From bench to bedside: The use of the li-Key technology to improve helper peptides for clinical use in cancer vaccines.

Abstract

2508 Background: Work involving peptide vaccines has shown that peptides containing MHC Class II epitopes, which elicit CD4+ T cell responses, may play a role in potentiating an immune response. The Ii-Key peptide (amino acids 77-80 of the immune-regulatory Ii protein), when covalently linked to an MHC Class II epitope, can induce conformational change in the epitope binding groove, increasing CD4+ T cell stimulation up to 250 fold. Here we present an update of results from clinical trials evaluating this novel technology in an adjuvant breast cancer vaccine targeting HER2/neu. Methods: We reviewed our trials investigating AE37, a hybrid peptide created by the addition of the Ii-Key peptide (LRMK) to AE36 (GVGSPYVSRLLGICL), an MHC Class II-binding peptide from the intracellular domain of the HER2 protein. We have completed a phase I study and are currently conducting a randomized phase II trial of the AE37 peptide + GM-CSF in the adjuvant treatment of disease-free breast cancer patients with any level of HER2 expression (IHC 1-3+ or FISH>1.2). Results: Phase I data showed the vaccine to be safe and effective in raising anti-HER2 immunity. Importantly, even the cohort of patients given AE37 without GM-CSF showed significant increases in both in vivo and in vitro immune responses. To date, we have enrolled 201 patients to our phase II trial (Vaccine (VG)=103, Control (CG)=98). Toxicity has been minimal (99% of local and systemic toxicities grade ≤2). VG patients have shown significant increases in both in vivo and in vitro responses to both AE36 and AE37, with consistently stronger responses to the AE37 hybrid peptide than the native AE36. With a median f/u of 22 months, Kaplan Meier projections estimate recurrence rates of 10.3% in the VG compared to 18% in the CG; a 43% risk reduction. Conclusions: The AE37 peptide vaccine appears to be effective in eliciting a strong immune response and possibly preventing breast cancer recurrence. These results provide an important proof of concept and suggest that additional studies evaluating Ii-Key hybrid peptide vaccines are warranted, whether in the field of immunotherapy or more traditional vaccines.