A novel treatment for recurrent localized cervical cancer using point-of-care ethyl cellulose ethanol ablation with concurrent cytotoxic therapy.
Authors: Agudogo Júlia Sroda , Nief Corrine Audrey , Chelales Erika , Gonzales Alana , Mueller Jenna , Crouch Brian , Previs Rebecca A. , Ramanujam Nimmi 
Published: June 2021

e17507

Background: Historically, the only curative option for patients with recurrent localized cervical cancer after platinum-based chemotherapy and radiation is pelvic exenteration. For non-surgical candidates, treatment options include systemic therapy with chemotherapy, bevacizumab or pembrolizumab. However, these therapies are not curative. Addition of local ablative therapy to systemic therapy is a promising option, as this combination can induce a more robust local antitumor immune response. We developed a polymer-assisted ethanol ablative therapy, Point-of-care Ethanol Ethyl Cellulose (PEEC), that overcomes the main shortcoming of traditional ethanol ablation: off-target ethanol leakage. We previously demonstrated the success of PEEC in pre-clinical head and neck and breast cancer models. Here, we hypothesized that combination of reduced tumor acidity using sodium bicarbonate (bicarb) and decreased regulatory T cells using systemic or local chemotherapy would prime the tumor immune microenvironment for PEEC as a novel treatment strategy for recurrent localized cervical cancer. Methods: An HPV16 E6/E7+ TC1-Luc cell line was used to establish a syngeneic cervicovaginal tumor model in C57BL/6 mice. First, intratumoral PEEC was compared to sham ablation (saline). Tumor bearing mice were randomized to receive either PEEC or sham (n = 5 each) 2 days after tumor inoculation. Tumor volume and growth were measured with calipers and a Perkin Elmer in vivo imaging system (IVIS) respectively; tumors were imaged on days 1, 2, 3, 7, 14 and 28. Tumor weight was measured by weighing reproductive tracts. Next, we tested whether local and/or systemic cyclophosphamide (cyclo) with bicarb improved response to PEEC. Tumor bearing mice were randomized to receive systemic or local cyclo+bicarb and/or PEEC. The same ablation and tumor monitoring schedule was used, with bicarb (200 mM) added to the drinking water and cyclo (50 mg/kg) given either intraperitoneally or locally on day 1 following tumor inoculation. Results: Tumors treated with PEEC had significantly smaller volumes by day 7 and onward compared to sham (p < 0.005). Tumors treated with PEEC also had significantly decreased tumor weights (at necropsy) compared to sham (p < 0.0002). The PEEC groups showed prolonged survival compared to sham (p < 0.05). Local cyclo+bicarb+PEEC therapy was superior to all other treatment groups with no measurable tumor luminescence signal (via IVIS) in all five mice (5/5) on day 14 and onward. Systemic cyclo+bicarb+PEEC resulted in 4/5 mice with no signal. PEEC alone led to no signal in 3/5 mice. Sham alone showed tumor progression in all 5 mice. Conclusions: PEEC ablation is enhanced by concurrent cytotoxic therapy and significantly controls HPV16 E6/E7+ cervicovaginal tumor growth, supporting future clinical translation for treatment of recurrent localized cervical cancer.