Novel Therapeutics for Recurrent Cervical Cancer: Moving Towards Personalized Therapy

Abstract

While screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the United States annually. Early stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being >90%. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective treatment options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the phase III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the US FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after one or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a phase III trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued are PARP inhibitors (rucaparib and olaparib are both in phase II) based on earlier study results.

Biological and clinical aspects of HPV-related cancers

“…However, patients with HPV-related cancers receive the same treatment as patients with HPV-unrelated cancers at the same anatomical site. An FDA-approved anti-PD-1 antibody, pembrolizumab, became a first-line treatment option for all PD-L1 expressing tumors including HPV-positive and -negative HNC 24 , 25 . It can be used as a monotherapy or in combination with chemotherapy.…”

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

“…Cervical cancer (CC) is one of the most common tumours, ranking fourth for both incidence and mortality in women worldwide [ 1 – 3 ]. CC is the result of continuous infection with some strains of human papillomavirus (HPV), such as HPV16 and HPV18 [ 4 , 5 ]. Though there are abundant measures of prevention and cure, cervical cancer continues to exhibit high invasion and poor prognosis [ 6 ].…”

Optimal treatment in locally advanced cervical cancer

“…Another approach involves using immune checkpoint receptors inhibitors, such as anti-programmed cell death/cell death ligand (PD-1/PD-L1) and anti-cytotoxic T lymphocyteassociated antigen 4 (CTLA-4). Currently, data are increasingly available regarding utilization of these molecules in the metastatic setting [97]. CCRT in combination with checkpoint -treatment period grade 3-4: higher in NACT arm (GI and hematologic) -follow-up period grade 3-4: higher in CCRT arm (GI and GU) ADC = adenocarcinoma; ADSC = adenosquamous carcinoma; AEs = adverse events; BT = brachytherapy; CCRT = concomitant chemoradiotherapy; CT = chemotherapy; DFS = disease-free survival; EBRT = external-beam radiotherapy; FIGO = International Federation of Gynecology and Obstetrics; GI = gastrointestinal; GU = genito-urinary; HDR = high-dose rate; IC = intra-cavitary; ITT = intention-to-treat; LDR = low-dose rate; NACT = neo-adjuvant chemotherapy; NS = not significant; OS = overall survival; PFS = progression-free survival; RT = radiotherapy; SCC = squamous cell carcinoma inhibitors may induce an increased immunogenic environment by initiating DNA breaks, cell death, and antigen presentation, leading to enhancing anti-tumor activity.…”