Adaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points. Mathematical models are ideal tools to facilitate adaptive therapy dosing and switch time points. We developed two different mathematical models to examine interactions between drug-sensitive and resistant cells in a tumor. The first model assumes genetically fixed drug-sensitive and resistant populations that compete for limited resources. Resistant cell growth is inhibited by sensitive cells. The second model considers phenotypic switching between drug-sensitive and resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6%-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy. The first model predicts 6-20 months gained from continuous therapy when the initial population of sensitive cells is large enough, and when the sensitive cells have a large competitive effect on resistant cells. The second model predicts 20-25 months gained from continuous therapy when the switching rate from resistant to sensitive cells is high and the growth rate of sensitive cells is low. This study highlights that there is a range of potential patient specific benefits of adaptive therapy, depending on the underlying mechanism of resistance, and identifies tumor specific parameters that modulate this benefit.

中文翻译：

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了解适应性疗法对转移性黑色素瘤的潜在益处

自适应疗法是一种基于进化的治疗方法，旨在通过采用最小有效药物剂量或定时的药物放疗来维持肿瘤体积。对于成功的适应性治疗结果，至关重要的是找到治疗转换点的最佳时机。数学模型是促进适应性治疗剂量和切换时间点的理想工具。我们开发了两种不同的数学模型来检查肿瘤中药物敏感性和耐药性细胞之间的相互作用。第一个模型假设遗传上固定的对药物敏感和耐药的种群竞争有限的资源。抗性细胞的生长被敏感细胞抑制。第二个模型考虑了药物敏感和耐药细胞之间的表型转换。我们校准了每种模型，以适应黑素瘤患者生物标志物随时间的变化，并预测了针对患者的适应性治疗方案。总体而言，模型预测，与连续治疗相比，适应性治疗将使进展时间延迟6-25个月，相对于连续治疗，剂量率为6％-74％。我们确定了预测因素，这些因素可驱动适应疗法获得的临床时间。第一个模型预测，当敏感细胞的初始种群足够大时，以及敏感细胞对耐药细胞产生较大竞争作用时，连续治疗将获得6-20个月的时间。第二种模型预测，当从耐药细胞向敏感细胞的转换速率很高而敏感细胞的生长速率较低时，连续治疗可获得20到25个月的时间。