DataSheet_1_Deep response to a combination of mTOR inhibitor temsirolimus and dual immunotherapy of nivolumab/ipilimumab in poorly differentiated thyroid carcinoma with PTEN mutation: a case report and literature review.pdf

Treating advanced thyroid cancer presents challenges due to its resistance to various treatment modalities, thereby limiting therapeutic options. To our knowledge, this study is the first to report the efficacy of temsirolimus in conjunction with dual immunotherapy of nivolumab/ipilimumab to treat heavily treated advanced PDTC. A 50-year-old female initially presented with a rapidly enlarging mass on her right neck. Subsequent diagnosis revealed poorly differentiated thyroid carcinoma, leading to a total thyroidectomy followed by post-operative radioablation therapy. After four years, an examination for persistent cough revealed a recurrence of the disease within multiple mediastinal nodes. Genetic analysis of blood samples uncovered somatic mutations in the tumor, specifically involving PTEN and TP53. The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. Consequently, temsirolimus, functioning as an mTOR inhibitor, was introduced as an adjunct to the nivolumab/ipilimumab regimen. This combination approach yielded remarkable clinical improvement and disease control for a duration of approximately six months. Temsirolimus likely suppressed the aberrantly activated PI3K/AKT/mTOR signaling pathway, facilitated by the PTEN genetic alteration, thus engendering an effective treatment response. This synergy between targeted agents and immunotherapy presents a promising therapeutic strategy for advanced PDTC patients with limited treatment alternatives. In previous clinical trials, mTOR inhibitors have demonstrated the ability to maintain stable disease (SD) in 65% to 74% for advanced thyroid cancer patients, including those with PDTC. When combined with other targeted therapies, the observed SD or partial response rates range from 80% to 97%. Many of these trials primarily involved differentiated thyroid carcinoma, with diverse genetic mutations. Thyroid cancer patients with alterations in the PI3K/mTOR/Akt appeared to benefit most from mTOR inhibitors. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

治疗晚期甲状腺癌面临着多重挑战，因其对多种治疗方式的抗性，从而限制了治疗选择。据我们所知，本研究首次报告了替莫唑胺与nivolumab/ipilimumab联合双免疫疗法的疗效，以治疗经过多次治疗的晚期PDTC。一名50岁的女性最初因右侧颈部迅速增大的肿块就诊。后续诊断揭示了分化不良的甲状腺癌，导致行甲状腺全切术，随后接受术后放射消融治疗。四年后，因持续咳嗽进行检查时发现疾病在多个纵隔淋巴结中复发。血液样本的遗传分析揭示了肿瘤中的体细胞突变，特别是PTEN和TP53。尽管接受了姑息性放疗、仑伐替尼和nivolumab/ipilimumab治疗，疾病仍继续进展。因此，作为mTOR抑制剂的替莫唑胺被引入作为nivolumab/ipilimumab方案的辅助治疗。这种联合治疗方法在约六个月的时间内显著改善了临床状况并控制了疾病。替莫唑胺可能通过PTEN基因突变介导的异常激活的PI3K/AKT/mTOR信号通路抑制，从而产生了有效的治疗反应。这种靶向药物与免疫疗法的协同作用为治疗选择有限的高级PDTC患者提供了一种有希望的疗法策略。在之前的临床试验中，mTOR抑制剂已显示出在65%至74%的晚期甲状腺癌患者中维持疾病稳定（SD）的能力，包括PDTC患者。当与其他靶向疗法联合使用时，观察到的SD或部分缓解率范围为80%至97%。许多这些试验主要涉及分化型甲状腺癌，具有不同的遗传突变。PI3K/mTOR/Akt发生改变的甲状腺癌患者似乎最能从mTOR抑制剂中获益。然而，尚未确立mTOR抑制剂的疗效与特定组织学或遗传突变之间的明确关联。未来的研究有必要阐明这些关联。