Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer.

Jana Wood,Wilfred Ngwa,Romy Mueller,Akila N Viswanathan,Sayeda Yasmin-Karim

doi:10.3390/cancers12041026

Abstract

Current treatment options for advanced cervical cancer are limited, especially for patients in poor-resource settings, with a 17% 5-year overall survival rate. Here, we report results in animal models of advanced cervical cancer, showing that anti-CD40 therapy can effectively boost the abscopal effect, whereby radiotherapy of a tumor at one site can engender therapeutically significant responses in tumors at distant untreated sites. In this study, two subcutaneous cervical cancer tumors representing one primary and one metastatic tumor were generated in each animal. Only the primary tumor was treated and the responses of both tumors were monitored. The study was repeated as a function of different treatment parameters, including radiotherapy dose and dosing schedule of immunoadjuvant anti-CD40. The results consistently suggest that one fraction dose of radiotherapy with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses, with a significant increase in animal survival (p = 0.0004). Overall, 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. Moreover, re-challenged responders to the treatment developed vitiligo, suggesting developed immune memory for this cancer. The findings offer a potential new therapy approach, which could be further investigated and developed for the treatment of advanced cervical cancer, with major potential impact, especially in resource-poor settings.

Highlights

According to the World Health Organization (WHO), cervical cancer is the fourth most common cancer in women worldwide, with almost 90% of deaths occurring in low- and middle-income countries (LMICs) [1,2]
As a first step to investigate this hypothesis, this study investigates whether one fraction of radiotherapy combined with anti-CD40 can boost the abscopal effect in mouse models of advanced cervical cancer
We demonstrate preclinical data of the abscopal effect in metastatic cervical cancer in the animal model

Summary

Introduction

According to the World Health Organization (WHO), cervical cancer is the fourth most common cancer in women worldwide, with almost 90% of deaths occurring in low- and middle-income countries (LMICs) [1,2]. In LMICs like India and in sub-Saharan Africa, cervical cancer is the second leading cause of cancer among women and the leading cause of female cancer deaths in Africa. Radiotherapy presents a major treatment modality for cervical cancer, with treatment prescribed for both curative and palliative care to ease pain connected with tumor progression. Radiotherapy may present the only curative option for patients with inoperable tumors [5]. Patients with stage IIB-IVA cervical cancer are treated with a combination of external beam radiotherapy, brachytherapy and chemotherapy [6]. Combined radiotherapy regimens offer maximal local control of cancerous lesions, while sparing the healthy tissues and extending the survival of patients [1,7]

Methods

Discussion

Conclusion