4.6 Article

Nanobody-Antigen Conjugates Elicit HPV-Specific Antitumor Immune Responses

Journal

CANCER IMMUNOLOGY RESEARCH
Volume 6, Issue 7, Pages 870-880

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0661

Keywords

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Funding

  1. Keck School of Medicine/USC Graduate School PhD Fellowship
  2. National Cancer Institute Cancer Center Support Grant [P30CA014089]
  3. Arnold O. Beckman Postdoctoral Fellowship
  4. Cancer Research Institute Irvington Postdoctoral Fellowship
  5. American Cancer Society
  6. NIH [R01 CA074397]
  7. Lustgarten Foundation [388167]
  8. Melanoma Research Alliance [51009]
  9. NATIONAL CANCER INSTITUTE [R01CA074397, P30CA014089] Funding Source: NIH RePORTER

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High-risk human papillomavirus-associated cancers express viral oncoproteins (e.g., E6 and E7) that induce and maintain the malignant phenotype. The viral origin of these proteins makes them attractive targets for development of a therapeutic vaccine. Camelid-derived single-domain antibody fragments (nanobodies or VHHs) that recognize cell surface proteins on antigen-presenting cells (APC) can serve as targeted delivery vehicles for antigens attached to them. Such VHHs were shown to induce CD4(+) and CD8(+) T-cell responses against model antigens conjugated to them via sortase, but antiiumor responses had not yet been investigated. Here, we tested the ability of an anti-CD11b VHH (VHHCD11b) to target APCs and serve as the basis for a therapeutic vaccine to induce CD8(+) T-cell responses against HPV+ tumors. Mice immunized with VHHCD11b conjugated to an H-2D(b)-restricted immunodominant E7 epitope (E7(49-57)) had more E7-specific CD8(+) Tcells compared with those immunized with E7(49-57) peptide alone. These CD8(+) T-cells acted prophylactically and conferred protection against a subsequent challenge with HPV E7-expressing tumor cells. In a therapeutic setting, VHHCD11b-E7(49-57) vaccination resulted in greater numbers of CD8(+) tumor-infiltrating lymphocytes compared with mice receiving E7(49-57) peptide alone in HPV+ tumor-hearing mice, as measured by in vivo noninvasive VHH-based immune-positron emission tomography (immunoPET), which correlated with tumor regression and survival outcome. Together, these results demonstrate that VHHs can serve as a therapeutic cancer vaccine platform for HPV-induced cancers. (C) 2018 AACR.

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