The field of cancer immunology or immuno-oncology (I/O) dates back to the 1890’s with efforts by William Coley to treat malignancies by infection with certain bacterial strains.1Fast forward 120 years, and we have observed the clinical success of multiple checkpoint inhibitor antibodies against cancer specific T cell negative regulatory pathways in multiple cancer types.2Because of these clinical successes with antibodies targeting CTLA-4, PD-1, and PD-L1 (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab), vast resources in biotech and large pharma are being directed toward preclinical I/O research in an effort to develop novel immunotherapies.
肿瘤学家和免疫学家试图开发免疫疗法的一个持久挑战是需要可靠的临床前模型来测试它们。根据定义，这些模型需要一个完整的免疫系统；因此，推动临床前肿瘤学研究的传统人类细胞系异种移植物是不合适的。临床前免疫肿瘤学研究还有哪些选择？在图1中，描述了测试新型I/O代yaboapp体育官网理最常用的模型，以及它们的一些优点和缺点。
Syngeneic Mouse Models
迄今为止最利用模型对临床前我/yaboapp体育官网O pharmacology are the syngeneic mouse tumor cell lines. These models were developed from either spontaneously arising tumors in older mice or from carcinogen induction. These lines can be implanted into their genetically syngeneic hosts to simulate the ability to generate an immune response against the tumor via its tumor antigens. While this doesn’t precisely replicate the dynamics of an immune system evolving with a developing malignancy, it does allow researchers to test novel immunotherapies that activate tumor-specific T cells and inhibit immuno-suppressive pathways that prevent effective anti-tumor immunity. These models are easily accessible for quick and efficient studies. Further, there is a large repository of published literature using these models for testing novel immunotherapies to turn to for comparison of one’s novel agent, effectively making them the “industry standard.”
虽然Syngeneic鼠标模型是许多I / O药物开发计划的理想选择，但他们确实具有一些重要的缺点。其中一个主要问题是，如果甚至存在，生物治疗剂必须对小鼠直向置的交叉反应，或者必须开发小鼠反应性替代。这通常是一个大障碍，因为它可以显着提高与候选治疗的发展相关的成本和时间。第二次缺点是它们通常具有新抗原载荷，非同义突变的结果显着高于大多数人类癌症中的结果。3,4.关于使用Syngeidic小鼠肿瘤患者进行免疫疗法的最大担忧之一是他们认为临床翻译的预测力。5An evaluation of the many cases where these models predict and fail to predict clinical response could fill multiple blogs; however, drug developers have to remain cognizant of the differences between the mouse immune system and the human immune system when modeling the biology of their target.
GEM Models
转基因小鼠（GEM）癌症模型代表了一种建模新型免疫疗法药理学的替代方法。这些模型依赖于引入临床相关的驾驶员癌肠和肿瘤抑制突变/损失以在组织类型的感兴趣中诱导多阶段致癌作用。这允许针对特异性致癌司机（例如，BRAF）与免疫疗法组合进行靶向疗法。由于肿瘤与完整的免疫系统在音乐会中开发De Novo，因此它们似乎更好地再现了人类免疫系统和癌细胞之间的细胞动态。
While GEM models have many advantages, they have some notable issues as well. The stochastic nature of de novo carcinogenesis in autochthonous GEM models makes experiments very long and challenging to stage without a rolling enrollment approach. This results in tremendous cost in maintaining mouse colonies and monitoring long studies. Use of GEM-derived transplantable fragments provides a more tractable approach to I/O pharmacology because studies can be implanted and staged as with mouse cell line models. However, GEM-fragments no longer simulate an “experienced” immune system because they are implanted into naïve syngeneic hosts. Finally, GEM models have a characteristically low mutational burden due to the use of strong oncogenic driver(s) and tumor suppressor losses to enable carcinogenesis. Thus, additional mutations are not required for tumor development.4This is a major barrier to eliciting tumor antigen specific T cell responses because there are very few neo-antigens available for the immune system to recognize.
HIS Models
人源化免疫系统mice are another体内模型I / O药理学方法。有相当数量的模型，落在他的老鼠的分类下;然而，大多数这些都是在非肥胖糖尿病（NOD）中的 -SCID.IL-2Rgamma无效的（NSG或NOG）鼠标背景。应用最广泛的两种模型是人外周血单个核细胞（PBMC）重组小鼠（huPBMC-NSG/NOG）和CD34+造血干细胞重组小鼠（huCD34-NSG/NOG）。他的小鼠使研究人员能够测试针对人类目标的抗体，而无需啮齿动物交叉反应或替代抗体。此外，由于免疫系统是亚博全站官网人源化的，因此可以将新试剂与临床上批准的检查点抑制剂抗体结合。将病人来源的异种移植物（PDX）模型植入huCD34-NSG小鼠，可以对保留大部分人类癌症微环境的肿瘤进行免疫治疗试验。
虽然当靶的小鼠反应性试剂或靶靶不存在的小鼠反应性试剂或鼠标矫正物时，但它们没有完全官能的人（或小鼠）免疫系统。Hupbmc-nsg小鼠仅与cd4一起植入+and CD8+T细胞。6此外，这些T细胞会在移植后4-5周内导致宿主小鼠发生致命的移植物抗宿主病（GVHD）。huCD34-NOG小鼠体内成熟的人T细胞存在多种功能缺陷，包括激活诱导的细胞死亡加快、增殖能力减弱、白细胞介素-2（IL-2）生成减少和CD8受损+T cell persistence.7,8HUCD34-NSG小鼠中出现的人NK细胞也在功能上惰性。8最后，当用于同种异体人PDX肿瘤或人细胞系时，这些模型比可靠的自体抗肿瘤免疫模型更准确地作为同种异体移植排斥模型。利用人类细胞因子转基因小鼠和移植额外的人体组织来获得更完整的人体免疫的努力正在进行中。9Nonetheless, these mice provide an opportunity to drug the actual human target, as long as investigators are aware of their limitations.
结论
While no model will ever perfectly replicate the biology of the human immune system, the cancerous cells or the response to a candidate therapeutic, being aware of the advantages and disadvantages of the various model options allows I/O pharmacologists to make the choice that best informs their research.联系我们今天我们来讨论你的治疗候选人的最佳模式。
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