Generex Biotechnology Corp. (fka GNBTQ)

[WeeZuhl]

HER2-Specific Vaccines for HER2-Positive Breast Cancer Immunotherapy


World Journal of Vaccines, 2015, 5, 106-128
Received 19 March 2015; accepted 18 April 2015; published 24 April 2015


4.9. HER2 Hybrid AE37 (AA: 776-790) Peptide Vaccine

Given the limitations associated with the HER2 peptide vaccines discussed above including waning of immunity with progressive decrease in specific CD8+ T cells, there is a need for booster inoculations to sustain an effective peptide-specific immune response [88]. While the GP2 (GP2 + GM-CSF) vaccines stimulate CD8+ T cells which effectively elicit cytolytic activity directed against HER2-expressing tumors, concern exists that a durable vaccine-specific immune response may require the use of a CD4+ helper T cell epitope to establish a long-term memory CTL response. This has led to the strategy of immunization with a vaccine capable of primarily stimulating CD4+ helper T cells, such as the AE37 vaccine. The AE37 HER2 peptide vaccine is an MHC class II epitopes which is embedded to the MHC class me epitopes with the hope that vaccination will stimulate both CD4+ and CD8+ T cell responses [88]. It is known that using longer peptides as MHC class II epitopes can function as a polyepitope vaccine with both CD4+ and CD8+ T cell epitopes present, this combination therefore could allow for more efficient immunization [88]. Consequently, a modification of the hybrid peptide vaccine has been reported [88] [89]. This involves amplifying the activity of MHC class II epitopes and linking it to a four-amino acid moiety (LRMK; Ii-Key) to the N-terminal end of the epitope peptide either directly or by using a simple polyethylene spacer (-ava-) to produce the li-key HER2 peptide vaccine otherwise known as the AE37 [89]. Ii- Key is derived from the MHC class II-associated invariant chain (Ii protein). It catalyzes binding of the linked epitope to the MHC class II molecule, thereby enhances the overall potency of presentation. Several studies have demonstrated that Ii-Key/HER2(776-790) hybrid (AE37) induces more potent immunologic responses, both in vitro and in vivo, compared with the non-modified HER2776–790 peptide (AE36) [90]-[92]. Indeed, the Ii-Key hybrid AE37 has been shown to generate robust and long lasting HER2-specific immune responses in women with breast cancer. Preliminary data from a phase II study evaluated AE37 in women with breast cancer suggested a better outcome and indicated that the Ii-Key hybrid technology is capable of enhancing the potency of peptide immunotherapy for cancer [92].

The results of the first human phase I trial of the Ii-Key hybrid HER peptide (AE37) vaccine in women with early stage node-negative breast cancer demonstrated vaccine induced dose-dependent immunologic responses, in vitro and in vivo, to AE37 and AE36 (unmodified type), and showed that the hybrid AE37 vaccine was safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER2-specific immune responses; even without the use of an adjuvant [93]. This trial represents the first human experience with the Ii-Key modification. Due to the fact that no immunoadjuvants was added, the AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

Furthermore, at the median follow up period of 22.3 months, 49% reduction in risk of breast cancer recurrence was noted in women treated with the AE37 peptide vaccine compared with the immunoadjuvant, GM-CSF alone. The risk reduction was higher (68%) in women with low HER2 expressers (HER21 + or 2 + on immunostaining) breast cancer [94], which is in line with the general concept that patients with biologically less aggressive disease may respond better to vaccination. Discussion on why HER2 negative patients had better outcome after vaccination is not within the scope of this work.