Adhikarla Vikram, Awuah Dennis, Brummer Alexander B, Caserta Enrico, Krishnan Amrita, Pichiorri Flavia, Minnix Megan, Shively John E, Wong Jeffrey Y C, Wang Xiuli, Rockne Russell C
Division of Mathematical Oncology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Cancers (Basel). 2021 Oct 15;13(20):5171. doi: 10.3390/cancers13205171.
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.
靶向放射性核素治疗（TRT）最近因使用与小分子和抗体偶联的放射性核素而大受欢迎。同样，免疫疗法也显示出有前景的结果，例如嵌合抗原受体T细胞（CAR-T）疗法在血液系统恶性肿瘤中的应用。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。这些特征使联合疗法的相加或协同效应变得复杂，因此需要一种数学方法来处理，该方法要考虑到与靶肿瘤细胞增殖和清除率相关的这些动态变化。在这里，我们结合两个先前发表的数学模型，来探讨在多发性骨髓瘤背景下TRT和基于CAR-T细胞的疗法的剂量、时间和顺序的影响。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疗法最佳时间的最重要参数。
