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USMCI Clinical Trials Program published makes cover of the journal Cancer
Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence
BACKGROUND.
E75, a HER-2/neu-derived peptide, was administered as a preventive vaccine with granulocyte-macrophage-colony-stimulating factor (GM-CSF) in disease-free lymph node-positive (NP) and lymph node-negative (NN) breast cancer (BCa) patients. The optimal biologic dose (OBD) was determined based on toxicity and immunologic response.
METHODS.
Patients were vaccinated over 6 months (3, 4, or 6 times) with different doses of E75 plus GM-CSF. Toxicities were graded per National Cancer Institute Common Terminology Criteria. GM-CSF was reduced for significant toxicity. Immunologic response was measured by delayed type hypersensitivity test (DTH), and E75-specific CD8+ T-cells were quantified with human leukocyte antigen-A2:immunoglobulin G dimer and flow cytometry.
RESULTS.
Ninety-nine patients (48 NP and 51 NN) were vaccinated in 7 dose groups. The OBD was 1000 g E75 plus 250 g GM-CSF monthly × 6. The optimal dose group (ODG, n = 29) experienced similar toxicities to the suboptimal dose group (SDG, n = 70), which was comprised of the remaining 6 groups. The ODG demonstrated a trend toward an increase in the average postvaccine dimer (0.87 ± 0.10% vs 0.67 ± 0.05%; P = .07), a significantly larger DTH response (21.5 ± 2.5 mm vs 11.3 ± 1.3 mm; P = .0002), and a trend toward decreased recurrences (3.4% vs 12.9%; P = .27). Compared with the SDG, the ODG had larger tumors (percentage T2: 55% vs 23%; P = .004), more positive lymph nodes (percentage NP: 76% vs 37%; P = .001), and higher grade tumors (percentage grade 3: 52% vs 30%; P = .07), but a shorter median follow-up time (20 months vs 32 months; P < .001).
CONCLUSIONS.
Compared with suboptimally dosed patients, the optimally dosed E75 vaccine in disease-free BCa patients had similar toxicity but enhanced HER-2/neu-specific immunity that may lead to decreased recurrences with additional follow-up. Cancer 2008;113:1666-75.
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USMCI Clinial Trials Program paper is published in the journal of Clinical Cancer Research
Purpose: E75 is an immunogenic peptide fromthe HER2/neu protein, which is overexpressed in
many breast cancer patients.We have conducted two overlapping E75 vaccine trials to prevent
recurrence in node-positive (NP) and node-negative (NN) breast cancer patients.
Experimental Design: E75 (HER2/neu 369-377) + granulocytemacrophage colony-stimulating
factor was given intradermally to previously treated, disease-free NP breast cancer patients in a
dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local
and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays
and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented.
Results: One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91).
Humanleucocyte antigen A 2 (HLA-A 2) and HLA-A 3 patients were vaccinated (n =101),whereas
all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a
dose-dependent immunologic response to the vaccine was shown. Planned primary analysis
revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls
(P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over
time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus
14.8%); however, a significant difference in the pattern of recurrence persisted.
Conclusions: E75 is safe and effective in raising a dose-dependent HER2/neu immunity in
HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce
recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These
findingswarrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster
to prevent breast cancer recurrences.
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USMCI Conducting Phase II Clinical Trial for Breast Cancer Vaccine
The United States Military Cancer Institute's (USMCI) Clinical Trials Group is engaged in ground-breaking research working towards cancer solutions in both military and civilian populations. One exciting study in which USMCI is currently involved is a prospective, randomized, multi-center Phase, II clinical trial investigating whether a new vaccine can prevent recurrence in disease-free, conventionally treated, node-positive and high-risk node-negative breast cancer patients who are at significant risk for recurrence. > More