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新辅助PD-1阻断治疗在可切除肺癌中的应用
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer


Patrick M. Forde ... 肿瘤 呼吸系统疾病 • 2018.05.24
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摘要


背景

阻断程序性死亡-1(PD-1)蛋白的抗体可提高晚期非小细胞肺癌(NSCLC)患者的生存率,但尚未在可切除NSCLC中进行试验。过去10年中在可切除NSCLC方面的进展甚微。

 

方法

在这项先导性研究中,我们在未经治疗、可手术切除的早期(Ⅰ、Ⅱ或ⅢA期)NSCLC成人患者中,术前给予两剂PD-1抑制剂纳武利尤单抗(nivolumab)。纳武利尤单抗(剂量为每千克体重3 mg)每2周静脉内给药1次,计划在第一剂给药后约4周进行手术。研究的主要终点是安全性和可行性。我们还评估了肿瘤病理缓解、程序性死亡配体-1(PD-L1)的表达、突变负荷和突变相关的新抗原特异性T细胞应答。

 

结果

纳武利尤单抗新辅助治疗的副作用可接受,且不会导致手术延迟。在切除的21个肿瘤中,20个完全切除。20个切除肿瘤中的9个(45%)出现明显病理缓解。PD-L1阳性和PD-L1阴性肿瘤均有缓解。病理缓解与治疗前肿瘤突变负荷显著相关。在接受评估的9例患者中,8例患者在PD-1阻断后,肿瘤和外周血中发现T细胞克隆数量系统性增加。治疗后2~4周,病理评估显示完全缓解的1个原发肿瘤,来自其中的突变相关的新抗原特异性T细胞克隆在外周血中迅速扩增;其中一部分克隆在给予纳武利尤单抗之前未检出。

 

结论

纳武利尤单抗新辅助治疗副作用很少,未导致手术延迟,在45%的切除肿瘤中诱导了明显病理缓解。肿瘤突变负荷可预测PD-1阻断后的病理缓解。治疗诱导了外周血中突变相关的新抗原特异性T细胞的克隆扩增(由美国癌症研究所联合对抗癌症慈善项目[Cancer Research Institute-Stand Up 2 Cancer]等资助;在ClinicalTrials.gov注册号为NCT02259621)。





作者信息

Patrick M. Forde, M.B., B.Ch., Jamie E. Chaft, M.D., Kellie N. Smith, Ph.D., Valsamo Anagnostou, M.D., Ph.D., Tricia R. Cottrell, M.D., Ph.D., Matthew D. Hellmann, M.D., Marianna Zahurak, M.S., Stephen C. Yang, M.D., David R. Jones, M.D., Stephen Broderick, M.D., Richard J. Battafarano, M.D., Ph.D., Moises J. Velez, M.D., Natasha Rekhtman, M.D., Ph.D., Zachary Olah, B.S., Jarushka Naidoo, M.B., B.Ch., Kristen A. Marrone, M.D., Franco Verde, M.D., Haidan Guo, B.S., Jiajia Zhang, M.D., M.P.H., Justina X. Caushi, B.S., Hok Yee Chan, M.S., John-William Sidhom, M.S., Robert B. Scharpf, Ph.D., James White, Ph.D., Edward Gabrielson, M.D., Hao Wang, Ph.D., Gary L. Rosner, Sc.D., Valerie Rusch, M.D., Jedd D. Wolchok, M.D., Ph.D., Taha Merghoub, Ph.D., Janis M. Taube, M.D., Victor E. Velculescu, M.D., Ph.D., Suzanne L. Topalian, M.D., Julie R. Brahmer, M.D., and Drew M. Pardoll, M.D., Ph.D.
From the Bloomberg–Kimmel Institute for Cancer Immunotherapy and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (P.M.F., K.N.S., V.A., T.R.C., M.Z., S.C.Y., S.B., R.J.B., J.N., K.A.M., F.V., H.G., J.Z., J.X.C., H.Y.C., J.-W.S., R.B.S., J.W., E.G., H.W., G.L.R., J.M.T., V.E.V., S.L.T., J.R.B., D.M.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (J.E.C., M.D.H., D.R.J., M.J.V., N.R., Z.O., V.R., J.D.W., T.M.) and the Ludwig Collaborative (J.D.W., T.M.) — all in New York; the Parker Institute for Cancer Immunotherapy, San Francisco (J.D.W., T.M.); and Swim Across America Laboratory, Charlotte, NC (J.D.W., T.M.). Address reprint requests to Dr. Pardoll at the Sidney Kimmel Comprehensive Cancer Center, Rm. 444, Bunting Blaustein CRB 1, 1650 Orleans St., Baltimore, MD 21287, or at dpardol1@jhmi.edu.

 

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