Bristol-Myers Squibb, Global Clinical Research, Wallingford 06492, USA.
Ann Oncol. 2012 Sep;23 Suppl 8:viii47-52. doi: 10.1093/annonc/mds263.
The effect of cancer immunotherapies is on the immune system and not directly on the tumour. The kinetics of immunotherapy are characterised by a cellular immune response followed by potential changes in tumour burden or patient survival. To adequately investigate immunotherapies in clinical trials, a new development paradigm including reconsideration of established end points addressing this biology is needed. Over the last 7 years, several initiatives across the cancer immunotherapy community were facilitated by the Cancer Research Institute Cancer Immunotherapy Consortium. They systematically evolved an immunotherapy-focused clinical development paradigm and proposed to redefine trial end points. On that basis, analysis of several large datasets generated throughout the immunotherapy community supports three novel end point proposals. First, results from T-cell immune response assays are highly variable and often nonreproducible. Harmonisation of assays can minimise this variability and support the investigation of the cellular immune response as a biomarker and testing it for clinical surrogacy. Secondly, immunotherapy induces novel patterns of the antitumour response not captured by World Health Organisation criteria or Response Evaluation Criteria in Solid Tumours. New immune-related response criteria were defined which more comprehensively capture all response patterns. Thirdly, survival curves in randomised immunotherapy trials can show a delayed separation, which can impact study results. Altered statistical models are needed to describe the hazard ratios as a function of time, and differentiate them before and after separation of curves to improve planning of phase III trials. Taken together, these recommendations may improve our tools for cancer immunotherapy investigations.
癌症免疫疗法的作用是针对免疫系统，而不是直接针对肿瘤。免疫疗法的动力学特征是细胞免疫反应，随后可能会发生肿瘤负荷或患者生存的变化。为了在临床试验中充分研究免疫疗法，需要一种新的开发范式，包括重新考虑针对这种生物学的既定终点。在过去的 7 年中，癌症免疫治疗联盟（Cancer Research Institute Cancer Immunotherapy Consortium）促进了癌症免疫治疗领域的多项倡议。它们系统地发展了以免疫疗法为重点的临床开发范式，并提出重新定义试验终点。在此基础上，对整个免疫治疗领域产生的多个大型数据集的分析支持了三个新的终点建议。首先，T 细胞免疫反应检测的结果变化很大，且通常不可重复。通过检测方法的标准化，可以最大限度地减少这种变异性，并支持将细胞免疫反应作为生物标志物进行研究，并对其进行临床替代物的测试。其次，免疫疗法会引起新的抗肿瘤反应模式，这些模式无法被世界卫生组织（World Health Organization）标准或实体瘤反应评价标准（Response Evaluation Criteria in Solid Tumours）所捕捉。新的免疫相关反应标准被定义出来，这些标准更全面地捕捉到所有的反应模式。第三，随机免疫治疗试验中的生存曲线可能会出现延迟分离，这可能会影响研究结果。需要改变统计模型来描述时间作为函数的风险比，并在曲线分离前后对其进行区分，以改善 III 期试验的规划。综上所述，这些建议可能会改进我们用于癌症免疫治疗研究的工具。
