Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.
Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.
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DOI：
10.1186/s13045-016-0328-4
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发表时间：
2016-09-23
影响因子：
28.5
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
Alexander GS;Palmer JD;Tuluc M;Lin J;Dicker AP;Bar-Ad V;Harshyne LA;Louie J;Shaw CM;Hooper DC;Lu B
Pembrolizumab是一种针对程序性细胞死亡蛋白1(PD-1)设计的单抗。Pembrolizumab和其他免疫检查点阻断单抗的工作原理是通过调节患者自己的免疫系统来增加抗肿瘤活性。虽然免疫检查点阻断已经显示出有希望的结果，但只有20%-40%的患者体验到了客观的临床好处。个体肿瘤生物学的差异和多个免疫检查点的存在给治疗带来了挑战。由于放射治疗对肿瘤微环境具有免疫调节作用，因此它有可能与免疫治疗协同作用，增强肿瘤反应。NCT02318771是一项1期临床试验，旨在研究放射治疗与培溴利珠单抗联合治疗的免疫调节效应。患者为，男性，转移性肾透明细胞癌，Fuhrman分级4级，病理分期为T3N0。使用舒尼替尼几年后，转移性疾病得到了很好的控制。随着疾病的发展，他被改用阿昔替尼。当病情继续发展时，患者进入NCT02318771，这是一项结合放射治疗和培溴利珠单抗的1期临床试验。患者在治疗过程中经历了异常快速的疾病进展，这一点通过反复进行CT扫描以排除假性进展而得到证实。在治疗前、治疗中和治疗后分别进行组织活检和外周血样采集。对样本进行了分析，为快速治疗失败提供了可信的理由。生物标志物分析显示缺乏TIL，这可能是治疗失败的原因，因为Pembrolizumab通过T细胞依赖的机制发挥作用。此外，在外周和肿瘤微环境中存在其他非冗余免疫检查点，这对治疗提出了挑战。此外，放射剂量和分割计划可能在治疗失败中发挥了作用，因为这些因素在放射治疗对肿瘤微环境的影响以及与免疫治疗的协同作用中发挥了作用。一项探讨放射治疗(RT)联合MK-3475治疗头颈部复发/转移、肾细胞癌、黑色素瘤和肺癌患者的免疫调节活性的探索性研究。
Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient’s own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20–40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab. The patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure. Biomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy. An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
10.9
作者：
Jing W;Gershan JA;Weber J;Tlomak D;McOlash L;Sabatos-Peyton C;Johnson BD
通讯作者：
Johnson BD
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
28.5
作者：
Smith AD;Roda D;Yap TA
通讯作者：
Yap TA
影响因子：
11.5
作者：
Nirschl, Christopher J.;Drake, Charles G.
通讯作者：
Drake, Charles G.