PMID- 18539480
OWN - NLM
STAT- MEDLINE
DCOM- 20090224
LR  - 20240312
IS  - 1044-5323 (Print)
IS  - 1044-5323 (Linking)
VI  - 20
IP  - 5
DP  - 2008 Oct
TI  - Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with 
      malignant glioma.
PG  - 267-75
LID - 10.1016/j.smim.2008.04.001 [doi]
AB  - 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 re-arrangement 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 lead to 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.
FAU - Sampson, John H
AU  - Sampson JH
AD  - Division of Neurosurgery, Department of Surgery, Duke University Medical Center, 
      Durham, NC 27710, USA. john.sampson@duke.edu
FAU - Archer, Gary E
AU  - Archer GE
FAU - Mitchell, Duane A
AU  - Mitchell DA
FAU - Heimberger, Amy B
AU  - Heimberger AB
FAU - Bigner, Darell D
AU  - Bigner DD
LA  - eng
GR  - P50 CA108786/CA/NCI NIH HHS/United States
GR  - R01 CA097222/CA/NCI NIH HHS/United States
GR  - R21 CA132891-02/CA/NCI NIH HHS/United States
GR  - R01 CA097222-05/CA/NCI NIH HHS/United States
GR  - R21 CA132891/CA/NCI NIH HHS/United States
GR  - R01 CA235612/CA/NCI NIH HHS/United States
GR  - P50 CA108786-050003/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20080609
PL  - England
TA  - Semin Immunol
JT  - Seminars in immunology
JID - 9009458
RN  - 0 (epidermal growth factor receptor VIII)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/genetics/immunology/*therapy
MH  - Clinical Trials as Topic
MH  - ErbB Receptors/*genetics/*immunology
MH  - Glioma/genetics/immunology/*therapy
MH  - Humans
MH  - Immunosuppression Therapy
MH  - *Immunotherapy
MH  - *Mutation
PMC - PMC2633865
MID - NIHMS81150
EDAT- 2008/06/10 09:00
MHDA- 2009/02/25 09:00
PMCR- 2009/10/01
CRDT- 2008/06/10 09:00
PHST- 2007/10/19 00:00 [received]
PHST- 2008/04/08 00:00 [revised]
PHST- 2008/04/17 00:00 [accepted]
PHST- 2008/06/10 09:00 [pubmed]
PHST- 2009/02/25 09:00 [medline]
PHST- 2008/06/10 09:00 [entrez]
PHST- 2009/10/01 00:00 [pmc-release]
AID - S1044-5323(08)00044-4 [pii]
AID - 10.1016/j.smim.2008.04.001 [doi]
PST - ppublish
SO  - Semin Immunol. 2008 Oct;20(5):267-75. doi: 10.1016/j.smim.2008.04.001. Epub 2008 
      Jun 9.