EGFRvIII expression

P2, N=0, Withdrawn, Masonic Cancer Center, University of Minnesota | N=36 --> 0 | Not yet recruiting --> Withdrawn

D2C7-CAR demonstrates effective preclinical results both in vitro and in vivo. D2C7-CAR is not cytotoxic against human keratinocytes, suggesting it will be well tolerated in clinical trials.

Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. This novel mouse model can be used to study diffuse glioma with a leptomeningeal component.

As the extension of the approach, we crossed the EGFRvIII-CAR Tg mice with mice carrying Vav-Cre, which allowed the expression of anti-EGFRvIII CAR in all hematopoietic cells...This transgenic mouse model offers rigorous and reproducible evaluations of CAR-expressing hematopoietic cells. Furthermore, the model provides a platform for developing combination therapies, such as CAR-T plus CAR-NKT or CAR-T plus CAR-NK cells, with potential implications for enhanced cancer treatment strategies.

This suggests that the enhanced resistance of EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase.

Incubation under hypoxic conditions, serum starvation and the reductive unfolding of CHCHD2 induced the nuclear accumulation of CHCHD2 in both cell lines. Collectively, the findings of the present study indicate that CHCHD2 mediates a variety of GBM characteristics, and highlights mitonuclear retrograde signaling as a pathway of interest in GBM cell biology.

pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225... In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. In ongoing work we are evaluating CAR-pNK cells in an orthotopic LNT-229 glioblastoma xenograft mouse model, which may provide the basis to translate this approach to early clinical testing.

Similarly, EGFR-amplified glioblastoma cell lines showed no 5-ALA fluorescence after 24 h of incubation. Our study demonstrates an association between non-fluorescent IDH-wildtype glioblastomas and EGFR gene amplification which should be taken into consideration for recurrent surgery and future studies investigating EGFR-amplified gliomas.

P1, N=22, Not yet recruiting, Beijing Tsinghua Chang Gung Hospital | Trial completion date: Apr 2025 --> Jul 2025 | Initiation date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2025 --> Jul 2025

IGFBP3 knockdown inhibited the activation of TGF-β and EGFRvIII signals and the malignant behaviors triggered by them in vitro and in vivo. Collectively, our results indicated a positive feedback loop of p-EGFRvIII/IGFBP3 under administration of TGF-β, blocking IGFBP3 may be an additional target in EGFRvIII-expressing GBM-selective therapeutic strategy.

P2, N=36, Not yet recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.

We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.

In vivo delivery of dual DBTEs targeting these two GBM-associated antigens exhibited enhanced tumor control and clearance in a heterogeneous orthotopic GBM challenge, while treatment with single-target DBTE ultimately allowed for tumor escape. These studies support that combined delivery of DBTEs, targeting both EGFRvIII and HER2, can potentially improve outcomes of GBM immunotherapy, and such multivalent approaches deserve additional study.

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.

The existing treatment (chemotherapy with temozolomide (TMZ)+radiotherapy) increases the median survival by 2-3 months...Conclusion. The results in toto suggest that the intact structure of AF143 is stable to metabolism, can cross the blood brain barrier and induce antitumour activity in a EGFRvIII expressing glioblastoma stem cell model.

We conclude that the inhibition of Wee1 is an effective targeting approach for the radiosensitization of both EGFRvIII- and EGFRvIII+ GBM cells and may therefore represent a promising new therapeutic option to increase response to radiotherapy.

Three treatments with the 40H3-Tesirine ADC at 1 mg/kg were sufficient to achieve complete remissions without evidence of mouse toxicity. Data support the development of ADCs derived from the 40H3 antibody for the treatment of cancers that express EGFRvIII or high levels of EGFR.

Additionally, computational docking analysis suggested that the identified peptide binds selectively to EGFRvIII. The novel VLGREEWSTSYW peptide is thus a promising EGFRvIII-targeting agent for future applications in cancer diagnosis and therapy.

The roles of TGFβ and EGF in the EGFRvIII context remain unclear. EGFRvIII appears as a weak oncogene and not a marker of GSC (glioma stem cells). Hence, it may not be a proper target for CAR-T (chimeric antigen receptor T cells).

EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft (PDX) models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Recurrent glioblastoma tumors with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criterion easy to implement in the clinical practice.

Given that anti-VEGF therapies have been approved for a number of solid tumors, including GBM, our study provides mechanistic insights and compelling preclinical data in support of testing the combination of vascular normalizing agents and CAR-T therapies in GBM patients. Furthermore, this approach may also improve CAR-T therapy of other solid tumors that share similar TME features as well as for other cell-based therapies using autologous or allogenic immune cells (e.g., NK cells, macrophages).

The results indicated that the EGFRvIII specific single domain antibody library with high capacity and diversity was constructed and the single domain antibody with binding activity to EGFRvIII was obtained by screening the library. This study may facilitate the diagnosis and treatment of EGFRvIII targeted malignant tumors in the future.

Our findings show that IL-12 CARvIII can effectively eradicate IC homogenous tumors without lymphodepletion. Surprisingly, IL12 CARvIII therapy also treated IC heterogeneous glioma. Heterogeneous tumor clearance required an endogenous CD8 T cell response.

D2C7 CAR demonstrates efficacy in vitro and in mouse models of medulloblastoma and glioblastoma. Future steps in our work will set out to assess the D2C7 CAR in NSG mice with DAOY in the posterior fossa.

FlaB can enhance the anti-tumor effect of P by increasing CD8 + T cell response in a mouse brain GBM model.

Here, we show that EGFRvIII CAR T specifically targeted and killed EGFRvIII + GBM cells in vitro , but failed to control tumor growth in vivo without GAM modulation. EGFRvIII-SGRP CAR T secretome analysis identified SGRP from the supernatants of unstimulated monocultures. SGRP impaired the binding of SIRPα-Fc to CD47-upregulated GBM cells in vitro , but did not elicit macrophage-mediated phagocytosis of GBM cells in our current in vitro experimental setup.

RWE findings demonstrate a heterogeneous EGFR mutational profile in GBM patients, with persistent prevalence over time. BDTX-1535 is currently in a phase I clinical study (NCT05256290).

Recurrent glioblastoma tumours with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criteria easy to implement in the clinical practice.

The conjugates were more cytotoxic to EGFR+ve cells than free CPT. Our results describe a novel cyclic peptide, which can be used for targeted drug delivery to cells overexpressing the EGFR and EGFRvIII mutation.

EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft (PDX) models. Conclusion Our results suggest that EGFRvIII-TCB may be active in EGFRvIII expressing GBMs, and support further evaluation of this molecule in a first-in human trial (NCT05187624).

Blinatumomab is approved for treatment of B-cell malignancies, but BiTE molecule development in solid tumors has been more challenging...We report that deletion of stimulatory conventional type I DCs (cDC1) diminished BiTE molecule-induced T-cell activation and tumor clearance, suggesting that in situ antigen-presenting cell (APC) engagements modulate the extent of BiTE molecule efficacy. In summary, our work identified multiple requirements for optimal BiTE molecule efficacy in solid tumors, providing insights that could be harnessed for solid cancer immunotherapy development.

No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.

Furthermore, these B-SYNC T cells were significantly more efficacious than conventional, constitutively expressed EphA2/IL-13Rα2 CART cells, associated with excellent persistence (>100 days in vivo) and less exhausted phenotype compared to conventional CART cells. Based on these data, we are currently developing phase I studies of both E-SYNC and B-SYNC approaches.

Importantly, D2C7 CAR significantly prolonged survival of mice bearing EGFR or EGFRvIII-expressing gliomas of both adult (U87) and pediatric (DAOY) origin. Toxicity experiments involving EGFR-expressing human skin grafts provided evidence that D2C7 CAR is safe and effective when administered intracranially to mice bearing intracranial tumors.

Our novel GBM models presented the growth advantage of heterozygous TPMs for the first time in the context of GBM driver mutations relative to isogenic controls, thereby allowing for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.