A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy.
A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy.
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DOI：
10.3390/cancers13205171
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发表时间：
2021-10-15
期刊：
影响因子：
5.2
通讯作者：
Rockne RC
中科院分区：
文献类型：
--
作者：
Adhikarla V;Awuah D;Brummer AB;Caserta E;Krishnan A;Pichiorri F;Minnix M;Shively JE;Wong JYC;Wang X;Rockne RC
靶向放射性核素疗法（TRT）和免疫疗法，例如嵌合抗原受体T细胞（CAR-T），代表了根除全身性癌症的两种有效手段。虽然每一个作为单一疗法可能有一个有限的效果，效力可以增加与两种疗法的组合。这些疗法的剂量和时间安排中涉及的并发症使得这些疗法的数学建模成为设计组合治疗方法的合适解决方案。在这里，我们研究了TRT和CAR-T细胞联合疗法的数学模型。通过对数学模型的分析，我们发现肿瘤增殖率是影响TRT和CAR-T细胞治疗时间安排的最重要因素，肿瘤增殖速度更快，两种治疗之间的间隔时间更短。靶向放射性核素治疗（TRT）最近出现了激增的普及与使用的放射性核素共轭的小分子和抗体。类似地，免疫疗法也显示出有希望的结果，一个例子是血液恶性肿瘤中的嵌合抗原受体T细胞（CAR-T）疗法。此外，TRT和CAR-T疗法具有独特的特征，在确定如何给药以及联合治疗的时间和顺序时需要特别考虑，包括TRT剂量在体内的分布，放射性核素的衰变率以及CAR-T细胞的增殖和持久性。这些特征使组合疗法的累加或协同效应复杂化，并且保证了包括与靶肿瘤细胞的增殖和清除率相关的这些动力学的数学处理。在这里，我们结合联合收割机两个先前发表的数学模型来探索剂量，时间和基于TRT和CAR-T细胞的治疗在多发性骨髓瘤环境中的顺序的影响。我们发现，对于固定的TRT和CAR-T细胞剂量，肿瘤增殖率是确定TRT和CAR-T治疗最佳时机的最重要参数。
Targeted radionuclide therapy (TRT) and immunotherapy, an example being chimeric antigen receptor T cells (CAR-Ts), represent two potent means of eradicating systemic cancers. Although each one as a monotherapy might have a limited effect, the potency can be increased with a combination of the two therapies. The complications involved in the dosing and scheduling of these therapies make the mathematical modeling of these therapies a suitable solution for designing combination treatment approaches. Here, we investigate a mathematical model for TRT and CAR-T cell combination therapies. Through an analysis of the mathematical model, we find that the tumor proliferation rate is the most important factor affecting the scheduling of TRT and CAR-T cell treatments with faster proliferating tumors requiring a shorter interval between the two therapies. Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.
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影响因子：
3.4
作者：
Brenner, DJ;Hlatky, LR;Sachs, RK
通讯作者：
Sachs, RK
影响因子：
7.5
作者：
Pinnix, Chelsea C.;Gunther, Jillian R.;Nastoupil, Loretta J.
通讯作者：
Nastoupil, Loretta J.
影响因子：
7.5
作者：
Krishnan, Amrita;Adhikarla, Vikram;Pichiorri, Flavia
通讯作者：
Pichiorri, Flavia
影响因子：
17.1
作者：
Patel RB;Hernandez R;Carlson P;Grudzinski J;Bates AM;Jagodinsky JC;Erbe A;Marsh IR;Arthur I;Aluicio-Sarduy E;Sriramaneni RN;Jin WJ;Massey C;Rakhmilevich AL;Vail D;Engle JW;Le T;Kim K;Bednarz B;Sondel PM;Weichert J;Morris ZS
通讯作者：
Morris ZS
DOI：
10.1016/j.ijrobp.2020.08.035
发表时间：
2021-03-15
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
St James S;Bednarz B;Benedict S;Buchsbaum JC;Dewaraja Y;Frey E;Hobbs R;Grudzinski J;Roncali E;Sgouros G;Capala J;Xiao Y
通讯作者：
Xiao Y