抵抗免疫抑制剂的抗癌T细胞铠装

StephenW

Armouring anti-cancer T cells against immunosuppressants

Duke-NUS Medical School

Research News

SINGAPORE, 19 January 2021 - Duke-NUS Medical School researchers, together with collaborators in Singapore, have designed armoured immune cells that can attack recurring cancer in liver transplant patients, while temporarily evading immunosuppressant drugs patients take to avoid organ rejection. The findings were published in the journal Hepatology.

Hepatocellular carcinoma is the most common type of primary liver cancer and the sixth most common cancer worldwide. It often develops in people with chronic liver disease following hepatitis B infection.

A common treatment for hepatocellular carcinoma is to completely remove the liver and replace it with a healthy one from a donor. However, hepatitis B-related hepatocellular carcinoma can recur in some patients following transplantation. To kill the cancer, doctors can inject immune cells, called T cells, which are specially designed to target hepatitis B material found in the cancer cells. However, liver transplant patients must take drugs that suppress their immune systems to prevent their bodies from attacking the transplants. This significantly hinders the effectiveness of T cell therapy.

"We developed a method to make T cells that specifically target the hepatitis B antigen in liver cancer cells while, at the same time, making them resistant to two commonly used immunosuppressants: tacrolimus and mycophenolate mofetil," said Professor Antonio Bertoletti, senior author of the study from Duke-NUS' Emerging Infectious Diseases Programme.

"Importantly, the resistance of our T cells to the immunosuppressants only lasted for about four days after which they regain their sensitivity to the drugs," added Prof Bertoletti.

This transient effect, a result of the engineering approach the team used, provides an additional layer of safety to minimise the possibility of organ rejection.

Prof Bertoletti and his colleagues began their investigations by testing the effects of tacrolimus and mycophenolate mofetil on T cells designed with a special receptor that targets hepatitis B antigens located on liver cancer cells. They found that both drugs significantly reduced the T cells' ability to kill the cancer cells.

The team then re-designed the T cells by adding genetic codes that disrupt the enzymes needed by the two drugs to suppress immune cells. They found that these 'immunosuppressive drug resistant armoured hepatitis B T cell receptor' (IDRA HBV-TCR) T cells showed "superior killing" power of hepatocellular carcinoma cell targets for up to four days.

"We also found that this strategy can be applied to target other pathologies that commonly occur in transplant patients receiving immunosuppressive drugs, like Epstein-Barr virus and cytomegalovirus reactivations," said Dr Anthony T Tan, a senior research fellow in Prof Bertoletti's lab and a co-author of the study.

"Innovative research like this lays the foundation for new discoveries and transformative change," said Professor Patrick Casey, Senior Vice-Dean for Research, Duke-NUS Medical School. "With waiting lists for organs lengthening around the world, ensuring that those patients who benefit from a much-needed transplant can remain in remission is a significant advance and offers much hope."

The team next aims to apply their approach in clinical trials.

StephenW

抵抗免疫抑制剂的抗癌T细胞铠装

国立杜克医学院

研究新闻

2021年1月19日，新加坡新加坡-国立杜克大学医学院的研究人员与新加坡的合作者一起设计了铠装免疫细胞，可以攻击肝移植患者复发的癌症，同时暂时避开患者使用的免疫抑制剂以避免器官排斥。研究结果发表在《肝病学》杂志上。

肝细胞癌是最常见的原发性肝癌，也是全球第六大最常见的癌症。它通常在乙型肝炎感染后的慢性肝病患者中发展。

肝细胞癌的常见治疗方法是完全切除肝脏，并用供体的健康肝脏代替。但是，某些患者在移植后会复发与乙型肝炎相关的肝细胞癌。为了杀死癌症，医生可以注射称为T细胞的免疫细胞，该细胞专门设计用于靶向癌细胞中发现的乙型肝炎物质。但是，肝移植患者必须服用抑制免疫系统的药物，以防止身体攻击移植物。这显着阻碍了T细胞疗法的有效性。

该杂志的资深作者安东尼奥·贝托莱蒂（Antonio Bertoletti）教授说：“我们开发了一种制造T细胞的方法，该方法可特异性靶向肝癌细胞中的乙型肝炎抗原，同时使其对两种常用的免疫抑制剂：他克莫司和霉酚酸酯具有抗性。”国立杜克大学新兴传染病计划的研究。

“重要的是，我们的T细胞对免疫抑制剂的抗性仅持续了大约四天，之后它们恢复了对药物的敏感性，”贝托莱蒂教授补充说。

团队使用的工程方法所产生的这种短暂影响提供了额外的安全层，以最大程度地减少器官排斥的可能性。

Bertoletti教授和他的同事们通过测试他克莫司和霉酚酸酯对T细胞的作用开始了他们的研究，该T细胞设计有针对肝癌细胞上乙型肝炎抗原的特殊受体。他们发现这两种药物都大大降低了T细胞杀死癌细胞的能力。

然后，研究小组通过添加破坏两种药物抑制免疫细胞所需的酶的遗传密码，重新设计了T细胞。他们发现这些“免疫抑制性耐药性铠装乙型肝炎T细胞受体”（IDRA HBV-TCR）T细胞在长达四天的时间内显示出对肝细胞靶标的“超强杀伤力”。

“我们还发现，该策略可用于针对接受免疫抑制药物的移植患者中常见的其他病理，例如爱泼斯坦-巴尔病毒和巨细胞病毒再激活，” Bertoletti教授实验室高级研究员Anthony T Tan博士说。该研究的合著者。

杜克大学-国大医学院高级副院长帕特里克·凯西教授说：“这样的创新研究为新发现和变革性变革奠定了基础。” “随着世界各地器官候补名单的增加，确保那些从急需的移植中受益的患者能够保持缓解是一项重大进步，并带来了很大希望。”

该团队的下一个目标是将其方法应用于临床试验。