EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells

Ochiai, Hidenobu; Archer, Gary E.; Herndon, James E.; Kuan, Chien-Tsun; Mitchell, Duane A.; Bigner, Darell D.; Pastan, Ira; Sampson, John H.

doi:10.1007/s00262-007-0363-7

Cited by 36 publications

(29 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In pre-clinical systems EGFRvIII-expressing cell lines or an EGFRvIII-specific 14-amino acid peptide, PEPvIII (H-Leu-Glu-Glu-Lys-Lys-Gln-Asn-Tyr-Val-Val-Thr-Asp-His-Cys-OH), which has been chemically conjugated to keyhole limpet hemocyanin (KLH) (PEPvIII-KLH) has generally been used for the generation of EGFRvIII-specific antibodies [115,[130][131][132][133][134][135][136][137][138], induction cellular immune responses [139][140][141], or derivation of targeted toxins [142][143][144][145].…”

Section: Pre-clinical Immunotherapy Studies With Egfrviiimentioning

confidence: 99%

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma

Sampson

Archer

Mitchell

et al. 2008

Seminars in Immunology

Self Cite

153

131

View full text Add to dashboard Cite

Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells.The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence rearrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs.We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T-and B-cell immunity in these patients, and an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity.These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral-and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , and patients with recurrent tumors usually survive <20 weeks [7]. Moreover, the non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues [8]. Thus, in order to be more effective, therapeutic strategies will have to precisely target tumor cells while minimizing collateral damage to neighboring eloquent cerebral cortex. The rationale for employing the immune system to target brain tumors is based on the p...

show abstract

Section: Pre-clinical Immunotherapy Studies With Egfrviiimentioning

confidence: 99%

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma

Sampson

Archer

Mitchell

et al. 2008

Seminars in Immunology

Self Cite

153

131

View full text Add to dashboard Cite

show abstract

“…It is worth noting that most existing RITs react not only with the EGFR overexpressed in cancer, but also react with the EGFR expressed in normal tissue, resulting in unwanted toxicity to key organs, and to date, only the monovalent RIT, D2C7-IT, has been reported to recognize both the wild type EGFR and EGFRvIII. [17][18][19] Because EGFRvIII is specifically expressed in cancer and plays a significant role in tumor progression and treatment failure, a RIT that recognizes the EGFRvIII is expected to enhance its anti-tumor benefits.…”

Section: Discussionmentioning

confidence: 99%

“…Because of the unique features of RITs such as high specificity, extraordinary potency and lack of drug resistance, EGFR-targeted RITs have been designed and constructed with different mAbs as the template such as the scFv(225)-ETA, scFv (14E1)-ETA, 425(scFv)-ETA', D2C7-IT, MR1scFvPE38KDEL, and scFv/rGel (E/rG). [16][17][18][19][20] RITs have also been generated by using epidermal growth factor (EGF) or transforming growth factor-a peptide as a template such as TP-38. 21 Several RITs have been advanced from laboratory to the stage of Phase I and Phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] The high specificity of mAb806 to the overexpressed EGFR and EGFRvIII in cancer, but not to the EGFR in normal tissue highlights its advantage over other mAbs for generation of RITs. [22][23][24] The mAb806 was raised against mouse fibroblast cells expressing the EGFRvIII, and its unique specificity contributes to the fact that mAb806 binds to an epitope exposed only in the transitional untethered form of EGFR when it is overexpressed in cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A bivalent recombinant immunotoxin with high potency against tumors with EGFR and EGFRvIII expression

Meng

Liu

Gao

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

kinase inhibitors; RIT, recombinant immunotoxin; biscFv, bivalent singlechain variable fragment; DT, diphtheria toxin; DT390, an engineered diphtheria toxin fragment; P. pastoris, Pichia pastoris; V L , light chain variable domain; V H , heavy chain variable domain; scFv, single-chain variable fragment; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; HPLC, high-performance liquid chromatography; IC 50 , half maximal inhibition concentration; RTV, individual relative tumor volume; %TGI, percentage tumor growth inhibition.EGFR and EGFRvIII are overexpressed in various types of cancer, serving as optimal targets for cancer therapy. Capitalizing on the high specificity of humanized antibody 806 (mAb806) to the EGFR and EGFRvIII overexpressed in cancer, we designed and generated a bivalent recombinant immunotoxin (RIT, DT390-BiscFv806) by fusing the mAb806-derived bivalent single-chain variable fragment with a diphtheria toxin fragment, DT390. In vitro, DT390-BiscFv806 efficiently internalized into the cells and exhibited high cytotoxicity against the U87 glioblastoma cells and the EGFRvIII-transfected U87 (U87-EGFRvIII) cells with a half maximal inhibition concentration (IC 50 ) of 1.47 nM and 2.26 £ 10 ¡4 nM, respectively. Notably, DT390-BiscFv806 was 4 orders of magnitude more potent against the U87-EGFRvIII cells than against the parent U87 cells. The cytotoxicity against a group of 6 head and neck squamous cell carcinoma cell lines were further analyzed, showing an IC 50 ranging from 0.24 nM to 156 nM, depending on the expression level of EGFR/EGFRvIII. In animals, the U87-EGFRvIII tumor xenografts grew extremely faster than the parental U87, and systemic administration of DT390-BiscFv806 significantly inhibited the growth of established U87-EGFRvIII and U87 tumor xenografts, showing a growth inhibition rate of 76.3% (59.82-96.2%) and 59.4% (31.5-76.0%), respectively. In pathology, the RIT-treated tumors exhibited a low mitotic activity and a large number of degenerative tumor cells, compared with the control tumors. The results indicate that DT390-BiscFv806 is promising for treatment of various types of cancer, especially for those with high EGFR expression or with EGFR and EGFRvIII co-expression.

show abstract

“…Because EGFRvIII is expressed exclusively by tumor cells, targeting of EGFRvIII may represent an attractive strategy to improve the clinical efficacy of chemoradiation as well as cetuximab-containing regimens without increasing the side effects of such multimodal treatment regimens. A specific antibody to EGFRvIII conjugated with cytotoxic compounds is currently being developed and has already proven efficacious in animal models of glioblastoma (35). Alternatively, SCCHN patients with EGFRvIII-positive tumors might benefit from nextgeneration tyrosine kinase inhibitors like HKI-272, which, when compared with gefitinib or erlotinib, showed a 100-fold higher potency in inhibiting the growth of EGFRvIII-transformed lung tumor cancer cells in vitro and in vivo (36).…”

Section: Wild-type Egfrmentioning

confidence: 99%

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Tinhofer

Klinghammer

Weichert

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown.Experimental Design: Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, and uni-and multivariate Cox regression analysis.Results: High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P ¼ 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P ¼ 0.002) and PFS (HR 2.2, P ¼ 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS.Conclusions: High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel.

show abstract

EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells

Cited by 36 publications

References 24 publications

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma

A bivalent recombinant immunotoxin with high potency against tumors with EGFR and EGFRvIII expression

Expression of Amphiregulin and EGFRvIII Affect Outcome of Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab–Docetaxel Treatment

Contact Info

Product

Resources

About