Vaccination against Her-2/neu, with focus on peptide-based vaccines

Abstract

Immunotherapy has been a milestone in combatting cancer, by complementing or even replacing classic treatments like surgery, chemotherapy, radiation, and anti-hormonal therapy. In 15%-30% of breast cancers, overexpression of the human epidermal growth factor receptor 2 (Her-2/neu) is associated with more aggressive tumor development.Passive immunization/immunotherapy with the recombinantly produced Her-2/neu-targeting monoclonal antibodies (mAbs) pertuzumab and trastuzumab has been shown to effectively treat breast cancer and lead to a significantly better prognosis. However, allergic and hypersensitivity reactions, cardiotoxicity, development of resistance, lack of immunological memory which results in continuous application over a long period, and cost-intensiveness are among the drawbacks associated with this treatment. Furthermore, intrinsic or acquired resistance is associated with the application of therapeutic mAbs, leading to the disease recurrence. Conversely, these drawbacks could be potentially overcome by vaccination, i.e. an active immunization/immunotherapy approach by activating the patient's own immune system to target cancer, along with inducing immunological memory. This review aims to summarize the main approaches investigated and undertaken for the production of Her-2/neu vaccine candidates, with the main focus on peptide-based vaccines and their evaluation in clinical settings.

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…With respect to therapeutic vaccines, different technical approaches are used to induce HER2-mediated immunization, including HER2 peptides and DNA-based, viral-vector-mediated, and cell-based vaccines [ 100 ]. Vaccines based on E75 or GP2 peptides are currently being tested in multiple clinical trials, with very variable results depending on the study [ 99 , 105 ]. In a recent meta-analysis evaluating 24 clinical trials, You et al [ 99 ] concluded that E75-based vaccines are generally safe, elicit strong immune response, and may provide significant, albeit reduced, clinical benefits.…”

“…In a recent meta-analysis evaluating 24 clinical trials, You et al [ 99 ] concluded that E75-based vaccines are generally safe, elicit strong immune response, and may provide significant, albeit reduced, clinical benefits. However, clinical trials testing distinct peptide vaccine formulations in combination with either trastuzumab or checkpoint inhibitors are underway [ 99 , 105 ]. Moreover, in addition to metastatic patients, peptide vaccines have been tested in the adjuvant setting to prevent progression to metastatic disease [ 99 , 100 , 105 ].…”

“…However, clinical trials testing distinct peptide vaccine formulations in combination with either trastuzumab or checkpoint inhibitors are underway [ 99 , 105 ]. Moreover, in addition to metastatic patients, peptide vaccines have been tested in the adjuvant setting to prevent progression to metastatic disease [ 99 , 100 , 105 ].…”

Immunological Landscape of HER-2 Positive Breast Cancer

“…Active immunization with mimotopes (B-cell peptides) representing the mAbs' binding epitopes might be an interesting strategy to activate a patient's own anti-tumour immune response. Tobias et al (2020) showed enhanced vaccine's anti-tumour effect in mouse models with the combination of HER-Vaxx (which comprises 3 fused single peptides from ECD of Her-2/neu) and anti-PD-1 blockade [144,145].…”

Combined Vaccination with B Cell Peptides Targeting Her-2/neu and Immune Checkpoints as Emerging Treatment Option in Cancer

“…The identification of mimotopes can be based on the use of phase display strategies [ 99 , 100 ] or, alternatively, as applied in our group, by computer algorithms or the use of synthesized overlapping bio-peptides from the sequence of the respective protein [ 62 , 101 , 102 , 103 ]. The peptides are screened and the mimotope candidates are selected based on their capacity to inhibit the binding of the examined mAb to the respective protein [ 62 , 101 , 102 , 104 ].…”