New Strategies in Advanced Cervical Cancer: From Angiogenesis Blockade to Immunotherapy

Abstract

Cervical cancer remains unique among solid tumor malignancies. Persistent infection with oncogenic subtypes of the human papillomavirus (HPV) results in carcinogenesis, predominantly occurring at the cervical transformation zone where endocervical columnar cells undergo metaplasia to a stratified squamous epithelium. The molecular cascade involving viral oncoproteins, E6 and E7 and their degradative interactions with cellular tumor suppressor gene products, p53 and pRb, respectively, has been precisely delineated. The precursor state of cervical neoplasia may last for years allowing for ready detection through successful screening programs in developed countries using cervical cytology and/or high-risk HPV DNA testing. Prophylactic HPV L1 capsid protein vaccines using virus-like-particle technology have been developed to prevent primary infection by the most common high-risk HPVs (16 and 18). Women who lack access to health care and those who undergo sporadic screening remain at risk. Although radical surgery (including fertility-sparing surgery) is available for patients with early-stage cancers, and chemoradiation plus high-dose-rate brachytherapy can cure the majority of those with locally advanced disease, patients with metastatic and nonoperable recurrent cervical cancer constitute a high-risk population with an unmet clinical need. On August 14, 2014, the FDA approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer. This review will highlight advances in translational science, antiangiogenesis therapy and immunotherapy for advanced disease. Clin Cancer Res; 20(21); 5349-58. Ó2014 AACR.

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

“…The 2 patients with no HPV reactivity did not respond to treatment, and 3 of 6 patients with HPV reactivity had objective tumor responses. 59,77 One patient had a 39% partial response. and 2 patients with widespread disease (1 with chemotherapy-refractory HPV-16 squamous cell carcinoma and 1 with chemoradiation- refractory HPV-18 adenocarcinoma) experienced complete tumor responses that were ongoing at the time of data presentation, 18 and 11 months after treatment.…”

“…57,59 The primary benefits of a DNA-based vaccine rest on the fact that naked DNA is stabile, safe, and cost-effective. In addition, DNA-based vaccines do not elicit neutralizing antibodies in the vaccinated patient and can therefore be administered repeatedly with similar efficacy.…”

“…and 2 patients with widespread disease (1 with chemotherapy-refractory HPV-16 squamous cell carcinoma and 1 with chemoradiation- refractory HPV-18 adenocarcinoma) experienced complete tumor responses that were ongoing at the time of data presentation, 18 and 11 months after treatment. 59,77 Given the positive response in 3 of the 9 patients examined, 2 of whom exhibited a durable remission, the advanced cervical cancer cohort will be expanded to 35 patients. Importantly, the investigators are also studying the efficacy of adoptive T-cell therapy in HPV-related oropharyngeal, anal, vaginal, vulvar, and penile cancers.…”

“…This paradigm has been described as inhibiting the inhibitors responsible for the facilitation of an immune-tolerant landscape. 59 To date, the primary therapeutic targets of immune modulation include CTL antigen-4 (CTLA-4) (Figure 8) 79,80 and programmed death receptor-1 (PD-1) ( Figure 9) 81 , which play a nonredundant role as negative regulators of immune function. CTLA-4, through engagement with its ligands CD80 and CD86, plays a pivotal role in attenuating early activation of naive and memory T cells.…”

“…59 This resulted in the development of a proposed randomized, Phase II, placebo-controlled trial of nivolumab monotherapy with a crossover and run-in randomized Phase II trial of nivolumab with and without ipilimumab for advanced cervical carcinoma after failure of anti-vascular endothelial growth factor therapy ( Figure 3).…”