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

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.

Phenotypic and Functional Characteristics of Exosomes Derived from Irradiated Mouse Organs and Their Role in the Mechanisms Driving Non-Targeted Effects

“…In vivo partial body irradiation (PBI) constitutes a major problem in radiation protection, with contradictory evidence suggesting that PBI may contribute to and/or protect against detrimental health effects. PBI exposures are the norm in diagnostic radiology, radiation therapy and occupational exposures and may have significant implications for systemic consequences and human health effects at low and intermediate doses of ionising radiation [40][41][42][43]. However, to date, only limited mechanistic studies are available in understanding the consequences of PBI effects.…”

Local Destruction of Tumors and Systemic Immune Effects

“…A possible abscopal effect was investigated in 48 studies ( Table 4 ) ( 39 , 156 , 157 , 159 – 201 ). It could be demonstrated in 7/48 (15%) studies when radiotherapy was used alone ( 162 , 164 , 166 , 168 , 173 , 183 , 197 ).…”

“…Rejection immunity was investigated in relatively few studies and was seen in 4/6 studies after radiotherapy alone ( 39 , 158 , 168 , 175 , 200 , 201 ) and in 11/11 studies after combined treatment.…”

Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy

“…Moreover, a single dose of 15 Gy was more effective than consecutive 5 × 3 Gy at priming antitumor T cells to antigen ovalbumin, but priming was seen with both regimens [ 75 ]. RT dose of 6 Gy showed equal to better abscopal responses than 10 Gy and 15 Gy with an anti-CD40 agonistic antibody [ 76 ]. Low dose RT can suppress the proliferation of T regulatory (Treg) cells, specifically at a dose of 0.94 Gy more than high dose RT with 15 Gy [ 77 ].…”