Dalgleish Angus G, Stern Peter L
Infection and Immunity Centre, St George's, University of London, Cranmer Terrace, London, UK.
Division of Molecular and Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
Ther Adv Vaccines Immunother. 2018 Dec 20;6(5-6):69-76. doi: 10.1177/2515135518815393. eCollection 2018 Sep.
All too often attempts to deliver improved cancer cure rates by increasing the dose of a particular treatment are not successful enough to justify the accompanying increase in toxicity and reduction in quality of life suffered by a significant number of patients. In part, this drive for using higher levels of treatment derives from the nature of the process for testing and incorporation of new protocols. Indeed, new treatment regimens must now consider the key role of immunity in cancer control, a component that has been largely ignored until very recently. The recognition that some drugs developed for cytotoxicity at higher doses can display alternative anticancer activities at lower doses including through modulation of immune responses is prompting a significant re-evaluation of treatment protocol development. Given that tumours are remarkably heterogeneous and with inherent genetic instability it is probably only the adaptive immune response with its flexibility and extensive repertoire that can rise to the challenge of effecting significant control and ultimately elimination of a patient's cancer. This article discusses some of the elements that have limited higher levels of treatment outcomes and where too much proved less effective. We explore observations that less can often be as effective, if not more effective especially with some chemotherapy regimens, and discuss how this can be exploited in combination with immunotherapies to deliver nontoxic improved tumour responses.
通常情况下，试图通过增加特定治疗的剂量来提高癌症治愈率，但成效并不显著，无法证明随之而来的毒性增加以及大量患者生活质量下降是合理的。部分原因在于，使用更高水平治疗的这种驱动力源于测试和纳入新方案的过程的性质。事实上，新的治疗方案现在必须考虑免疫在癌症控制中的关键作用，而这一组成部分直到最近才在很大程度上被忽视。认识到一些为高剂量细胞毒性开发的药物在低剂量时可表现出包括通过调节免疫反应在内的其他抗癌活性，这促使人们对治疗方案的开发进行重大重新评估。鉴于肿瘤具有显著的异质性和内在的基因不稳定性，可能只有具有灵活性和广泛多样性的适应性免疫反应才能应对有效控制并最终消除患者癌症这一挑战。本文讨论了一些限制更高水平治疗效果的因素，以及在哪些方面过多治疗反而效果不佳。我们探讨了一些观察结果，即有时少治疗甚至可能同样有效，甚至更有效，特别是对于某些化疗方案，并讨论了如何将其与免疫疗法相结合，以实现无毒的更好肿瘤反应。
