Priming the Abscopal Effect in Cervical Cancer

Abstract

Current treatment options for advanced cervical cancer are limited, especially for patients in low-resource settings. The purpose of this study is to investigate a potential therapeutic approach by priming the abscopal effect, leading to regression of both locally treated and distant untreated tumors. We hypothesize that radiotherapy combined with locally delivered anti-CD40 will boost the abscopal effect, with initial investigation in mice. Naïve healthy female mice C57BL/6 were injected with mice cervical cancer cells TC-1 subcutaneously on contralateral flanks, mimicking primary and metastatic tumors. The animals were then randomized into different cohorts. In the treatment cohort, only the primary tumor was treated and response of both tumors was monitored. The treatment consisted of image-guided radiotherapy (IGRT) with a single 6 Gy dose with 10x10 mm2 field size using the Small Animal Radiation Research Platform (SARRP), followed by intratumoral injection of 20 μg anti-CD40. The study was repeated while also varying different treatment parameters including radiotherapy dose (6 Gy, 10 Gy, and 15 Gy) and dosing schedule (one versus three times administration over 2 weeks) of immunoadjuvant anti-CD40. For each study, the size of both treated and untreated tumors was measured with a caliper and SARRP computed tomography imaging and responses compared to those in appropriate control cohorts. Statistical analyses for tumor volume and Kaplan–Meier survival assay were achieved using ANOVA and Log-rank test. The results consistently showed that one 6 Gy compared to 10 Gy or 15 Gy fraction doses of RT with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses after 14 days, with a significant increase in animal survival (p = 0.0004). 60% of the mice treated with this combination showed long term survival with complete tumor regression, where tumors of mice in other cohorts continued to grow (see Table below). Moreover, re-challenged responders to the treatment developed vitiligo suggesting developed immune memory for this cancer. The findings corroborate the hypothesis and show that a single RT fraction dose optimized at 6 Gy in combination with locally delivered anti-CD40 can generate effective abscopal responses. Further investigations to optimize and advance mechanistic understanding of the abscopal effect associated with cervical cancer could lead to innovative treatment methods offering a new more accessible therapy option for cervical cancer care, with a major potential impact, especially in resource-poor settings.Tabled 1Abstract 3022; TableGroupsShrinkage Rate: Treated Tumors [responders/mice in group]Shrinkage Rate: Untreated Tumors: [responders/mice in groups]Complete Tumors Regression [%]Control0/150/1506 Gy2/100/100mAb (1 dose)1/102/100mAb (3 doses)1/51/506 Gy + mAb10/159/156010 Gy + mAb2/51/5015 Gy + mAb4/51/506 Gy + mAb (3 doses)3/53/50 Open table in a new tab