Effectiveness of combination therapy with ISA101 vaccine for the treatment of human papillomavirus-induced cervical cancer

Abstract

Cervical cancer is one of the women-associated tumors that affects numerous people yearly. It is the fourth most common malignancy in women worldwide. Following early diagnosis, this cancer can be cured mainly by traditional methods such as surgery, tumor resection, and chemotherapy; nonetheless, it becomes more challenging to treat in advanced and metastatic stages. With the advent of novel treatments such as angiogenesis inhibitors or immuno-checkpoint blockers in recent years, the survival rate of patients with advanced cervical cancer has significantly increased. However, it has not yet reached a satisfactory level. It has been revealed that human papillomavirus (HPV) infection is responsible for more than 90% of cervical cancer cases. However, evidence revealed that monotherapy with anti-HPV vaccines such as ISA101 could not affect tumor growth and progression in patients with HPV-induced cervical cancer. Therefore, combining ISA101 and immune checkpoint blockers or other immunotherapeutic approaches may be more robust and effective than monotherapy with ISA101 or immune checkpoint blockers for treating cervical cancer. This review summarizes the ISA101 properties, advantages and disadvantages. Furthermore, various conducted combination therapies with ISA101 and the effectiveness and challenges of this treatment have been discussed.

Keywords: ISA101; cervical cancer; human papilloma virus; immunotherapy; vaccine.

Figure 1

HPV-16 genome. HPV-16 is a relatively small, uncoated virus containing the L1 and L2 capsid proteins and the E proteins involved in proliferation and tumorigenesis (E1, E2, E4, E5, E6, E7), of which E6 and E7 are associated with tumorigenesis in cervical cancer.

Figure 2

HPV-induced cervical cancer and available therapeutic approaches. Following infection with HPV-16 and HPV-18 subtypes, the basal cells in the cervix are affected, and after a few weeks, the infection spreads to the epithelial cells and HPV replicate in the cytoplasm of these cells (episomal viral DNA replication). Regularly, most people recover spontaneously after a period of one to two years. However, after 10 to 30 years, in about 0.08% of patients, persistent infections along with untreated lesions could be associated with disruption of E2 and E6/E7 oncogenes upregulation and the HPV genome integration into the host DNA, resulting in HPV-induced cervical cancer. There are various treatments such as surgery, radiotherapy, chemotherapy, and vaccination for these patients. Among the peptide-based vaccines, the ISA101 vaccine, which consists of two synthetic proteins, E6 and E7, along with Montanide ISA 51 adjuvant, can activate the specific responses of T cells against HPV-infected cells. Although due to obstacles such as the immunosuppressive TME and other unknown reasons, this vaccine is not effective. Therefore, combining of chemotherapy and other immunotherapeutic approaches, such as immune checkpoint blockers with ISA101 could be more effective than ISA101 monotherapy for advanced cervical cancer.