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Published on: March 8, 2012
Circular RNA-based HPV16 therapeutic vaccine elicits potent and durable antitumor immunity
Rong Zhou1, Chonghui Li2, Kunlun Xiang2
1Therorna Inc., Beijing, China.
Background:
Human papillomavirus (HPV) 16 infection is associated with several human malignancies. Developing therapeutic vaccines holds great potential for patients who do not benefit from standard care. Circular RNA (circRNA) is an emerging next-generation platform for cancer vaccine development owing to its superior stability and convenient manufacturing process. Herein, we report development of a synthetic circRNA encoding fused HPV16 E7/E6 antigens encapsulated with lipid nanoparticles (LNP) to treat HPV16-related solid tumors.
Methods:
The immunogenicity and anti-tumor immune response of the LNP-circRNA vaccine was determined in naïve C57BL/6 mice and TC-1 tumor-bearing mice, respectively. Changes in immune cells were examined using flow cytometry and immunofluorescence assay. RNA sequencing was used to identify differentially expressed genes and changes in the tumor microenvironment (TME) of tumors treated with LNP-circRNAE7E6 and empty LNP. Anti-tumor efficacy was further evaluated in LNP-circRNAE7E6 vaccine combined with anti-PD-L1 antibody treatment.
Results:
Prime-boost vaccination with LNP-circRNAE7E6 induced a large pool of functional antigen-specific cytotoxic T cells in both the peripheral blood and spleen. This immunization led to profound changes in the TME, characterized by the upregulation of immune activation genes, heavy infiltration of immune cells, and polarization toward a proinflammatory state. Consequently, circRNAE7E6 immunization could mediate complete tumor regression and prevent tumor growth. Moreover, vaccination sensitized non-inflamed tumors to immune checkpoint blockade therapy.
Conclusions:
The present study results demonstrate that LNP-circRNAE7E6 vaccine is capable of eliciting robust anti-tumor immunity in the periphery and TME, highlighting the potential for treating HPV16-related cancers and preventing tumor recurrence.
Insights
A novel circular RNA (circRNA) vaccine effectively targets human papillomavirus (HPV) 16-related cancers. This lipid nanoparticle-encapsulated circRNA vaccine generates a strong anti-tumor immune response, leading to tumor regression and enhanced immunotherapy efficacy.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Human papillomavirus (HPV) 16 infection is linked to various human cancers.
- Therapeutic vaccines offer potential for patients unresponsive to standard treatments.
- Circular RNA (circRNA) presents a stable and manufacturable platform for next-generation cancer vaccines.
Purpose of the Study:
- To develop and evaluate a synthetic circRNA vaccine encoding fused HPV16 E7/E6 antigens.
- To assess the vaccine's immunogenicity and anti-tumor response in preclinical models.
- To investigate the combination therapy of circRNA vaccine with immune checkpoint inhibitors.
Main Methods:
- Developed a lipid nanoparticle (LNP)-encapsulated circRNA vaccine (LNP-circRNAE7E6) encoding fused HPV16 E7/E6 antigens.
- Assessed vaccine immunogenicity and anti-tumor immune response in C57BL/6 and TC-1 tumor-bearing mice.
- Analyzed immune cell changes via flow cytometry and immunofluorescence; examined gene expression and tumor microenvironment (TME) using RNA sequencing.
- Evaluated combination therapy with anti-PD-L1 antibody.
Main Results:
- Prime-boost vaccination with LNP-circRNAE7E6 induced significant antigen-specific cytotoxic T cells.
- Immunization modulated the TME, increasing immune cell infiltration and pro-inflammatory gene expression.
- LNP-circRNAE7E6 vaccination achieved complete tumor regression and prevented tumor growth.
- Vaccination sensitized tumors to immune checkpoint blockade therapy.
Conclusions:
- LNP-circRNAE7E6 vaccine elicits potent anti-tumor immunity in both peripheral and tumor environments.
- This circRNA-based vaccine demonstrates significant potential for treating HPV16-related cancers.
- The findings highlight the therapeutic promise for preventing cancer recurrence.
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