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Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM.

Posted on: 05/14/2009

Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM.


Author(s): A. B. Heimberger, G. E. Archer, D. A. Mitchell, D. D. Bigner, R. J. Schmittling, J. E. Herndon, T. Davis, H. S. Friedman, T. Keler, D. A. Reardon, J. H. Sampson; University of Texas M. D. Anderson Cancer Center, Houston, TX; Duke University Medical Center, Durham, NC; Celldex Therapeutics, Inc., Philipsburg, NJ



Background: Unlike conventional therapies for GBM, immunologic targeting of tumor-specific gene mutations allows precise eradication of neoplastic cells with reduced toxicity. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBM and other neoplasms. The cancer vaccine CDX-110 is comprised of an EGFRvIII-specific peptide sequence linked to keyhole limpet hemocyanin (KLH). Methods: A phase II multi-center trial assessed the immunogenicity and efficacy of CDX-110 in patients with newly-diagnosed, EGFRvIII+ GBM. After resection and radiation / TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression. Sequential cohorts received CDX-110 alone [ACTIVATE (n = 18)] or in combination with TMZ (200 mg/m2 x 5/28 days [ACT II A (n = 13)]) or (100 mg/m2 x 21/28 days [ACT II B (n=10)]). Results: Reversible systemic drug hypersensitivity reactions were seen in 1 ACTIVATE and 4 ACT II patients. Two patients had non-specific changes on MRI which were possibly due to the vaccine but which resolved. Despite grade 2 or 3 lymphopenia in all ACT II patients, EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Although ACT II B patients had more severe TMZ-induced lymphopenia, they developed greater EGFRvIII-specific immune responses (p = 0.028) when compared to ACT II A. EGFRvIII-specific IgG1 also increased in avidity with vaccination (Ka>>2x109M-1) in a randomly selected subset of 4 patients (p = 0.000068). Of the 23 recurrent tumors studied, 18 lost EGFRvIII expression (p = 0.001). There are no significant differences between ACT II A and B in estimated median TTP (18.5 vs. 14.9 months, p = 0.31) and OS (23.6 vs. 19.9 months, p = 0.75). ACTIVATE TTP (14.2 months) and OS (26.0 months) and ACT II TTP (15.2 months) and OS (23.6 months) compare favorably to a TMZ-treated, matched historical control group (TTP: 6.3 months; OS: 15.0 months). Conclusions: CDX-110 vaccination in patients with GBM appears very promising. TMZ enhances immune responses despite lymphodepletion. CDX-110 with simultaneous TMZ is under further investigation in a larger phase II trial.



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