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Cancer vaccine strategies: translation from mice to human clinical trials

Abstract

We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells (“epitope enhancement”). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.

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Abbreviations

DC:

Dendritic cell

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HLA:

Human leukocyte antigen

KLH:

Keyhole limpet hemocyanin

MHC:

Major histocompatibility complex

PSA:

Prostate-specific antigen

TARP:

T cell receptor gamma-chain-alternate reading frame protein

TCR:

T cell receptor

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Acknowledgments

We thank all the laboratory members and clinical staff who made these studies possible.

Funding

This work was supported by National Cancer Institute Center for Cancer Research Intramural funding under project Z01-SC-004020 to Jay A. Berzofsky.

Author information

Authors and Affiliations

Authors

Contributions

Jay A. Berzofsky—planned and supervised all the preclinical and clinical projects and wrote the manuscript. Masaki Terabe—oversaw and supervised the preclinical research. Jane Trepel—planned and supervised the testing of circulating tumor cells. Ira Pastan—discovered the TARP antigen, provided unpublished information, and helped plan the clinical trials. David F. Stroncek—supervised the preparation of DCs for the clinical trials and planned and supervised the study of DC phenotype as a correlate of DC vaccine efficacy. John C. Morris—Prepared the original Adeno-HER2 vaccine and planned and supervised some of the preclinical studies of that vaccine, as well as helping to plan the HER2 clinical protocol. Lauren V. Wood—wrote both clinical protocols and carried out the clinical trials.

Corresponding author

Correspondence to Jay A. Berzofsky.

Ethics declarations

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval and ethical standards

The animal protocols were approved by the NCI Animal Care and Use Committee accredited by the AAALAC and followed all the AAALAC regulations for animal care and use. The human protocols (NCI 09-C-0139 and 13-C-0016) were all approved by the NCI-NIH Institutional Review Board and the US Food and Drug Administration, and met all the United States ethical standards required for human studies.

Informed consent

After appropriate explanation provided by the protocol principal investigator, all human subjects signed informed consent documents approved by the NCI-NIH Institutional Review Board.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Fifth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2017), held in Prague, Czech Republic, 24th–27th April 2017. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Berzofsky, J.A., Terabe, M., Trepel, J.B. et al. Cancer vaccine strategies: translation from mice to human clinical trials. Cancer Immunol Immunother 67, 1863–1869 (2018). https://doi.org/10.1007/s00262-017-2084-x

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  • DOI: https://doi.org/10.1007/s00262-017-2084-x

Keywords

  • Cancer vaccine
  • TARP
  • Prostate cancer
  • PSA slope
  • HER2
  • DC vaccines