Serre Raphaël, Barlesi Fabrice, Muracciole Xavier, Barbolosi Dominique
Simulation & Modelling Adaptive Response for Therapeutics in Cancer (SMARTc), Center for Research on Cancer of Marseille, CRCM Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, Marseille, France.
Multidisciplinary Oncology & Therapeutic Innovations Department, Assistance Publique-Hopitaux Marseille, Marseille, France.
Oncotarget. 2018 Aug 7;9(61):31812-31819. doi: 10.18632/oncotarget.25746.
Concomitant radiotherapy with immune checkpoint blockade could be synergistic. Out-of-field effects could improve survival by slowing or blocking metastatic spreading. However, not much is known about the optimal size per fraction and inter-fraction time in that new context.
The new concept of Immunologically Effective Dose (IED) is proposed: it models an intrinsic immunogenicity of radiotherapy schedules, i.e. the fraction of immunogenicity that results from the choice of the dosing regimen. The IED is defined as the single dose, given in infinitely low dose rate, that produces the same amount of abscopal response as the radiation schedule being considered. The IED uses the classic parameters of the BED formula and adds two parameters for immunogenicity that describe the local availability of immune effectors within the tumor micro-environment. Fundamentally, the IED adds a time dimension in the BED formula and describes an intrinsic immunogenicity level for radiotherapy.
The IED is positively related to the intensity of the out-of-field, radiotherapy-mediated, immune effects described in some preclinical data. Examples of numerical simulations are given for various schedules. A web-based calculator is freely available.
Out-of-field effects of radiotherapy with immune checkpoint blockers might be better predicted and eventually, radiotherapy schedules with better local and systemic immunogenicity could be proposed.
A model for the intrinsic level of immunogenicity of radiotherapy schedules, referred to as the Immunologically Effective Dose (IED), that is independent of the type of immunotherapy.
免疫检查点阻断与放疗联合应用可能具有协同作用。野外效应可通过减缓或阻断转移扩散来提高生存率。然而，在这种新背景下，关于每次分割的最佳剂量大小和分割间期知之甚少。
提出了免疫有效剂量（IED）的新概念：它模拟了放疗方案的内在免疫原性，即由给药方案的选择所产生的免疫原性部分。IED定义为以无限低剂量率给予的单次剂量，其产生的远隔效应量与所考虑的放疗方案相同。IED使用BED公式的经典参数，并增加了两个描述肿瘤微环境中免疫效应器局部可用性的免疫原性参数。从根本上说，IED在BED公式中增加了一个时间维度，并描述了放疗的内在免疫原性水平。
IED与一些临床前数据中描述的野外放疗介导的免疫效应强度呈正相关。给出了各种方案的数值模拟示例。可免费使用基于网络的计算器。
放疗联合免疫检查点阻断剂的野外效应可能得到更好的预测，最终可提出具有更好局部和全身免疫原性的放疗方案。
一种放疗方案内在免疫原性水平的模型，称为免疫有效剂量（IED），它独立于免疫治疗类型。
