Rapid Generation of Sustainable HER2-specific T-cell Immunity in Patients with HER2 Breast Cancer using a Degenerate HLA Class II Epitope Vaccine

Abstract

Purpose: Patients with HER2 þ breast cancer benefit from trastuzumab-containing regimens with improved survival. Adaptive immunity, including cytotoxic T-cell and antibody immunity, is critical to clinical efficacy of trastuzumab. Because Th cells are central to the activation of these antitumor effectors, we reason that HER2 patients treated with trastuzumab may benefit by administering vaccines that are designed to stimulate Th-cell immunity. Patients and Methods: We developed a degenerate HER2 epitope-based vaccine consisting of four HLA class II-restricted epitopes mixed with GM-CSF that should immunize most (!84%) patients. The vaccine was tested in a phase I trial. Eligible women had resectable HER2 þ breast cancer and had completed standard treatment prior to enrollment and were disease free. Patients were vaccinated monthly for six doses and monitored for safety and immunogenicity. Results: Twenty-two subjects were enrolled and 20 completed all six vaccines. The vaccine was well tolerated. All patients were alive at analysis with a median follow-up of 2.3 years and only two experienced disease recurrence. The percent of patients that responded with augmented T-cell immunity was high for each peptide ranging from 68% to 88%, which led to 90% of the patients generating T cells that recognized naturally processed HER2 antigen. The vaccine also augmented HER2-specific antibody. Immunity was sustained in patients with little sign of diminishing at 2 years following the vaccination. Conclusions: Degenerate HLA-DR-based HER2 vaccines induce sustainable HER2-specific T cells and antibodies. Future studies, could evaluate whether vaccination during adjuvant treatment with trastuzumab-containing regimens improves patient outcomes.

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“…and Prism, V.8., GraphPad, San Diego CA). A patient was considered to have immunologically responded if she had developed a ≥3-fold increase in FRα-specific T cells or a ≥2-fold increase antibodies at any point during the vaccine period 25,63 . If baseline T cell immunity was undetectable, a positive response was defined as ≥50 antigen-specific T cells/million PBMC.…”

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“…Collectively, these studies suggest that HER2+ BCs are more immunologically responsive with a clear oncogene target, yet may require additional stimulation and direction of anti-tumor immunity, as opposed to the use of systemic checkpoint blockade. These observations suggest utility in targeting HER2 through vaccination with multiple strategies showing some efficacy in this approach in both nonmetastatic and metastatic HER2+ BC patient populations [22][23][24][25][26]. Targeting HER2 is further supported by pre-clinical studies that demonstrate the critical importance of targeting oncogenic drivers, in contrast to vaccines to targeting nononcogenic tumor expressed antigens [27].…”

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“…Initial results for many vaccines varied among different research, while some patients benefited from them but the others not, which showed the possibility of vaccines as a personalized treatment for BC patients. In a phase I trial on resectable HER2 + breast cancer ( Knutson et al, 2019 ), kinds of research developed a degenerate HER2 epitope-based vaccine consisting of four HLA class II-restricted epitopes mixed with granulocyte-macrophage colony stimulating factor. Only two experienced disease recurrence.…”