Optimal dose and schedule of an HER‐2/neu (E75) peptide vaccine to prevent breast cancer recurrence

Abstract

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.

The Impact of HER2/neuExpression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02

“…Prepost -DTH responses were compared using unpaired two-tailed Student t test because node-positive patients did not have pre-DTH test done. A correlation between CD8 + E75-specific cells and DTH has been previously reported (30).…”

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine

“…In phase 1-2 trials with 3 different peptide vaccines, our group has observed that patients who required dose reduction because of large local reactions had significantly fewer recurrences than unvaccinated patients, suggesting a correlation between large local reaction and clinical response to vaccination. 31 Patients boosted at 6 months had significantly greater local reactions to the booster than those boosted later, indicating greater immune response to early boosting, presumably because of greater numbers or function of memory lymphocytes to vaccination. However, a limitation of local reactions is that they are generated in response to both the peptide and GM-CSF immunoadjuvant, unlike DTH measurements in response to small doses (100 lg) of the peptide alone performed prevaccination and at the completion of the primary series.…”

“…17 Briefly, the HLA-A2:immunoglobulin (Ig) dimer (Pharmingen, San Diego, Calif) was loaded with the E75 or control peptide (folate binding protein peptide-E37 [25][26][27][28][29][30][31][32][33] RIA-WARTEL) by incubating 1 lg of dimer with an excess (5 lg) of peptide and 0.5 lg of b 2 -microglobulin (Sigma Chemical Co, St Louis, Mo) at 37 C overnight, then storing it at 4 C until used. PBMCs were washed and resuspended in Pharmingen Stain Buffer and were added at 5 Â 10 5 cells/100 lL/tube in 5 mL round-bottom polystyrene tubes (Becton Dickinson) and stained with the loaded dimers and antibodies as described previously.…”

The importance of correctly timing cancer immunotherapy

“…As can be deduced from above, resection of the tumor mass may alleviate immune suppression allowing the use of immunotherapy to prevent new tumors to arise. Indeed, vaccination of patients with completely resected colorectal cancer metastases showed a significant survival advantage when compared to controls [37], whereas HER2 peptide vaccination in disease-free breast cancer patients was associated with a favourable trend for lower recurrences [38]. Unfortunately, this is not always the case as exemplified by a recent report on patients with surgically resected early stage non-small-cell lung cancer whom were vaccinated with MAGE-A3 but failed to show any improvement in disease free survival [39,40].…”