Optimal method of dosing HER2/neu peptide vaccines: U.S. Military Cancer Institute Clinical Trials Group Study 1-01, 1-02, 1-03, and 1-04

Abstract #3139 Background: Our Cancer Vaccine Development Program has performed phase I and II clinical trials using immunogenic peptides from the HER2/neu protein. AE37 (aa:776-790+Ii-Key) is HLA promiscuous whereas E75 (aa:369-377) and GP2 (aa:654-662) are HLA-A2/A3+ restricted. The peptides are located on the intracellular, extracellular, and transmembrane portions of the HER2/neu protein. We evaluate patients who required dose reductions and compare them to those who did not in our three peptide vaccine trials to determine the immunologic and clinical relevance of different responses to the peptide vaccines. Methods: Three vaccine trials were performed separately with similar dose escalation design by varying the amount of AE37, GP2 or E75 peptide and GM-CSF adjuvant. Dose reductions (DR) were made in event of significant toxicity (>100mm local or ≥grade 2 systemic) by decreasing GM-CSF (or peptide if no GM-CSF) by 50% for subsequent inoculations. We compared patients necessitating DR and those who did not. Immune response was measured ex vivo via 3H-thymidine proliferative assays or HLA-A2:Ig dimer assays and in vivo via DTH reactions pre- and post-vaccine. Recurrence and mortality data were available for E75 treated patients at 30-month median follow-up. Results: 132 patients underwent peptide vaccination and 39 patients required DR (Table 1). No patient had grade 3-5 local or systemic toxicities. DR patients, particularly those reduced for robust local reactions (DR-L), had greater immune responses ex vivo and in vivo. The post-vaccine DTH in DR-L patients compared to all other vaccinated patients was significantly larger in E75 (24.5±4.1mm vs. 12.7±1.3mm; p=0.001) and trended towards significant in AE37 (69.4±10.3mm vs. 35.8±14.9mm; p=0.08) and GP2 (48.9±14.1mm vs. 24.1±3.3mm; p=0.08). No recurrences or deaths were noted in the E75 DR patients; but for patients not requiring dose reductions there were 10 (12.5%) recurrences and 1 (1.25%) death.Discussion: All three peptide vaccines are safe and well-tolerated with minimal toxicity. The safety was partly due to reducing GM-CSF (or peptide if no GM-CSF) by 50% for patients with >100mm local reactions or >grade 2 systemic toxicity. DR patients, particularly DR-L patients, immunological responses were larger. This increased immune response (noted by DTH) suggests improved clinical response as there have been no recurrences or deaths among DR patients. Our analysis indicates that the optimal method of dosing HER2/neu peptide vaccines consists of constant peptide dose with a large enough dose of adjuvant to generate robust local reactions and that when local reactions are >100mm performing DR of adjuvant by 50% for subsequent inoculations. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3139.