Written by:
Daniel Freeman,
Vice President, Projects, Early Development Oncology R&D, AstraZeneca
Mark Cobbold,
Vice President, Discovery, Early Development Oncology R&D, AstraZeneca
Matthew Hellmann,
Vice President, Head of Clinical Group, Early Development Oncology R&D, AstraZeneca
In recent years we’ve seen plenty of excitement around immuno-oncology (IO), from transformative results in the clinic to a Nobel prize for the field’s pioneers.1,2,3
The first wave of IO therapies, aimed at overcoming immune checkpoints and unleashing the power of the immune system on cancer, have become the backbone of many treatment regimens, with PD-1, PD-L1 and CTLA-4 inhibitors in regular clinical use for a number of tumour types.2 But while these medicines have opened up the field, 并非所有患者都对检查点抑制有反应，而且反应并不总是像澳门葡京赌博游戏希望的那样深刻或持久.
Defend, ignore or attack cancer cells
Historically, drug development has focused on targeting the molecular characteristics of tumours, 最值得注意的是基因突变已被确定为促进癌细胞的生长和扩散. But cancer isn’t just a disease of rogue, 突变细胞生长失控:肿瘤本身的存在证明了癌细胞是如何逃避通常通过控制异常细胞来保护澳门葡京赌博游戏的免疫过程的.
The immune system is the body’s natural defence system, 负责对细菌和病毒等外部病原体作出反应，并保护澳门葡京赌博游戏免受癌症等内部异常疾病的侵害.4 t细胞和骨髓细胞在这种抗癌反应中发挥着重要作用，它们识别和消除肿瘤细胞，同时不伤害健康细胞.5,6 免疫检查点是决定t细胞是否攻击的决策过程的关键部分, and can be manipulated by cancer cells in order to evade the immune response.5
We’re addressing the challenge of immune evasion from two angles. Firstly, 通过寻找新的方法来克服肿瘤用来逃避免疫系统的防御机制, 突破PD-L1阻断，探索靶向其他免疫检查点(如TIM-3和GDF-15)的潜力.
And secondly, if immune cells are ignoring the threat of nearby cancer cells, 澳门葡京赌博游戏正在寻找方法，在肿瘤周围创造一个更具免疫原性的环境，提醒免疫细胞注意癌细胞带来的危险.
Hacking the immune response
Antibody-based checkpoint inhibitors work by engaging a specific receptor (or its ligand) on the surface of immune cells, such as PD-1 or CTLA-4.7 However, 因为这些受体也参与监视和自身免疫之间的正常平衡, 检查点信号通路的破坏可导致免疫相关的全身副作用，包括对健康组织的损害.8
To overcome this issue, 澳门葡京赌博游戏正在利用澳门葡京赌博游戏悠久的蛋白质工程历史来设计双特异性抗体，同时针对同一细胞上的不同免疫检查点. By combining both medicines in one, 这些双重用途抗体可以帮助在临床中驱动更持久的反应或克服对PD-1/PD-L1轴阻断的进化抗性.
Looking to the future, we are exploring ways to redirect T-cells that do not recognise cancer, which are much more abundant and more potent than those that do. To this end, T-cell engagers, 引导t细胞到达肿瘤并增强患者自身的抗癌免疫反应, are a growing area of interest in immune-oncology.
We are exploring different facets of immunity, including the potential of modulating other immune cells, such as myeloid cells, as a way to target cancer. 澳门葡京赌博游戏也在寻找操纵肿瘤微环境的方法，使其更适合T细胞的功能, either through blocking cancer-promoting molecules like LIF and CD73 or by adding in cytokines such as IL-12 to encourage anti-tumour immune responses.9,10
Beyond this, innovative advanced therapies such as cell therapies基因工程免疫细胞可以发现并摧毁癌细胞，在癌症治疗中变得越来越重要.
在下面的动画中，了解澳门葡京赌博游戏如何使用t细胞接合物激活免疫系统来破坏癌细胞，并可能帮助解决难以治疗的癌症:
Right medicines, right patient, right time
To fully unlock the power of immunotherapy, 澳门葡京赌博游戏不仅需要新的强效药物，还需要为每个病人提供最有可能对他们有效的治疗方法.
澳门葡京赌博游戏多样化的潜在药物组合有助于测试不同的联合治疗策略. For example, combining immunotherapy in combination with drugs designed to kill cancer cells, such as antibody drug conjugates (ADCs), 当死亡细胞吸引免疫系统的注意以进一步增强效果时，是否会导致附加或协同反应. 澳门葡京赌博游戏还在探索将澳门葡京赌博游戏早期开发的药物与PD-L1检查点抑制结合起来的潜力，以诱导更深入、更持久的抗肿瘤反应.
开发下一代生物标志物对于患者分层和确定最合适的治疗或联合治疗非常重要. 通过将生物学的深刻理解与早期临床试验中患者的新数据联系起来, 澳门葡京赌博游戏可以开发和测试新的假设，以发现哪些患者将从哪种治疗中获益最多.
The earlier cancer is diagnosed and treated, the greater the chance of survival.11 每一轮化疗或放疗都会对免疫系统造成损害，并导致更有抵抗力的癌细胞, leaving the disease harder to treat and the immune system less capable of responding.12 通过靶向治疗和免疫治疗的合理结合进行早期干预，可能会给患者带来最好的治愈机会.
The future of immuno-oncology
Looking to the future, 想想免疫疗法如何与液体活检等诊断领域的进步相结合，这是令人兴奋的, 识别癌症的早期迹象，激活免疫系统，寻找并清除任何可能存在的危险细胞. 有一天，澳门葡京赌博游戏甚至有可能控制人体的免疫环境，从一开始就阻止癌症的发展.
