Clinical Cancer Research Joint Metastasis Research Society-AACR Conference on Metastasis Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Clinical Cancer Research Vol. 8, 3407-3418, November 2002
© 2002 American Association for Cancer Research

Clinical Trials

Toxicity, Immunogenicity, and Induction of E75-specific Tumor-lytic CTLs by HER-2 Peptide E75 (369–377) Combined with Granulocyte Macrophage Colony-stimulating Factor in HLA-A2+ Patients with Metastatic Breast and Ovarian Cancer1

James L. Murray2, Michael E. Gillogly, Donna Przepiorka, Hannah Brewer, Nuhad K. Ibrahim, Daniel J. Booser, Gabriel N. Hortobagyi, Andrzej P. Kudelka, Kenneth H. Grabstein, Martin A. Cheever and Constantin G. Ioannides

Departments of Bioimmunotherapy [J. L. M., M. E. G., H. B.], Immunology and Gynecologic Oncology [C. G. I.], Breast Medical Oncology [N. K. I., D. J. B., G. N. H.], and Gynecologic Medical Therapeutics [A. P. K.], M. D. Anderson Cancer Center, Houston, Texas 77030; Center for Gene Therapy, Baylor College of Medicine, Houston, Texas [D. P.]; and Corixa Corporation, Seattle, Washington [K. H. G., M. A. C.]

To determine the toxicity and immunogenicity of the HER-2/neu, HLA-A2-restricted peptide E75 in patients with metastatic breast and ovarian cancer, 14 patients were vaccinated with escalating amounts of E75 (100, 500, and 1000 µg) mixed with 250 µg granulocyte macrophage colony-stimulating factor as adjuvant. Each vaccine dose was administered in a total volume of 1.5 ml divided into four intradermal injections and administered weekly for 4 weeks, followed by monthly boosts for a total of 10 injections. Vaccinations were well tolerated without significant toxicity. Blood was drawn before, at 8 weeks, and up to 13–16 months after vaccination for measurement of cellular immunity. Seven of 8 patients tested had significant delayed type hypersensitivity to E75 defined as >5 mm induration. Peripheral blood mononuclear cells from 5 of 9 patients tested proliferated to E75 with a stimulation index of >=2.0. Of 8 vaccinated patients tested for induction of a CTL response, 4 responded to stimulation by autologous dendritic cells plus cytokines by eliciting E75-specific lytic activity consistent with the presence of activated/memory cells, 2 others after in vitro stimulation with E75 + interleukin-12 ± anti-CD15233KD, whereas 2 others did not respond. Four patients with E75-specific CTLs present specifically recognized E75 on indicator tumors as demonstrated by cold-target inhibition of tumor lysis. These 4 patients showed E75-specific IFN-{gamma} production. peripheral blood mononuclear cell from 3 of these patients proliferated to E75, but stimulation indices were higher in the prevaccine samples. All 4 of the patients showed DTH responses to E75. These results demonstrate that vaccination with E75+ granulocyte macrophage colony-stimulating factor can induce both peptide-specific IFN-{gamma} and epitope specific CTLs, which lyse HER-2/neu+ tumors in stage IV patients.




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Copyright © 2002 by the American Association for Cancer Research.