Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer.
Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer.
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DOI：
10.3934/mbe.2023783
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发表时间：
2023-09-15
期刊：
影响因子：
--
通讯作者：
Yankeelov TE
中科院分区：
文献类型：
--
作者：
Lima EABF;Song PN;Reeves K;Larimer B;Sorace AG;Yankeelov TE
本研究的目的是开发一种数学模型，该模型可以捕获evofosfamide，免疫治疗和肿瘤治疗中肿瘤的缺氧景观之间的相互作用。最近，我们发现，evofosfamide，缺氧激活的前药，可以协同改善治疗结果时，与免疫治疗相结合，而evofosfamide单独显示在体内同源模型的结直肠癌没有影响。然而，肿瘤微环境在氧合（低氧、常氧）、免疫治疗和肿瘤细胞背景下的相互作用背后的机制尚未完全了解。为了开始理解这个问题，我们开发了一个常微分方程系统来模拟肿瘤的生长和衰退及其血管化（氧合）对evofosfamide和免疫疗法治疗的反应（6种方案组合）。该模型根据来自植入结肠腺癌细胞的小鼠的体内实验的数据进行校准，并用[18 F]-氟咪唑（[18 F]FMISO）正电子发射断层扫描（PET）进行纵向成像以量化缺氧。结果表明，evofosfamide能够拯救免疫应答并使缺氧肿瘤对免疫疗法敏感。在缺氧情况下，与单独免疫治疗相比，evofosfamide使肿瘤负荷降低了45.07 ± 2.55%，如肿瘤体积所测量的。该模型准确地预测了五种不同治疗方案的时间演变，包括对照、接受免疫治疗的低氧肿瘤、接受免疫治疗的常氧肿瘤、单独使用evofosfamide以及接受联合免疫治疗和evofosfamide的低氧肿瘤。预测和观察肿瘤体积之间的平均一致性相关系数（CCC）为0.86 ± 0.05。有趣的是，拟合这五个治疗组的模型值无法准确预测含氧量正常的肿瘤对evofosfamide和免疫治疗联合治疗的反应（CCC =-0.064 ± 0.003）。然而，在灵敏度分析的指导下，对肿瘤体积最具影响力的参数进行排名，我们发现，由于免疫治疗导致的肿瘤死亡率增加18.6 ± 9.3倍，CCC增加0.981 ± 0.001。据我们所知，这是第一项数学预测和描述evofosfamide后免疫治疗疗效增加的研究。
The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evofosfamide alone showed no effects in an in vivo syngeneic model of colorectal cancer. However, the mechanisms behind the interaction between the tumor microenvironment in the context of oxygenation (hypoxic, normoxic), immunotherapy, and tumor cells are not fully understood. To begin to understand this issue, we develop a system of ordinary differential equations to simulate the growth and decline of tumors and their vascularization (oxygenation) in response to treatment with evofosfamide and immunotherapy (6 combinations of scenarios). The model is calibrated to data from in vivo experiments on mice implanted with colon adenocarcinoma cells and longitudinally imaged with [18F]-fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) to quantify hypoxia. The results show that evofosfamide is able to rescue the immune response and sensitize hypoxic tumors to immunotherapy. In the hypoxic scenario, evofosfamide reduces tumor burden by 45.07 ± 2.55%, compared to immunotherapy alone, as measured by tumor volume. The model accurately predicts the temporal evolution of five different treatment scenarios, including control, hypoxic tumors that received immunotherapy, normoxic tumors that received immunotherapy, evofosfamide alone, and hypoxic tumors that received combination immunotherapy and evofosfamide. The average concordance correlation coeffcient (CCC) between predicted and observed tumor volume is 0.86 ± 0.05. Interestingly, the model values to fit those five treatment arms was unable to accurately predict the response of normoxic tumors to combination evofosfamide and immunotherapy (CCC = −0.064 ± 0.003). However, guided by the sensitivity analysis to rank the most influential parameters on the tumor volume, we found that increasing the tumor death rate due to immunotherapy by a factor of 18.6 ± 9.3 increases CCC of 0.981 ± 0.001. To the best of our knowledge, this is the first study to mathematically predict and describe the increased efficacy of immunotherapy following evofosfamide.
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影响因子：
15.9
作者：
Jayaprakash, Priyamvada;Ai, Midan;Curran, Michael A.
通讯作者：
Curran, Michael A.
DOI：
10.1158/1078-0432.ccr-18-1325
发表时间：
2019-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
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通讯作者：
Ghobrial IM
DOI：
10.1016/j.cma.2022.115484
发表时间：
2022-11-25
影响因子：
7.2
作者：
Lima, Ernesto A. B. F.;Wyde, Reid A. F.;Yankeelov, Thomas E.
通讯作者：
Yankeelov, Thomas E.
影响因子：
4.3
作者：
Hamis, Sara;Kohandel, Mohammad;Powathil, Gibin G.
通讯作者：
Powathil, Gibin G.
影响因子：
5
作者：
Kumar S;Sun JD;Zhang L;Mokhtari RB;Wu B;Meng F;Liu Q;Bhupathi D;Wang Y;Yeger H;Hart C;Baruchel S
通讯作者：
Baruchel S