Office of Biostatistics and Pharmacovigilance, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
Office of Therapeutic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
PLoS Comput Biol. 2024 Mar 1;20(3):e1011247. doi: 10.1371/journal.pcbi.1011247. eCollection 2024 Mar.
The advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient's cancer. These vaccines can provide significant clinical benefit by leveraging the patient's immune response to eliminate malignant cells. However, determining the optimal vaccine dose for each patient is a challenge due to the heterogeneity of tumors. To address this challenge, we formulate a mathematical dose optimization problem based on a previous mathematical model that encompasses the immune response cascade produced by the vaccine in a patient. We propose an optimization approach to identify the optimal personalized vaccine doses, considering a fixed vaccination schedule, while simultaneously minimizing the overall number of tumor and activated T cells. To validate our approach, we perform in silico experiments on six real-world clinical trial patients with advanced melanoma. We compare the results of applying an optimal vaccine dose to those of a suboptimal dose (the dose used in the clinical trial and its deviations). Our simulations reveal that an optimal vaccine regimen of higher initial doses and lower final doses may lead to a reduction in tumor size for certain patients. Our mathematical dose optimization offers a promising approach to determining an optimal vaccine dose for each patient and improving clinical outcomes.
下一代测序技术的进步使得有效检测体细胞突变成为可能,这导致了针对患者癌症中发现的独特变体的个性化新抗原癌症疫苗的发展。这些疫苗可以通过利用患者的免疫反应来消除恶性细胞,从而提供显著的临床益处。然而,由于肿瘤的异质性,确定每个患者的最佳疫苗剂量是一个挑战。为了解决这个挑战,我们根据以前的数学模型,该模型包含了疫苗在患者体内产生的免疫反应级联,制定了一个数学剂量优化问题。我们提出了一种优化方法来确定最佳的个性化疫苗剂量,同时考虑固定的接种计划,同时最大限度地减少肿瘤和激活的 T 细胞的总数。为了验证我们的方法,我们对 6 名患有晚期黑色素瘤的真实世界临床试验患者进行了计算机模拟实验。我们将应用最佳疫苗剂量的结果与次优剂量(临床试验中使用的剂量及其偏差)的结果进行了比较。我们的模拟表明,对于某些患者,更高初始剂量和更低最终剂量的最佳疫苗方案可能会导致肿瘤缩小。我们的数学剂量优化为确定每个患者的最佳疫苗剂量和改善临床结果提供了一种有前途的方法。