Results of a phase I clinical trial of an Ii-Key/HER2/neu MHC class II peptide-based vaccine in breast cancer patients.

2532 Background: HER2/neu is over-expressed in breast cancer (BCa) and is the source of immunogenic peptides currently being evaluated in clinical trials as cancer vaccines. Ii-Key is a 4-amino-acid modification of peptides that has been reported to increase their occupancy of MHC class II molecules and enhance CD4 T cell responses. We are currently conducting a phase I clinical trial with an Ii-Key/HER2/neu MHC class II peptide (AE37) in BCa patients. Methods: The dose escalation safety trial design is for 3 groups of 3 patients to receive either 100, 500, or 1,000 μg of AE37 with 250 μg of GM-CSF in 6 monthly inoculations. Six additional patients will then be vaccinated at the optimal dose. Local and systemic toxicity is monitored and graded by the Common Toxicity Criteria. Immunologic response is monitored by peptide-stimulated proliferation (3H-thymidine incorporation) and ELISPOT (IFN-γ) assays for both AE37 and AE36 [the unmodified peptide HER2 776–790 (GVGSPYVSRLLGICL)]. Thus far 6 BCa patients have been vaccinated. Results: The 100μg dose group has completed all 6 vaccinations with maximum local and systemic toxicities of grade 2 and 1, respectively. All 3 patients developed increasing peptide-specific proliferation post-vaccination to both AE37 and AE36. ELISPOT responses were more variable with 1 minimal responder (30 IFN-γ spot-forming cells (SFC)/106 cells), 1 moderate responder (600 IFN-γ SFC/106 cells), and 1 good responder (1500 IFN-γ SFC/106 cells) post-vaccination. The 500μg dose group has thus far experienced earlier and larger local reactions but limited systemic toxicity. All 3 patients have demonstrated >1500 IFN-γ SFC /106 cells after just 2 inoculations. Peptide-specific proliferation after 2 inoculations has ranged between 3200–11500 cpm for the 500μg patients compared with 1200–2000 cpm after 6 inoculations for the 100μg dose group. Conclusions: AE37 appears to be safe and well-tolerated. A dose-dependent immunologic response has been demonstrated to the Ii-Key modified peptide as well as the naturally occurring sequence. These encouraging early results suggest that AE37 may prove to be useful as a CD4-specific vaccine either alone or in combination with CD8-specific HER2/neu peptides for improved cancer immunotherapy. [Table: see text]