Naomi McCauley

Introduction: Cervical cancer is diagnosed in over 500,000 women and causes over 300,000 deaths worldwide annually.¹ The primary cause of cervical cancer is chronic infection with high-risk human papillomavirus (HPV).¹ Usually, HPV infections are cleared by the host’s immune system.² However, HPV virulence factors such as E6 and E7 promote immune escape that can lead to persistent infection and microenvironment changes with increased inflammatory cytokines, oxidative stress, barrier vulnerability, and local immunosuppression.² Cervical intraepithelial neoplasia (CIN) is a precancerous lesion.³ Today, only surgical excisions can treat CIN.³ However, some surgical treatments increase the risk of preterm birth.³ Given the limited options, development of less invasive therapies are warranted. Lactobacillus casei (L. casei) has anti-tumor effects against HeLa cells and suggests potential for therapeutic probiotic use.⁴ An oral vaccine composed of L. casei expressing E2 Bovine Viral Diarrhea increased CD4+Th2 cells, CD8+TH1 cells, IFNγ, and IL-4 levels in a bovine model.⁵ The use of L. casei vaccines for HPV related lesions were investigated. Methods: In a clinical trial, L. casei HPV (GLBL101c) oral vaccine expressing E7 plasmid was administered to CIN2 patients (19 vaccine/19 placebo) to investigate changes in immune response and disease staging over 16 weeks.⁶ In effort to optimize L. casei expression of E7, IGMKK16E7 vaccine with endogenous expression of E7 on the bacterial cell surface was developed and tested on a murine model.⁷ The efficacy of immune response induction by combing probiotic L. casei with GM-CSF was investigated with a murine model.⁸ Results: The L. casei HPV (GLBL101c) oral vaccine marginally increased E7-specific IFNγ-producing cervical lymphocytes at week 9.⁶ At the end point, there was no significant difference between the two groups in disease staging.⁶ However, the 2 patients with complete CIN remission were in the vaccine group and had increased E7-specific Th1 immune response at week 16.⁶ The L. casei IGMKK16E7 displayed more E7 and produced a 4-fold increase in E7-specific lymphocytes compared to the GLBL101c oral vaccine.⁷ Combined treatment of L. casei and GM-CSF synergistically increased lymphocyte proliferation upon re-stimulation, increased IFNy and IL-4 levels in mononuclear cell supernatant re-pulsed with E7, and strongest inhibition of tumor growth over 6 weeks after TC-1 tumor transplantation.⁸ Conclusion: Existing clinical trials have shown a need for stronger immunogenicity of L. casei HPV vaccines. Optimizing the expression of viral proteins and combining immunotherapy show promising results. More studies are needed to optimize L. casei HPV vaccines for therapeutic use.

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