuvant therapies such irradiation to improve antitumor efficacy of IL-12 CARvIII against heterogeneous glioma.

Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer exciting opportunities to recondition the vascular microenvironment and strengthen cancer immunotherapy.

We identified several mRNAs including Gli3, STAG2, ELF3, PHLPP1 which play an important role in cancer. CONCLUSION The ability to sort and characterize tumor specific PpIX EVs following 5-ALA administration opens new avenues for liquid biopsy-based glioma diagnosis.

This was demonstrated by their enhanced cytokine-producing function, cytotoxic capacity, and therapeutic efficacy in vivo . Results from this study provide a novel rationale for repurposing multi-specific CAR T cells as a strategy to improve efficacy against LAD tumors, in addition to the recognized benefit of reducing antigen-negative escape.

The ligand-induced internalization of epidermal growth factor receptor (EGFR) is generally considered to attenuate downstream signaling via its endosomal degradation. Moreover, phosphorylation and endocytosis were abrogated by the selective p38 inhibitor SB203580, but not gefitinib, indicating that EGFRvIII is recruited to p38-mediated non-canonical endocytosis. The combination of TMZ and SB203580 also showed potential inhibitory effects on the proliferation and motility of glioblastoma cells.

A total of 11 patients (15%) received bevacizumab (Bev) prior to HFSRT... Salvage treatments for rHGG remain a challenge. This study provides further insight into prognostic molecular determinants in the setting of HFSRT, PD-1 blockade and Bev.

Salvage treatments for rHGG remain a challenge. This study provides further insight into prognostic molecular determinants in the setting of HFSRT, PD-1 blockade and Bev.

PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.

GCL, PDCL and PT display heterogenic antigen surface expression with high variability within each group, thereby complicating clinical translation of in vitro results obtained using cell lines. This aspect should be taken into account in GBM target antigen research.

Once GBM progresses after SOC, lomustine is the standard second-line treatment, while rechallenge with TMZ may be employed in selected patients with methylated promoter of MGMT, and bevacizumab is reserved for patients with extensive edema and need for steroids. To our knowledge, this is the first report of a recurrent GBM with a significant and long-lasting neuroradiological response following a combined treatment with TTFields, Depatux-M, and intensified schedule of TMZ. A synergistic effect of TTFields with compounds interfering with the microtubular system should be further investigated.

These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours.

When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.

They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

Finally, TSSC4 suppresses tumorsphere formation and tumor growth by inhibiting autophagy and maintaining cell survival in tumorspheres. Taken together, sustainable cancer cell growth can be achieved by autophagy inhibition via TSSC4 expression.ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; CQ: chloroquine; EGFRvIII: epidermal growth factor receptor variant III; ERBB2: erb-b2 receptor tyrosine kinase 2; GBM: glioblastoma multiforme; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule Associated protein 1 light chain 3; TSSC4: tumor suppressing subtransferable candidate 4.

While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.

Our study determined that weakness and memory loss/confusion were the symptoms that predicted diminished survival, and weakness alone was the symptom that predicted an earlier diagnosis. This study further elucidates the complexities of glioblastoma and provides clinicians with more data for their patients when discussing prognostication after diagnosis of glioblastoma.