Podcasts 科学播客 | 「逆转癌症的力量：T细胞突变增强抗癌活性」

Benjamin Thompson

Immunotherapy has revolutionized the treatment of certain types of cancer. One approach is to engineer immune cells like our own T cells to hunt out and kill cancer cells. You may have heard of CAR-T therapy, for example, which has shown great promise in treating some blood cancers but proved less effective at attacking solid tumours, like lung or liver cancer.

免疫疗法已经彻底改变了某些类型癌症的治疗方法，例如通过基因工程修改诸如T细胞的免疫细胞，使其能够寻找并杀死癌细胞。你可能听说过CAR-T疗法，它在治疗一些血液癌症方面表现出了很大的潜力，但在攻击实体肿瘤（如肺癌或肝癌）时效果较差。

Jae Choi

For solid tumours, these cancers have evolved to create these walls that make it very difficult for the immune system to penetrate, survive and kill them.

对于实体肿瘤，这些癌症已经进化出一层屏障，使得免疫系统很难穿透并消灭它们。

Benjamin Thompson

This is Jae Choi a dermatologist and geneticist from Northwestern University in the US. He and his colleagues have been trying to find new ways to give T cells a boost and overcome these walls. And they’ve come across a rather unexpected way to do it.

这位是来自美国西北大学的皮肤科医生兼遗传学家Jae Choi，他和他的同事们一直在尝试寻找新的方法去增强T细胞并突破这些屏障。

Jae Choi

The way I got into this is actually I see all these patients with skin T cell lymphoma. And I've always just been thinking, like, why is it there? What are the cells doing?

我之所以深入研究这个领域，是因为我接触了很多皮肤T细胞淋巴瘤的患者。我一直在想，为什么会出现这种情况？这些细胞到底在发挥什么作用？

Benjamin Thompson

Jae and his colleagues started looking at these lymphomas, cancers that affect T cells themselves, and asking how they are so persistent.

Jae和他的同事们开始研究这些影响T细胞本身的淋巴瘤，并思考它们是如何保持如此持久的寿命。

Jae Choi

And it turns out through the work that we've been doing for the last five to ten years, we've repeatedly seen, that these lymphomas actually have to overcome the same exact challenges that occur with T cells in the cell tumour microenvironment.

事实证明，通过我们过去五到十年的研究发现，这些淋巴瘤实际上需要克服与T细胞在肿瘤微环境中所面临的相同挑战。

Benjamin Thompson

These T cell cancers have evolved mechanisms to overcome many of the challenges cancerous tumours create for our own immune system. And that gave them an idea.

这些T细胞癌症已经进化出机制来克服肿瘤为我们自己的免疫系统创造的许多挑战。这一点给了团队一个启发。

Jae Choi

So, we hypothesize that evolution has given us a roadmap by which we can learn how T cells have been designed to overcome these challenges. And we can use the power of evolution to power next generation therapies.

所以我们假设，进化给了我们一条路线图，通过它我们可以了解T细胞是如何被设计来克服这些挑战的。我们可以利用进化的力量来推动下一代疗法的发展。

Benjamin Thompson

Jae wanted to take the mutations that lymphomas have evolved and use them to his advantage — by inserting them into therapeutic T cells, thus empowering our own immune cells with the cancer’s capabilities. But with one big caveat.

Jae想利用淋巴瘤进化出的突变为自己所用——即将这些突变插入到治疗性T细胞中，从而赋予我们自己的免疫细胞癌症的能力。但是这需要有一个很大的前提。

Jae Choi

What we didn't want was a mutation that would be by itself able to cause cancer, that really didn't make any sense to us at all. So, all of our studies are really geared to find this safe, but supercharged T cell that can actually kill the tumour, and its home base, this solid tumour microenvironment.

我们不希望有一种突变，它本身就能引发癌症，这对我们来说完全没有意义。所以我们所有的研究都集中在寻找这种既安全又超强的T细胞，它能够真正杀死肿瘤，并且能够在实体肿瘤微环境中发挥作用。

Benjamin Thompson

So they searched for useful mutations which wouldn’t cause cancer, and it wasn’t just lymphomas they looked at.

因此，他们寻找了那些不会引发癌症的有用突变，并且不仅局限于研究淋巴瘤。

Jae Choi

The vast majority of our work have come from these lymphomas, which are cancers. But actually it turns out many of these mutations are shared with T cells that happen to be in even autoimmune and autoinflammatory diseases. We were trying to highlight the fact that many of these mutations are not in and of themselves sufficient to cause cancer, because they can be found in patients where it actually doesn't turn into cancer.

我们的大部分工作都来自这些淋巴瘤。但实际上，许多这些突变也出现在一些自身免疫和自炎性疾病中的T细胞中。我们试图强调的是，许多突变本身并不足以引发癌症，因为它们同样可以出现在一些没有发展为癌症的患者中。

Benjamin Thompson

The team identified 71 mutations that offered these cells an advantage and they introduced them into therapeutic T cells designed to target tumours. Then they assessed what effect the mutations had, both in a dish, and in in vivo mouse models. In particular, they were looking for cells that gained the ability to stick around, something that’s previously been an issue in solid tumours.

团队共识别出71种突变，这些突变赋予了这些细胞优势，他们将这些突变引入到旨在靶向肿瘤的治疗性T细胞中。然后他们在培养皿中和小鼠体内评估了这些突变的效果。特别的是，他们在寻找那些获得了持续存活能力的细胞，这是以前在实体肿瘤中一直存在的问题。

Jae Choi

For large part is these T cells don't persist in the patient or in the tumour. They may get there originally, they may cause some killing, but they're gone before you know it. So our first in vivo screen was actually looking for, can we find mutations to increase persistence in the tumour microenvironment. And then we want to look at the ability to recognize and kill tumour cells in vitro in vivo, because that would absolutely be needed for potential clinical products.

在很大程度上，这些T细胞无法在患者或肿瘤中持续存在。它们可能最初会到达肿瘤，造成一些杀伤，但很快就消失了。所以我们第一次的体内筛选实际上是在寻找能够增加在肿瘤微环境中持续性的突变。随后我们还想研究它们在体外和体内识别并杀死肿瘤细胞的能力，这对于潜在的临床产品是绝对必要的。

Benjamin Thompson

One mutation in particular seemed to fit the bill — a fusion between two genes, called CARD-11 and PIK3R3.

有一个突变特别符合要求，它是两个基因的融合，分别叫做CARD-11和PIK3R3。

Jae Choi

So actually, what the fusion does is it eliminates the brake from CARD-11, which allows the CARD-11 to be stronger and active in more situations and actually to be active longer. And so it's been fused with another domain, PIK3R3, we don't really know what that does, per se, but we think that it allows it to bind to very desirable Protein-Protein binding partners, which enables for like a very unique Goldilocks-type signalling, which enables enough, but not too much signalling in our T cells.

实际上，这种融合的作用是去除CARD-11的制动，使得CARD-11在更多情况下变得更强、更活跃，并且能够持续更长时间。因此它与另一个域——PIK3R3融合。我们并不完全了解PIK3R3的作用，但我们认为它能够与非常理想的蛋白质-蛋白质结合伙伴结合，从而实现一种非常独特的“金发姑娘”类型的信号传导，即在我们的T细胞中提供适度的信号。

Benjamin Thompson

It appears that these fused genes are able to activate biochemical pathways that are advantageous to T cells, and downregulate pathways that aren’t, giving them a boost when tested in mice.

看来，这些融合基因在小鼠实验中提供了增强作用，能够激活对T细胞有利的生化途径并下调不利的途径。

Jae Choi

It created this profound ability to thrive in the tumour microenvironment, but then from this study, it turned out that we discovered that using even a small number of T cells we’re able to cause durable complete remission of very difficult to treat tumours in vivo in these preclinical models. And so we don't know exactly the mechanism, but it seems to get in better, it seems to thrive better in the microenvironment it seems to proliferate better, and it seems to kill better.

它在肿瘤微环境中展现出了强大的生长能力，但从这项研究中我们发现，即使使用少量的T细胞，也能够在这些临床前模型中引起非常难治肿瘤的持久完全缓解。因此我们并不完全了解机制，但它似乎能更好地进入肿瘤，似乎能在微环境中更好地生长、繁殖，并且似乎能更有效地杀死肿瘤细胞。

Benjamin Thompson

But despite these positive outcomes, there were cases when cancer came back.

尽管取得了这些积极成果，仍然出现了癌症复发的情况。

Jae Choi

And we think that's because it absolutely relies on recognition of the antigen to be able to activate the pathways which enabled it to kill the cell.

我们认为这是因为它完全依赖于对抗原的识别，才能激活使其杀死细胞的途径。

Benjamin Thompson

T cells work by latching on to specific molecules called antigens found on the surface of cancers or infected cells. The team found that when the antigens aren’t present, perhaps when the tumour is destroyed or the antigens it presents shift, their fusion-equipped T cells don’t show the same abilities. And that can allow the cancer to return.

T细胞通过附着在癌症或感染细胞表面的抗原上来发挥作用。团队发现，当抗原缺失时，可能是在肿瘤被摧毁或其所呈现的抗原发生变化时，这些融合型T细胞就不能展现出相同的能力，从而可能导致癌症复发。

Jae Choi

So in some ways, it's disappointing because if we could solve all things and prevent cancer, you know, resistance, that'd be great. But also, it's another highlight of its potential safety that just couldn't do it an antigen is gone.

从某种程度上来说，这是令人失望的，因为如果我们能够解决所有问题并防止癌症的抗药性，那将是非常棒的。但这也是其潜在安全性的另一个亮点——如果抗原消失，它就无法继续发挥作用。

Benjamin Thompson

And safety is paramount with this approach, after all Jae and the team are choosing to take mutations which make T cell lymphoma better at being cancer, and then insert them into otherwise healthy T cells. And the last thing anyone wants is a therapy to treat, say liver cancer which ends up giving someone lymphoma in the process. And Jae is completely aware why this approach could be worrisome for people.

而在这种方法中，安全性至关重要，毕竟Jae和他的团队选择了那些使T细胞淋巴瘤更容易成为癌症的突变，并将它们插入到健康的T细胞中。没人希望治疗肝癌的疗法，最终却让人得上淋巴瘤。Jae完全意识到，为什么这种方法可能让人担忧。

Jae Choi

I totally understand it. What I would say is just a couple things. Number one is that people have knocked out genes and not realise that they're actually tumour suppressors in T cells and given it to patients. And we have not really found a high evidence of this kind of manipulation causes lymphomas. Number two is that actually because it seems to really work optimally only when it has the cancer antigen, what we think is happening is that once the cancer is cleared, it should only be able to be maximally functional when the cancer is there for its express, you know, clinical purpose. So that's another safeguard which just happens to be part of the biochemistry of the molecule.

我完全理解这一点。我想说的有几点。第一，人们曾经去除基因，但没意识到这些基因实际上是T细胞中的肿瘤抑制基因，并且将其给了患者。我们并没有发现这种操作会显著导致淋巴瘤。第二，实际上，它似乎只有在拥有癌症抗原时才能最佳发挥作用，我们认为一旦癌症被清除，它应该只在癌症存在时才能最大化地发挥作用，以达到其明确的临床目的，所以这是另一个安全保障。

Benjamin Thompson

The team looked for any evidence of T cell lymphomas — in some cases looking in mice over a year after their cancers had been cleared – and they didn’t find any. In fact, they say that the populations of their fusion-carrying cells had dropped to less than 1% of the total T cell population. And yet, understandably, the safety of T cell therapies remains in sharp focus, especially at the moment. In January, the US Food and Drug Administration wrote to several manufacturers of CAR-T therapies, asking them to add warnings about the risks of secondary cancers to their products. These numbers are low compared to the numbers of people who have received CAR-T therapy, and an FDA spokesperson has been quoted in news reports saying, quote, “we would like to underscore that the overall benefits of these products continue to outweigh their possible risks,” end quote. Lionel Apetoh from Indiana University is an immunologist who works on boosting immune cells’ ability to fight cancer but wasn’t part of the research team. He also has concerns about therapeutic T cells transforming into secondary cancers, especially when it comes to scaling up a therapy.

团队寻找了T细胞淋巴瘤的任何证据，在一些案例中，他们甚至在小鼠的癌症清除一年后进行了检查，但没有发现任何证据。实际上他们表示，携带融合基因的细胞群体已经降至总T细胞群体的不到1%。可以理解的是，在当前的背景下，T细胞疗法的安全性依然备受关注。今年1月，美国食品药品监督管理局（FDA）向几家CAR-T疗法制造商发函，要求他们在产品上增加关于二次癌症风险的警告。与接受CAR-T疗法的患者人数相比，这些风险的发生率较低，FDA发言人在新闻报道中表示：“我们想强调的是，这些产品的总体效益仍然超过其可能的风险。”印第安纳大学的免疫学家Lionel Apetoh也对治疗性T细胞转化为二次癌症表示担忧，尤其是在治疗规模扩大时。

Lionel Apetoh

The difficulty is the numbers game, poor choice of word because it's not a game. But the thing is testing it on a few patients and seeing like the T cells can be there for ten years, it's already like a major achievement. But now, making sure that if you treat hundreds, or thousands of patients, making sure that those cells they persist, and making sure that they are not getting transformed is a major, major challenge. Because even if a tiny proportion of patient experience issues, that is of course devastating and that is the reason for these investigations.

困难在于数量的挑战，虽然这个词用得不好，因为这并不是一个游戏。但问题在于测试几个患者并看到T细胞能存在十年已经是一个巨大的成就。但目前来看，确保在治疗成百上千名患者时，这些细胞能够持续存在并且不发生转化才是一个重大挑战。因为即使只有极小比例的患者出现问题，也会带来灾难性的后果，这也是这些研究持续进行的原因。

Benjamin Thompson

Jae is thinking about further safety precautions for his fusion T cells, like adding molecular switches which would allow them to be turned off if something goes wrong. But there is a lot more work to do beyond that. Lionel was impressed by Jae’s choice to use only one fused mutation which is likely to reduce the risk of secondary cancers developing, although it is still not without risk.

Jae正在考虑为他的融合T细胞增加更多的安全预防措施，比如添加分子开关，允许在出现问题时将其关闭。但除此之外还有很多工作要做。Lionel对Jae选择只使用一个融合突变表示赞赏，这可能有助于减少二次癌症发展的风险，尽管这仍然不是没有风险的。

Lionel Apetoh

That has to be taken with caution, because sometimes it's true that even a single mutation can drive transformation. But if that mutation is in normal cells, and using the strategy they used, I think it can be really an approach that can be tested, and actually they ensured about the safety in multiple ways, like they transferred the cells, they waited more than a year. So keeping in mind that they work with mice and the mouse lifespan is usually two years and they didn't see any transformation or any secondary cancers.

这必须小心对待，因为有时即使是一个突变也可能引发转化。但是我认为,如果该突变发生在正常细胞中，并且采用他们所使用的策略，这确实可以成为一种可测试的方法。实际上他们通过多种措施确保了安全性，例如转移细胞并监测了一年多的时间。因此要记住，他们的研究是在小鼠身上进行的，而小鼠的寿命通常为两年并且他们没有发现任何转化或二次癌症。

Benjamin Thompson

Lionel thinks there’s still a lot to learn about exactly what the fusion gene is doing in different types of T cells. And Jae and the team are keen to learn more about the mechanism through which their powered-up T cells are killing tumours so efficiently. And of course it remains to be seen whether their lab results will translate from mice into humans. But Jae thinks that the approach they’ve taken could offer their method an advantage in the long run, helping to develop therapies that stick around, particularly for difficult to treat solid tumours.

Lionel认为，仍然有很多需要了解的关于融合基因在不同类型的T细胞中所起作用的内容。Jae和团队也很希望进一步了解他们增强型T细胞杀死肿瘤的机制。当然，是否能够将实验室的结果从小鼠模型转化到人类身上，还需观察。但Jae认为，他们所采取的方法可能在长期内为他们的治疗方法提供优势，尤其是在开发能够长期存在的疗法方面，尤其对于难治的实体肿瘤。

Jae Choi

None of these preclinical models predicts exactly what happens in patients. But I think that we're potentially opening up new paradigms to think about how do we control functions biochemically and genetically with our data. I think we're potentially within a couple of years of really testing this to see whether it can actually go through. And in addition, we're within a couple of years of really finding out whether this is enough or whether we need to add and layer on more things with it. Using superpower analogy. I think you want someone that can be Clark Kent when the tumour is not there and become Superman in the tumour microenvironment and be able to transition back and forth and so we're really thinking very carefully about how to make this happen in patients.

这些临床前模型并不能准确预测患者会发生什么。但我认为，我们可能正在开辟一种新的范式，思考如何利用我们的数据在生化和遗传学上控制功能。我认为我们可能在几年内就能真正测试这个方法看看它是否能够成功。而且我们也将在几年内真正弄清楚，我们是否需要在其基础上添加更多的内容。用超级英雄的类比来说，我认为我们希望能找到一个在肿瘤不在时能变成克拉克·肯特，而在肿瘤微环境中变成超人的人，并且能够在两者之间自由转换。因此我们正在非常谨慎地思考如何在患者中实现这一点。

Benjamin Thompson

That was Jae Choi from Northwestern University in the US. You also heard from Lionel Apetoh from Indiana University, also in the US. To read Jae’s paper head over to the show notes for a link.

以上是来自美国西北大学的Jae Choi的分享。你还听到了来自美国印第安纳大学的Lionel Apetoh的观点。欲阅读Jae的论文，请前往节目提及的链接。