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PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model

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Abstract

Introduction

The human papillomavirus (HPV) encoded oncoproteins E6 and E7 are constitutively expressed in HPV-associated cancers, making them logical therapeutic targets. Intramuscular immunization of patients with HPV16 L2E7E6 fusion protein vaccine (TA-CIN) is well tolerated and induces HPV-specific cellular immune responses. Efficacy of PD-1 immune checkpoint blockade correlates with the level of tumor-infiltrating CD8 + T cells, yet most patients lack significant tumor infiltration of immune cells making immune checkpoint blockade suboptimal. We hypothesized that intratumoral vaccination with TA-CIN could increase the number of tumor-infiltrating CD8 + T cells, synergize with PD-1 blockade and result in better control of tumors compared with either PD-1 blockade or vaccination alone.

Methods

We examined the immunogenicity and antitumor effects of intratumoral vaccination with TA-CIN alone or in combination with PD-1 blockade in the TC-1 syngeneic murine tumor model expressing HPV16 E6/E7.

Results

Intratumoral vaccination with TA-CIN induced stronger antigen-specific CD8 + T cell responses and antitumor effects. Intratumoral TA-CIN vaccination generated a systemic immune response that was able to control distal TC-1 tumors. Furthermore, intratumoral TA-CIN vaccination induced tumor infiltration of antigen-specific CD8 + T cells. Knockout of Batf3 abolished antigen-specific CD8 + T cell responses and antitumor effects of intratumoral TA-CIN vaccination. Finally, PD-1 blockade synergizes with intratumoral TA-CIN vaccination resulting in significantly enhanced antigen-specific CD8 + T cell responses and complete regression of tumors, whereas either alone failed to control established TC-1 tumor.

Conclusions

Our results provide rationale for future clinical testing of intratumoral TA-CIN vaccination in combination with PD-1 blockade for the control of HPV16-associated tumors.

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Data availability

Data generated from this study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

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Funding

This work was supported by the National Institutes of Health under award numbers R01CA237067 and P50CA098252.

Author information

Author notes

  1. Shiwen Peng and Marietta Tan co-first authors.

Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA

    Shiwen Peng, Yen-Der Li, Max A. Cheng, Emily Farmer, Louise Ferrall, Richard B. S. Roden, Chien-Fu Hung & T.-C. Wu

  2. Department of Otolaryngology, The Johns Hopkins University, Baltimore, MD, USA

    Marietta Tan

  3. Oncology, The Johns Hopkins University, Baltimore, MD, USA

    Stephanie Gaillard, Richard B. S. Roden, Chien-Fu Hung & T.-C. Wu

  4. Obstetrics and Gynecology, The Johns Hopkins University, Baltimore, MD, USA

    Stephanie Gaillard, Chien-Fu Hung & T.-C. Wu

  5. Molecular Microbiology and Immunology, The Johns Hopkins University, Baltimore, MD, USA

    T.-C. Wu

  6. Johns Hopkins School of Medicine, 1550 Orleans St, CRB II – Room 309, Baltimore, MD, 21287, USA

    T.-C. Wu

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  1. Shiwen Peng
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Contributions

SP contributed to the design and conduction of the experiment. MT contributed to the interpretation of the data. Y-DL contributed to the performance of the experiments. MAC and EF contributed to the original draft preparation. LF, SG, and MT contributed to substantial review and preparation of the manuscript. RBSR contributed to the design of the study. C-FH contributed to the design of the study and interpretation of data. T-CW supervised the study.

Corresponding author

Correspondence to T.-C. Wu.

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The authors declare that they have no conflict of interest.

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All procedures were performed under a prior-approved protocol of the Johns Hopkins Animal Care and Use Committee, and in accordance with recommendations for the proper use and care of laboratory animals.

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Peng, S., Tan, M., Li, YD. et al. PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model. Cancer Immunol Immunother 70, 1049–1062 (2021). https://doi.org/10.1007/s00262-020-02754-x

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