PDF(Pubmed)
Abstract：
UNASSIGNED: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies.
UNASSIGNED: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies.
UNASSIGNED: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy.
UNASSIGNED: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.
UNASSIGNED: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies.
UNASSIGNED: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy.
UNASSIGNED: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.
摘要：
■涉及免疫疗法与靶向放射疗法的癌症组合治疗处于治疗癌症的最前沿。然而,这些疗法的给药和安排带来了挑战。数学模型提供了优化这些疗法的独特方式。
■以多发性骨髓瘤的临床前模型为例，我们展示了一个数学模型的能力，将这些疗法结合起来，以达到最大的反应，定义为肿瘤生长延迟。来自靶向放射性核素治疗(TRT)和嵌合抗原受体(CAR)-T细胞单一疗法以及它们之间具有不同间隔的组合的小鼠研究的数据用于校准数学模型参数。无进展生存期（PFS）的依赖性，总生存期（OS），并评估了在给药和计划上达到最低肿瘤负荷的时间。评估了不同的给药和计划方案，以最大化PFS并优化TRT和CAR-T细胞疗法的时机。
■距离太近或太远的治疗间隔被证明对治疗效果有害，由于TRT太接近CAR-T细胞治疗导致辐射相关的CAR-T细胞杀伤，而治疗距离太远导致肿瘤再生长，对肿瘤控制和生存产生负面影响。我们表明,当组合施用时,分裂一定剂量的TRT或CAR-T细胞仅在递送的第一疗法可以产生作为单一疗法的显著益处时才是有利的。
数学模型是优化癌症联合治疗方案的关键工具，可根据治愈的思路进行应用。最大限度地提高生存率或减少毒性。
■以多发性骨髓瘤的临床前模型为例，我们展示了一个数学模型的能力，将这些疗法结合起来，以达到最大的反应，定义为肿瘤生长延迟。来自靶向放射性核素治疗(TRT)和嵌合抗原受体(CAR)-T细胞单一疗法以及它们之间具有不同间隔的组合的小鼠研究的数据用于校准数学模型参数。无进展生存期（PFS）的依赖性，总生存期（OS），并评估了在给药和计划上达到最低肿瘤负荷的时间。评估了不同的给药和计划方案，以最大化PFS并优化TRT和CAR-T细胞疗法的时机。
■距离太近或太远的治疗间隔被证明对治疗效果有害，由于TRT太接近CAR-T细胞治疗导致辐射相关的CAR-T细胞杀伤，而治疗距离太远导致肿瘤再生长，对肿瘤控制和生存产生负面影响。我们表明,当组合施用时,分裂一定剂量的TRT或CAR-T细胞仅在递送的第一疗法可以产生作为单一疗法的显著益处时才是有利的。
数学模型是优化癌症联合治疗方案的关键工具，可根据治愈的思路进行应用。最大限度地提高生存率或减少毒性。
