Novel high‐affinity EGFRvIII‐specific chimeric antigen receptor T cells effectively eliminate human glioblastoma

Abbott, Rebecca C; Verdon, Daniel J; Gracey, Fiona M; Hughes‐Parry, Hannah E; Iliopoulos, Melinda; Watson, Katherine A.; Mulazzani, Matthias; Luong, Kylie; D’Arcy, Colleen; Sullivan, Lucy C.; Kiefel, Ben R; Cross, Ryan; Jenkins, Misty R.

doi:10.1002/cti2.1317

Cited by 14 publications

(7 citation statements)

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“…EGFRvIII-positive cells seems to be an ideal target for CAR-T [ 1 ]. However, the presence of EGFRvIII-negative and -positive cells in a single tumor is a very intriguing phenomenon typical of glioblastoma and is represented by the DK-MG high subline.…”

Section: Discussionmentioning

confidence: 99%

“…Despite many years of analysis, the biological role and molecular mechanism of action of EGFRvIII remain unexplained. It is very important to recognize the complicated responses of EGFRvIII-positive cells to different environments, especially since EGFRvIII is regarded as an ideal (in terms of cancer uniqueness—a specific neo-antigen) target for immunotherapies, such as chimeric antigen receptor T (CAR-T) [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGFβ and EGF on These Cells—EGFRvIII Appears as a Weak Oncogene

Włodarczyk

Tręda

Rutkowska

et al. 2022

IJMS

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Background: The biological role of EGFRvIII (epidermal growth factor receptor variant three) remains unclear. Methods: Three glioblastoma DK-MG sublines were tested with EGF (epidermal growth factor) and TGFβ (transforming growth factor β). Sublines were characterized by an increased percentage of EGFRvIII-positive cells and doubling time (DK-MGlow to DK-MGextra-high), number of amplicons, and EGFRvIII mRNA expression. The influence of the growth factors on primary EGFRvIII positive glioblastomas was assessed. Results: The overexpression of exoEGFRvIII in DK-MGhigh did not convert them into DK-MGextra-high, and this overexpression did not change DK-MGlow to DK-MGhigh; however, the overexpression of RASG12V increased the proliferation of DK-MGlow. Moreover, the highest EGFRvIII phosphorylation in DK-MGextra-high did not cause relevant AKT (known as protein kinase B) and ERK (extracellular signal-regulated kinase) activation. Further analyses indicate that TGFβ is able to induce apoptosis of DK-MGhigh cells. This subline was able to convert to DK-MGextra-high, which appeared resistant to this proapoptotic effect. EGF acted as a pro-survival factor and stimulated proliferation; however, simultaneous senescence induction in DK-MGextra-high cells was ambiguous. Primary EGFRvIII positive (and SOX2 (SRY-Box Transcription Factor 2) positive or SOX2 negative) glioblastoma cells differentially responded to EGF and TGFβ. Conclusions: 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).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGFβ and EGF on These Cells—EGFRvIII Appears as a Weak Oncogene

Włodarczyk

Tręda

Rutkowska

et al. 2022

IJMS

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“…Malignant glioma is a common brain tumor type and the traditional treatment, such as surgical resection, radiotherapy or chemotherapy, is not satisfactory. A novel CAR-T cell (GCT02) that may recognize epidermal growth factor receptor variant III (EGFRvIII) on the tumor cells' surface may mediate tumor cell elimination, indicating a promising treatment for glioblastoma ( 70 ). In a study, 10 patients with recurrent glioblastoma accepted EGFRvIII-CAR-T cell infusion; the EGFRv expression level decreased in 5 patients, and 1 patient had no disease progression at the 18-month follow-up ( 71 ).…”

Section: Application Of Car-t Cells In Hematological Tumor Treatmentmentioning

confidence: 99%

Current progress in CAR‑T cell therapy for tumor treatment (Review)

et al. 2022

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Chimeric antigen receptor T (CAR-T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR-T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR-T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR-T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR-T cell therapy mainly focuses on improving CAR-T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR-T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR-T cell technology to provide a reference for clinical practice and research on tumor treatment.

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“…Finally, chimeric-antigen-receptor (CAR) T cells utilize a scFv coupled through a transmembrane domain to signaling domains from CD3z, CD28 and/or 4-1BB. Most prominently deployed against CD19-expressing cells in haematological malignancies, where they have achieved remarkable clinical efficacy [149], the only current clinically relevant mutant antigen target for CAR-T cells is the exon 2-7 deletion vIII variant of EGFR, commonly expressed in glioma [150,151]. CAR-T incorporating a TCR mimic scFv specific for the HLA-A*02:01retricted NY-ESO-1 157-165 epitope as their antigen binding domain have been reported [152], reinforcing the tractability of this approach and CAR-T directed against public neoantigens may represent a promising future therapeutic modality.…”

Section: Tgtcr Car-t and Antibody-mediated Therapiesmentioning

confidence: 99%

Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy

Verdon

Jenkins

2021

Cancers

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In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination.

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Novel high‐affinity EGFRvIII‐specific chimeric antigen receptor T cells effectively eliminate human glioblastoma

Cited by 14 publications

References 0 publications

Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGFβ and EGF on These Cells—EGFRvIII Appears as a Weak Oncogene

Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGFβ and EGF on These Cells—EGFRvIII Appears as a Weak Oncogene

Current progress in CAR‑T cell therapy for tumor treatment (Review)

Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy

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