The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

Paff, Michelle; Alexandru-Abrams, Daniela; Hsu, Frank P.K.; Bota, Daniela

doi:10.4161/21645515.2014.983002

Cited by 27 publications

(18 citation statements)

References 67 publications

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“…However, antitumor response was reduced after NK and CD8 + T cell depletion, suggesting a key element to the treatment response is antibody-dependent cell-mediated cytotoxicity (ADCC) [34]. Importantly, tumor relapse in murine models tended to occur in a delayed fashion; immunohistochemistry of such relapses demonstrated a loss of EGFRvIII expression, suggesting treatment failure in EGFRvIII POS tumors could be associated with antigen escape and a proliferation of EGFRvIII NEG tumor cells [34,46,47]. …”

Section: Rindopepimut Propertiesmentioning

confidence: 99%

Prospect of rindopepimut in the treatment of glioblastoma

Elsamadicy

Chongsathidkiet

Desai

et al. 2017

Expert Opinion on Biological Therapy

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Introduction Rindopepimut (CDX-110) is a peptide vaccine that targets epidermal growth factor receptor variant III (EGFRvIII), a tumor-specific epitope expressed in the most common and lethal primary malignant neoplasm of the brain – glioblastoma (GBM). Areas covered The EGFRvIII mutation introduces an 801 base pair in-frame deletion of the extracellular domain of the transmembrane tyrosine kinase, resulting in constitutive kinase activity, amplification of cell growth, and inhibition of apoptosis. Rindopepimut contains a 14mer amino acid peptide spanning the EGFRvIII mutation site that is conjugated to keyhole limpet hemocyanin (KLH). The EGFRvIII neoantigen is exclusively present on GBM cells, providing rindopepimut tumor-specific activity. The authors review rindopepimut’s clinical efficacy, administration, safety, and prospects in the treatment of GBM. Expert opinion Rindopepimut showed clinical benefit and significant efficacy in phase II clinical trials, including as part of a multi-immunotherapy approach. A phase III clinical trial was terminated early, however, as it was deemed likely the study would fail to meet its primary endpoint. Longer term and sub-group analyses will be necessary to better understand rindopepimut’s future role in GBM therapy.

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Section: Rindopepimut Propertiesmentioning

confidence: 99%

Prospect of rindopepimut in the treatment of glioblastoma

Elsamadicy

Chongsathidkiet

Desai

et al. 2017

Expert Opinion on Biological Therapy

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“…Contrasting this view is the tumor immunology perspective that considers ErbB/HER proteins as bonafide tumor antigens ( Zaks and Rosenberg, 1998 ; Nistico et al, 1999 ; Disis et al, 2000 ). From this perspective, ErbB/HER-derived peptides including those derived from activating mutations, such as the EGFRvIII variant with a mutation in the extracellular domain of the receptor, have the potential to stimulate an anti-tumor immune response innately or via vaccination ( Li and Wong, 2008 ; Nedergaard et al, 2012 ; Paff et al, 2014 ; Schneble et al, 2014 ). Vaccine studies using a 14-amino acid peptide spanning the mutated extracellular domain of EGFRvIII (CDX-110) fused to adjuvant have shown durable oncogene-specific antibody and CD8 T cell responses as well as improved survival in glioblastoma multiforme patients ( Sampson et al, 2008 ).…”

Section: Linking Erbb/her To the Mhcmentioning

confidence: 99%

Understanding the Impact of ErbB Activating Events and Signal Transduction on Antigen Processing and Presentation: MHC Expression as a Model

et al. 2016

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Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient’s cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity. To realize the promise of ‘personalized medicine’, it will be important to develop a more integrated understanding of the relationships between oncogenic events and processes governing anti-tumor immunity. One area of investigation to explore such relationships centers on defining how ErbB/HER activation and signal transduction influences antigen processing and presentation.

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“…Of notion, PGE 2 is markedly increased in many types of human cancers, including lung, colon, bladder, breast and head and neck cancer, and is often associated with a poor prognosis [16][17][18][19][20]. Increased PGE 2 has a major impact on intratumoral inflammatory cells, promoting the immunosuppressive microenvironment [21,22]. However, due to lack of an animal model that resembles the pathological features of human disease, the biological roles of PGE 2 signaling in immunosuppression and lung metastasis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Wang

Jing

et al. 2020

Oncogene

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Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE 2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE 2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE 2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE 2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE 2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.

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The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients

Cited by 27 publications

References 67 publications

Prospect of rindopepimut in the treatment of glioblastoma

Prospect of rindopepimut in the treatment of glioblastoma

Understanding the Impact of ErbB Activating Events and Signal Transduction on Antigen Processing and Presentation: MHC Expression as a Model

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

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