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

Publication ,  Journal Article
Crosby, EJ; Gwin, W; Blackwell, K; Marcom, PK; Chang, S; Maecker, HT; Broadwater, G; Hyslop, T; Kim, S; Rogatko, A; Lubkov, V; Snyder, JC ...
Published in: Clin Cancer Res
May 1, 2019

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

May 1, 2019

Volume

25

Issue

9

Start / End Page

2725 / 2736

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Vaccines, Subunit
  • Tumor Cells, Cultured
  • Survival Rate
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Middle Aged
  • Mice, Nude
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Crosby, E. J., Gwin, W., Blackwell, K., Marcom, P. K., Chang, S., Maecker, H. T., … Hartman, Z. C. (2019). Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study. Clin Cancer Res, 25(9), 2725–2736. https://doi.org/10.1158/1078-0432.CCR-18-3102
Crosby, Erika J., William Gwin, Kimberly Blackwell, Paul K. Marcom, Serena Chang, Holden T. Maecker, Gloria Broadwater, et al. “Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.Clin Cancer Res 25, no. 9 (May 1, 2019): 2725–36. https://doi.org/10.1158/1078-0432.CCR-18-3102.
Crosby EJ, Gwin W, Blackwell K, Marcom PK, Chang S, Maecker HT, et al. 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):2725–36.
Crosby, Erika J., et al. “Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.Clin Cancer Res, vol. 25, no. 9, May 2019, pp. 2725–36. Pubmed, doi:10.1158/1078-0432.CCR-18-3102.
Crosby EJ, Gwin W, Blackwell K, Marcom PK, Chang S, Maecker HT, Broadwater G, Hyslop T, Kim S, Rogatko A, Lubkov V, Snyder JC, Osada T, Hobeika AC, Morse MA, Lyerly HK, Hartman ZC. 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.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

May 1, 2019

Volume

25

Issue

9

Start / End Page

2725 / 2736

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Vaccines, Subunit
  • Tumor Cells, Cultured
  • Survival Rate
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Middle Aged
  • Mice, Nude