Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX, 79409-1042, USA.
Department of Mathematics and Statistics, University of the Incarnate Word, San Antonio, TX, 78209, USA.
Bull Math Biol. 2019 Jun;81(6):1885-1915. doi: 10.1007/s11538-019-00591-3. Epub 2019 Mar 6.
We develop a mathematical model of pancreatic cancer that includes pancreatic cancer cells, pancreatic stellate cells, effector cells and tumor-promoting and tumor-suppressing cytokines to investigate the effects of immunotherapies on patient survival. The model is first validated using the survival data of two clinical trials. Local sensitivity analysis of the parameters indicates there exists a critical activation rate of pro-tumor cytokines beyond which the cancer can be eradicated if four adoptive transfers of immune cells are applied. Optimal control theory is explored as a potential tool for searching the best adoptive cellular immunotherapies. Combined immunotherapies between adoptive ex vivo expanded immune cells and TGF-[Formula: see text] inhibition by siRNA treatments are investigated. This study concludes that mono-immunotherapy is unlikely to control the pancreatic cancer and combined immunotherapies between anti-TGF-[Formula: see text] and adoptive transfers of immune cells can prolong patient survival. We show through numerical explorations that how these two types of immunotherapies are scheduled is important to survival. Applying TGF-[Formula: see text] inhibition first followed by adoptive immune cell transfers can yield better survival outcomes.
我们开发了一个包含胰腺癌细胞、胰腺星状细胞、效应细胞以及促进肿瘤生长和抑制肿瘤的细胞因子的胰腺癌数学模型，以研究免疫疗法对患者生存的影响。该模型首先使用两项临床试验的生存数据进行验证。参数的局部敏感性分析表明，如果进行四次免疫细胞的过继转移，存在一个关键的促肿瘤细胞因子的激活率，超过该激活率，癌症就可以被根除。最优控制理论被探索作为寻找最佳过继细胞免疫疗法的潜在工具。我们研究了过继体外扩增免疫细胞与 TGF-β 抑制的 siRNA 治疗之间的联合免疫疗法。这项研究得出的结论是，单一免疫疗法不太可能控制胰腺癌，而抗 TGF-β 和过继转移免疫细胞的联合免疫疗法可以延长患者的生存时间。我们通过数值研究表明，这两种免疫疗法的治疗时间安排对生存时间很重要。首先应用 TGF-β 抑制，然后进行过继免疫细胞转移，可以获得更好的生存结果。
