BACKGROUND The authors conducted exploratory phase 1–2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3–restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3+) expressing tumors. HLA-A2/A3+ patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.
BACKGROUND:The authors are conducting clinical trials of the HER-2/neu E75-peptide vaccine in clinically diseasefree breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 þ granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8 þ T cells.They assessed the need for and response to a booster after completion of primary vaccination series. METHODS: BC patients enrolled in the E75 vaccine trials who were !6 months from completion of their primary vaccination series were offered boosters with E75 þ GM-CSF. Patients were monitored for toxicity. E75-specific CD8 þ T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting. RESULTS: Fiftythree patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8 þ lymphocytes. Elevated residual immunity (ERI) (CD8 þ E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P ¼ .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 AE 6.1 mm vs 81.8 AE 4.1 mm, P ¼ .01). In patients lacking ERI, 85% had increased ERI after vaccination (P ¼ .0014). CONCLUSIONS: The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series. Peptide-based vaccines are being used in clinical trials either to treat 1,2 or to prevent recurrence of malignancy. 3,4Peptide-based vaccination techniques involve inoculating patients with immunogenic epitopes from tumor-associated antigens, typically given with an immunoadjuvant, to stimulate proliferation of peptide-specific lymphocytes. Peptidespecific lymphocytes then identify and eliminate tumor cells presenting the vaccine-targeted epitope. Peptide-based vaccines are attractive immunotherapeutic options because they have no malignant potential, have low toxicity profiles, are simple and inexpensive, are easily monitored and studied, and eventually will be easily exportable to the community. The individual peptides used in cancer vaccine preparations are often major histocompatibility complex (MHC) class-restricted and human leukocyte antigen (HLA) type-specific, thus stimulating either CD4 þ or CD8 þ lymphocytes and sometimes limiting the applicability of peptides to patients with the correct HLA type. Peptide vaccination techniques
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 μg E75 plus 250 μg 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. Published 2008 by the American Cancer Society.
Background: We have completed phase I/II clinical trials vaccinating breast cancer patients (pts) with E75, a HLA-A2/A3-restricted HER2/neu (HER2) peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrences in high risk patients rendered disease-free with standard of care therapy. We have previously reported preliminary results indicating that the vaccine (including booster inoculations) is safe and effective in stimulating an anti-tumor immune response. Here, we report the final 5 year results from these trials. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node negative breast cancer patients with tumors expressing any level of HER2. HLA-A2/A3+ pts were enrolled into the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as the untreated control group (CG). The VG pts were given 4–6 monthly intradermal inoculations of E75 with GM-CSF during the primary vaccine series (PVS). In addition, a voluntary booster program was initiated during the trial, with booster inoculations being offered every 6 months after completion of the PVS. Patients were monitored for local and systemic toxicity (graded by NCI Common Terminology Criteria for Adverse Events). In vivo immune response was assessed in the VG by delayed type hypersensitivity (DTH) reactions to both E75 and saline, pre- and post-PVS. VG and CG pts were followed for 60 months (mo) and recurrences were documented. Demographic differences were compared with the Fisher's exact test and disease-free survival was determined using the Kaplan-Meier method and compared by log-rank test. Results: 195 pts were enrolled, 6 withdrew (2 from VG, 4 from CG), 1 was lost to follow-up prior to vaccination, and 1 was found to be ineligible, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. 53 pts volunteered for the booster program and received at least one booster inoculation. The VG and CG were well-matched with the only statistically significant difference being ER−/PR- status (31.1% in VG vs 17.7% in CG, p = 0.04). Vaccination was well tolerated (maximum local toxicity: 73.1% Grade 1, 26.9% Grade 2, 0% Grade 3; maximum systemic toxicity: 72.2% Grade 1, 15.7% Grade 2, and 2.8% Grade 3). In the VG, pre- to post-PVS E75 DTH significantly increased (mean 3.8 ±1.0 vs 14.8±1.4, p < 0.001) and post-PVS E75 DTH was significantly greater than post-PVS saline DTH (1.84±0.5 vs 14.8±1.4, p < 0.001). At the end of the trial, analysis of the Kaplan Meier curves at 60 mo shows increased disease-free survival in the VG compared to the CG with a trend toward significance (89.7% vs 80.6%, p = 0.076). Conclusions: The E75 breast cancer vaccine is safe and well–tolerated. It elicits strong immune responses in vaccinated patients. At the end of the 5 year follow-up period, the E75 vaccine shows a strong trend toward preventing breast cancer recurrence in vaccinated patients. To investigate this vaccine (now known as NeuVax) further, the PRESENT trial, a prospective, randomized, double-blind, placebo-controlled, multi-center phase III registration trial has been initiated and is actively enrolling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-02.
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