The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu-specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

BACKGROUND: HER-2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER-2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented. METHODS: Disease-free, lymph node-negative, human leukocyte antigen (HLA)-A2 þ breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte-macrophage colony-stimulating factor (GM-CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA-A2:immunoglobulin dimer assay to detect GP2-specific CD8 þ T cells (and E75-specific CD8 þ T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges). RESULTS: Eighteen patients were enrolled. All toxicities were grade 2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM-CSF dose reductions for local reactions !100 mm or grade !2 systemic toxicity. GM-CSF dose was reduced to 125 lg for the final dose group. All patients responded immunologically ex vivo (GP2-specific CD8 þ T cells from prevaccination to maximum, 0.4% [0.0%-2.0%] to 1.1% [0.4%-3.6%], P < .001) and in vivo (GP2 pre-to postvaccination DTH, 0 mm [0.0-19.5 mm] to 27.5 mm [0.0-114.5 mm, P < .001). E75-specific CD8 þ T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%-2.41%] to 1.6% [0.86%-3.72%], P < .001). CONCLUSIONS: The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER-2/neu-specific immune responses, including epitope spreading, in high-risk, lymph node-negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence. Cancer 2010;116:292-301. V C 2010 American Cancer Society.KEYWORDS: breast cancer, GP2, HER-2/neu, peptide, vaccine.Breast cancer is the most common malignancy in women (excluding cancers of the skin), and is the second leading cause of cancer mortality among women. 1 HER-2/neu is a tumor-associated antigen that is overexpressed in approximately 25% to 30% of breast cancer patients and correlates with more aggressive tumor behavior. 2,3 Immunogenic peptides derived from HER-2/neu can induce peptide-specific cytotoxic T lymphocytes (CTLs) that recognize tumor cells expressing these peptides complexed with major histocompatibility complex class I molecules. 4 Two such peptides include E75 and GP2. Our group has previously tested and reported on the E75 peptide used as a preventive clinical vaccine in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) and found it to be safe and effective in raising HER-2/neu immunity. Furthermore, this immunity may confer a clinical benefit in the adjuvant setting. 5

Purpose: HER2/neu, a source of immunogenic peptides, is expressed in >75% of breast cancer patients. We have conducted clinical trials with the HER2/neu E75 peptide vaccine in breast cancer patients with varying levels of HER2/neu expression. Vaccine response based on HER2/neu expression level was analyzed. Experimental Design: Patients were stratified by HER2/neu expression. Low expressors (n = 100) were defined as HER2/neu immunohistochemistry (IHC) 1 + to 2 + or fluorescence in situ hybridization < 2.0. Overexpressors (n = 51) were defined as IHC 3

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.

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Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.

The vaccinated patients who recurred had more aggressive disease compared to V-NR patients. V-R patients had no difference in immune response to the vaccine either in vitro or in vivo. V-R patients, when compared to C-R patients, trended towards more aggressive disease, decreased recurrence rates, decreased mortality, and no bone-only recurrences.

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