Intratumoral Injection of a Human Papillomavirus Therapeutic Vaccine-Induced Strong Anti-TC-1-Grafted Tumor Activity in Mice

Abstract

Purpose The route of administration of a therapeutic tumor vaccine is a critical factor in inducing antitumor activity. In this study, we explored the effects of three vaccination routes (subcutaneous, peritumoral, and intratumoral injection) on antitumor activity induced by a human papillomavirus (HPV) therapeutic vaccine containing HPV16 E7 peptide combined with the adjuvant CpG ODN in established TC-1 grafted tumors. Methods We used flow cytometry to evaluate splenic and tumor-infiltrating immune cells. We also assessed transcriptional changes in a sequence of immune-related genes in tumors of different treatment groups using quantitative real-time polymerase chain reaction. Immunohistochemistry was used to determine the expression of molecules related to tumor infiltrating immune cells, angiogenesis, and cancer-associated fibroblasts in tumor tissues. Results Our results suggested that intratumoral and peritumoral vaccination generated enhanced antitumor activity compared to subcutaneous delivery. In particular, intratumoral vaccination elicited a stronger antitumor effect, with two of the six treated mice being nearly tumor-free at day 28. Three vaccination routes induced increases in splenic CD4+ and/or CD8+ T lymphocytes, and marked decreases in immunosuppressive cells. Peritumoral vaccination increased the tumor-infiltrating CD8+T cells in tumors, while intratumoral vaccination enhanced the tumor-infiltrating CD4+ and CD8+ T lymphocytes, as well as decreased the tumor-infiltrating of immunosuppressive cells, which may result in stronger inhibition of tumor growth and prolonged survival in mice bearing tumors. Furthermore, compared to the subcutaneous route, intratumoral vaccination led to a significant increase in antitumor cytokines and chemokines. In addition, our data showed marked downregulation of MMP-2, MMP-9, VEGF, CD31, and α-SMA in the intratumoral vaccination group, which might contribute to the suppression of tumor invasion, angiogenesis, and metastasis. Conclusion Overall, intratumoral vaccination is superior to subcutaneous delivery and has the potential to inhibit tumor growth by improving the tumor microenvironment.

mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

“…Intramuscular injection is commonly recommended for the administration of most vaccines to enhance vaccine efficacy and promote local immunomodulation at the injection site 44 . However, Che et al 45 reported that peritumoral injection of HPV peptide therapeutic vaccines induced a significantly higher immune response than subcutaneous injection. Similarly, the peritumoral S.C. route of immunization demonstrated superior tumor suppression and extended survival compared to the I.M.…”

Advances in Cancer Vaccine Research

“…Results showed that intratumoral vaccination produced enhanced antitumor activity compared with SC injection. The data showed significant downregulation of MMP-2, MMP-9, VEGF, CD31, and α-SMA in the intratumoral vaccination group, which may contribute to the inhibition of tumor invasion, angiogenesis, and metastasis . Then, in 2022, Jiang et al systematically investigated the effects of SC and intratumoral vaccination on nanovaccine performance and found that intratumoral injection of nanovaccines showed more effective antitumor effects in a variety of tumor models and that vaccine immunization using the currently clinically feasible intratumoral injection technique was able to form intratumoral compared to conventional SC injection of vaccine.…”

“…The data showed significant downregulation of MMP-2, MMP-9, VEGF, CD31, and α-SMA in the intratumoral vaccination group, which may contribute to the inhibition of tumor invasion, angiogenesis, and metastasis. 157 Then, in 2022, Jiang et al systematically investigated the effects of SC and intratumoral vaccination on nanovaccine performance and found that intratumoral injection of nanovaccines showed more effective antitumor effects in a variety of tumor models and that vaccine immunization using the currently clinically feasible intratumoral injection technique was able to form intratumoral compared to conventional SC injection of vaccine. A positive feedback loop of myeloid/CXCL9-T cells/IFN-γ significantly promotes T cell recruitment to the tumor, thus optimizing the TME and producing a more effective therapeutic effect on distant metastatic tumors as well.…”

Cell penetrating peptide: A potent delivery system in vaccine development

“…This strategy is important to develop tumor cells-based vaccines against a variety of cancers. On the other hand, the reports showed that intratumoral injection is more efficient than subcutaneous delivery in suppressing tumor growth using improvement of the tumor microenvironment ( Che et al, 2021 ). Thus, the use of cell-specific CPPs can be effective for delivery of antigens intratumorally.…”