Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study

Clin Cancer Res. 2019 May 1;25(9):2725-2736. doi: 10.1158/1078-0432.CCR-18-3102. Epub 2019 Jan 11.

Abstract

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).

Patients and methods: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.

Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.

Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alphavirus / genetics
  • Animals
  • Apoptosis
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Cell Proliferation
  • Dendritic Cells / immunology
  • Female
  • Follow-Up Studies
  • Genetic Vectors / administration & dosage
  • Humans
  • Immunity, Humoral / immunology*
  • Immunologic Memory / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Prognosis
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • Survival Rate
  • Tumor Cells, Cultured
  • Vaccines, Subunit / administration & dosage*
  • Vaccines, Subunit / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Cancer Vaccines
  • Vaccines, Subunit
  • ERBB2 protein, human
  • Receptor, ErbB-2