Robust generation of T cell immunity to HER2 in HER2+ breast cancer patients with a degenerate subdominant HLA-DR epitope vaccine
Knutson KL, Kalli KR, Block MS, Hobday TJ, Padley DJ, Erskine CL, Dockter T, Suman VJ, Wilson G, Degnim AC. Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester, MN; TapImmune, Inc., Seattle, WA
Background: Recent studies have indicated that vaccination can protect against cancer development. One key aspect of developing vaccines is circumventing peripheral tolerance by identifying subdominant epitopes that are unique to the deregulated tumor microenvironment. While existing subdominant epitope vaccines are showing efficacy in preventing cancer, these vaccines are applicable only for subsets of patients with specific HLA subtypes. Therefore, we recently developed a degenerate HER2 subdominant epitope-based vaccine that should be useful in approximately 85% of all patients. The vaccine consists of a pool of four HLA-DR-restricted 15-amino acid epitopes (p59, p88, p422, and p885) that are naturally processed and are designed to elicit helper T cell immunity, the cornerstone of immune surveillance. Here we present Phase I trial results of this multi-peptide HER2 vaccine.
Methods: Eligible women had HER2+ breast cancer (Stages II-III) and had completed standard treatment (i.e. surgery, chemotherapy, and trastuzumab) at least 90 days prior to enrollment and were rendered disease free. Vaccine included the above epitope pool along with adjuvant GM-CSF. Patients were vaccinated six times over six months and were monitored for toxicity at each visit. Peripheral blood samples were collected for immune responses evaluating for T cell and antibody immunity. Endpoints were safety and immunogenicity leading to the development CD4 helper T cells that recognized naturally-processed HER2.
Results: Twenty-two subjects (age 33 to 69 years) were enrolled. At the present analysis, 21 have completed all 6 vaccination cycles; one patient withdrew after developing a grade 1 injection site reaction during the first vaccination cycle. Twenty patients have had LVEF measured after vaccination; only 2 patients had an LVEF drop of 10% or more but remained in the normal LEVF range. One severe toxicity was reported: a grade 3 INR increase considered unrelated to treatment. Mild to moderate (grade 1-2) toxicities included injection site reactions, fatigue, and white blood cell count decreases. All patients were alive at analysis and only one experienced a recurrence (median follow-up 507 days, range 22 – 844). Twenty patients have had immune response assessments. Vaccine induced T cell immunity was observed in 94% of patients to p59, in 94% of patients to p88, in 82% of patients to p422, and in 74% of patients to p885. Importantly, T cell immunity to naturally processed HER2 proteins occurred in 94% of patients. The mean number of T cells specific for each peptide, post vaccination, ranged from 349–528 T cells per million peripheral blood mononuclear cells (PBMCs). The mean number of T cells specific for whole HER2 protein was 783 T cells per million PBMCs compared to a mean of 898 T cells/million PBMCs specific for the foreign tetanus toxin. In contrast to T cell responses, modestly increased antibody immunity to HER2 occurred in 35% of patients, consistent with the T cell-inducing design of the vaccine.
Conclusion: Our results show that it is possible to develop vaccines with broad HLA coverage that circumvent natural tolerance and induce tumor antigen-specific immunity in the vast majority of patients.
