Regulatory (FOXP3⁺) T cells (T_regs) comprise a subpopulation of CD4⁺ T cells that suppress autoreactive immune cells, thereby protecting organs and tissues from autoimmunity. T_regs have also been detected in human malignancies and their depletion or inactivation substantially improves cellular antitumor immunity in preclinical studies. Novel therapeutic strategies for cervical cancer and precancerous cervical intraepithelial neoplasia (CIN) focus on immune‐modulatory and cancer vaccination approaches. In this context, the frequency of T_regs in cervical cancer and precancerous CIN could influence therapeutic strategies. We determined the frequency of infiltrating CD4⁺ and CD8⁺ T cells as well as FOXP3⁺ T_regs in high‐grade CIN lesions (CIN III) and cervical carcinoma compared to colon carcinoma, skin melanoma, and bronchial carcinoma. We show that human papilloma virus‐derived lesions have a significantly higher number of infiltrating lymphocytes and FOXP3⁺ T_regs compared to three other common tumor entities. In addition we explored the therapeutic effect of agonistic anti‐glucocorticoid‐induced tumor necrosis factor receptor family‐related protein antibodies that, by single systemic application, inactivate T_regs and induce strong intratumoral invasion of CD8⁺ T cells and complete tumor eradication in 70% of treated animals. The large number of T_regs in human papilloma virus‐derived lesions suggests a pivotal role of T_regs for counteracting the host immune response. We therefore regard CIN and cervical cancer as prime targets for new immune‐based non‐invasive therapies. (Cancer Sci 2009; 100: 1112–1117)

We generated an adenovirus-based T-cell vaccine (Ad-p14) that reliably elicits T-cell responses to human papillomavirus (HPV) oncogenes of the 2 most common high-risk HPV serotypes. The artificial gene used to create the vaccine comprising 415 aa (1248 bp) was cloned by fusing 14 polymerase chain reaction fragments of HPV16 and HPV18 E6 and E7 oncogenes devoid of sequences with transforming potential. Although ensuring maximal biologic safety, the construct includes approximately 70% of the relevant T-cell epitopes. In a tumor model for cervical cancer (C3), therapeutic vaccination led to complete eradication in 100% of the mice. In a second model (TC1), it induced initial tumor mass reduction, but 90% of the animals showed delayed tumor progression. To further improve the therapeutic effect, vaccination was combined with systemic application of imiquimod, anti-CD4, α-interferon, or anti-GITR. Although adding α-interferon improved the therapeutic potential of Ad-p14 by 40%, the combination with anti-GITR resulted in complete and permanent eradication of all TC1 tumors. Ad-p14 has clinical potential for treating HPV-induced lesions, and the added effect of immune response modifiers stresses the importance of combined protocols for immunotherapy of malignant tumors.

: Our aim was to present our initial clinical experience using a novel exoscopically based colposcopy system (VITOM) for the evaluation of cervical, vulvar, and vaginal diseases. : Women referred to the Charite Cervix Center, Charite University, Berlin, Germany, were included. Patients with abnormal Pap smear results, vulvar lesions, or a biopsy report of neoplasia of the lower genital tract were included into the study. The VITOM was used for colposcopic evaluation and directed biopsies. Colposcopic findings were reported according to the criteria of the Committee on Nomenclature of the International Federation of Cervical Pathology and Colposcopy. Histologic diagnosis was described as normal, low-grade lesion, high-grade lesion (including cervical intraepithelial neoplasia 2,3, vulvar intraepithelial neoplasia 2,3, vaginal intraepithelial neoplasia 2,3), or cancer. : We recruited 76 patients (54 with cervical, 4 with vaginal, and 18 with vulvar disease) to the prospective study. Four patients were pregnant. Of patients with cervical disease, 29% had a history of previous conization and 3.7% had a history of trachelectomy. The sensitivity, specificity, negative predictive value, and positive predictive value of the VITOM for cervical intraepithelial neoplasia 2, 3 were 90%, 77%, 90% and 77%, respectively. Concordance of exocolposcopic impressions and histologic results was higher in high-grade lesions (K = 0.68, 95% CI = 0.32-0.87, p < .001) than in low-grade lesions (K = 0.41, 95% CI = 0.1-0.41, p < .05). : Exocolposcopy with the VITOM is accurate and shows good correlation to histologic findings in high-grade disease of the lower genital tract. The potential advantages include patient and trainee involvement in examination, decision making, and documentation.

Purpose: The cell surface glycoprotein Mesothelin is overexpressed in ovarian, fallopian tube, endometrial, cervical and primary peritoneal cancer and, therefore, might become a particular interesting tumor target in gynecologic oncology. However, even in malignant tumors of the same entity the level of Mesothelin expression varies between individuals, hence it can be expected that the response to Mesothelin-targeting therapies will be variable as well. In this study we explored the therapeutic potency of a novel anti-Mesothelin antibody–drug conjugate (Anetumab ravtansine) as a function of Mesothelin expression in the targeted tumor cells. Methods: Anti-tumor activity studies were performed in human uterine xenograft tumor models that express Mesothelin at high, moderate or low levels. The antibody–drug conjugate (ADC) was applied in varying doses ranging from 2 to 15 mg/kg at variable intervals in tumor bearing SCID/beige mice and the impact on tumor growth was monitored. Results: The therapeutic response to the anti-Mesothelin ADC correlated closely with the level of Mesothelin expression in tumor cells. Within the applied dose levels complete tumor regression was achieved only in tumors which expressed Mesothelin at particularly high levels (Hela cell tumors). The application of high anti-Mesothelin ADC doses less frequently was more efficious than giving lower doses at a higher frequency. Conclusion: The studies confirm the great therapeutic potential of Anetumab ravtansine. However, a favorable treatment outcome requires strong Mesothelin expression in tumor cells. Future clinical trials may benefit from a more rigorous selection of appropriate patients based on the level of Mesothelin expression in their tumor tissue. If, in addition, it is possible to better control side effects by introducing protective measures and by doing so to increase the maximum tolerated dose, Anetumab ravtansine has the potency to become a valuable therapeutic tool, especially in the field of gynecological oncology.

With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.