Modeling liver cancer with syngeneic hepa 1-6: an update

Hepatocellular carcinoma (HCC) affects over one million people globally and is currently the third leading cause of cancer related deaths in the world.^[1]在世界范围内,有800000名新诊断和700年,000 patient deaths each year. The incidence of HCC is highest in Southeast Asia and Sub-Saharan Africa due to high prevalence of hepatitis B and C viruses which strongly predisposes one to develop chronic liver disease and subsequent HCC.^[1,2]In the United States, there are expected to be 42,030 new diagnoses and 31,780 patient deaths in 2019.^[2]根据疾病的不同阶段，肝癌可以通过手术、化疗、靶向治疗和放疗进行治疗。^[4]Current clinical trials are tackling unresectable or advanced stage HCC with mono or combination immunotherapy, monoclonal antibodies or oncolytic virus therapy.^[1-4]These approaches have demonstrated tumor shrinkage and improved survival, but are not curative. Hence, there is a need for improved treatment options. Covance has developed the syngeneic HCC model, Hepa 1-6, for preclinical evaluation of immunomodulatory drug candidates.

Hepa 1-6 is a murine hepatoma derived from the BW7756 hepatoma that arose spontaneously in C57L/J mice, which contrasts with most available hepatoma models (BNL, A.7R.1, MH-129, MH134 and MH-22A) that are chemically transformed or induced lines. Therefore, the Hepa 1-6 tumor model established in immunocompetent mice represents a clinically relevant model for preclinical testing of immunotherapy.

Review of Earlier Data

在我们的2018 Hepa 1-6 Model Spotlight，我们介绍了模型的初始皮下生长和小但已建立的肿瘤（平均肿瘤体积约80-90mm）给药后的反应数据³). Treatment of Hepa 1-6 with checkpoint inhibitors体内was extremely effective against early stage disease, resulting in 50-100% durable complete responses, but leaving little room for improvement in combination with drug candidates. Throughout 2019, we have continued efforts to refine this model to enable checkpoint inhibition as a reasonable combination strategy with investigational drug candidates. Herein we present anti-tumor response data in a model of more advanced subcutaneous Hepa 1-6 disease.

Checkpoint Blockade Response Data for Hepa 1-6

Initiating treatment with more advanced Hepa 1-6 tumors (at a mean tumor volume of ~130 mm³)结合检查站封锁，对候选药物的检测反应良好。图1显示了对照肿瘤和接受抗mPD-1或抗mPD-L1单药治疗的肿瘤的平均（A）和个体（B-D）生长。在肿瘤体积增加的情况下，每种单一疗法产生40%的持久完全应答，这表明虽然这种策略确实可以提供一种方法来测试合理的组合策略，但模型可能会进一步优化。我们将继续完善这个模型，以允许检查点封锁保持一个适度的反应，理想情况下较少的完整反应。平均肿瘤体积的微小差异可能意味着反应的巨大差异，因此我们正在系统地逐步探讨这一挑战，正在进行的一项研究测试了在平均肿瘤体积~150 mm处开始给药的检查点阻断的抗肿瘤疗效³. This study is not yet complete but is already indicating fewer complete responses compared to lower initiating tumor volumes (data not shown).