莫德纳个性化癌症疫苗的内部揭秘

这是第一次有癌症疫苗起作用。

It's the first time there is a cancer vaccine working.

这个领域已经做了二十多年，超过一千项临床试验都失败了。

The field has been doing that for twenty plus years, more than a thousand clinical trials that have all failed.

这次有什么不同？

What was different this time?

mRNA技术有什么特别之处，能让免疫系统以其他方法无法做到的方式学习？

What is it about mRNA technology that enables the immune system to learn in a way that other approaches were unable.

我们体内一直都有癌细胞。

We all have cancer cells all the time in our body.

我们的免疫系统训练有素，基本上能很早发现这些癌细胞并清除它们。

Our immune system is very well trained to basically notice those cancer cells very early and get rid of them.

但如果癌症发展起来，问题就是如何重新训练免疫系统。

But if your cancer grows, then the question is how you reteach the immune system.

我们会取你肿瘤的活检样本，读取其DNA的所有序列，然后对你的健康细胞做同样的处理。

We're going to basically take a biopsy of your tumor, we're going read all the letters of its DNA, and then we're going to do the same things with the healthy cell of your body.

我们会逐字逐句、逐个核苷酸地比较，然后用算法找出哪些突变是最关键的。

And we're going to literally compare letter by letter, nucleotide by nucleotide, and then we're going to use an algorithm to identify which one of those mutations are the most relevant.

所以当这个注射到你的体内时，它会教会免疫系统识别它之前漏掉的那些癌细胞的特征。

And so when this is injected in your body, it teaches the immune system the signature of your cancer cell that it missed.

这里监管的是什么？

What gets regulated here?

因为每一剂都不一样，所以显然不是每一剂都能获批。

Because every dose is different, so obviously every dose doesn't get approved.

基本上，Jorge，FDA想知道的是……

Basically, Jorge, what the FDA wants to know.

在Moderna的mRNA平台帮助生产出新冠疫苗之前，公司就已经在朝着另一个目标努力了：用mRNA来对抗癌症。

Before Moderna's mRNA platform helped produce a COVID vaccine, the company was already working toward another goal: using mRNA to fight cancer.

十年后，这个赌注已经达到了一个重要的里程碑。

A decade later, that bet has reached a major milestone.

A16z普通合伙人Jorge Conde与Moderna首席执行官Stephane Bancel坐下来交谈，此前Moderna和默克公司针对黑色素瘤的个性化mRNA治疗在第三期临床试验中取得了积极结果。

A16z general partner Jorge Conde sits down with Moderna CEO Stephane Bancel following positive Phase three results from Moderna and Merck's individualized mRNA treatment for melanoma.

这是Moderna大约十年来一直在推进的项目的最终成果。

It's the culmination of a project Moderna has been working on for roughly a decade.

Stéphane解释了Moderna如何获取患者的肿瘤，将其与健康细胞进行比对，识别出该癌症特有的突变，并利用这些信息制造个性化的mRNA，以教导免疫系统该攻击什么。

Staphane explains how Moderna takes a patient's tumor, sequences it against their healthy cells, identifies the mutations unique to that cancer, and uses that information to manufacture a personalized mRNA designed to teach the immune system what to attack.

而且由于大约90%的选定抗原在患者之间是不同的，个性化并不是一个边缘情况。

And because roughly 90% of the selected antigens differ from one patient to another, personalization isn't an edge case.

它是这种治疗方法运作的基础。

It's fundamental to how the treatment works.

他们还深入探讨了这背后的巨大运营挑战。

They also get into the extraordinary operational challenge behind this.

如何一次为一位患者制造数千种不同的药物，并且要快速可靠，才能使个性化医疗大规模运作？

How do you manufacture thousands of different medicines, one patient at a time, quickly and reliably enough to make personalized medicine work at scale?

最后，他们展望了这个平台未来的发展方向，从其他癌症到罕见的遗传病和自身免疫性疾病。

And finally, they look at where the platform could go next, from other cancers to rare genetic and autoimmune diseases.

你好。

Hi.

欢迎收听a16z播客。

Welcome to the a16z Podcast.

我是Jorge Conde，a16z BioHealth团队的普通合伙人。

I'm Jorge Conde, a general partner on the a16z BioHealth team.

今天我非常高兴地再次邀请到Moderna的首席执行官Staphane Bancel。

I am thrilled today to welcome back Moderna CEO, Staphane Bancel.

长期收听我们节目的朋友们可能还记得，Staphane曾在2020年12月做客a16z播客，当时我们聊了Moderna为推出mRNA新冠疫苗所做的所有工作。

For folks that have been longtime listeners may recall, Staphane joined us on the a6z podcast back in December 2020 when we were talking about all of the work Moderna did to bring us the mRNA COVID vaccine.

当时，如果你回去听那一期节目，你会听到Moderna对病毒的出现反应有多快，分析病毒，基本上就是打印出一种疫苗来保护人们免受新冠病毒的侵害，从而让我们在应对新冠疫情时处于更有利的位置。

And at the time, if you can go back and listen to that episode, you'll hear how quickly Moderna was able to react to the existence of the virus, to analyze it, to essentially print a vaccine that would protect people against the COVID-nineteen vaccine, and hence put us in a much better position with respect to the COVID pandemic.

我们把那一期节目命名为《制造疫苗的机器》。

We titled that episode The Machine That Made the Vaccine.

我们今天在2026年8月再次对话，是因为Moderna在mRNA技术应用于癌症方面取得了重大进展，并发布了相关消息。

And the reason why we're talking again today in August 2026 is because Moderna has put out news on a really big advancement on what they can do with mRNA technology when it comes to cancer.

所以，Staphane，我想把话筒交给你。

And so I wanna hand it over to you, Staphane.

再次热烈欢迎。

Again, a very big welcome.

感谢你再次光临。

Thank you for coming back.

不过，也许我们应该从新闻开始说起。

But maybe the place to start is let's lead with the news.

本月早些时候，也就是八月份，Moderna和默克宣布，你们在黑色素瘤方面进行了三期临床试验，并且取得了非常令人鼓舞的结果。

Moderna and Merck announced earlier this month in August that you had conducted a Phase three clinical trial in melanoma and have gotten very encouraging results.

所以，不如你来告诉我们，你们宣布了什么？

So why don't I hand it over to you and tell us what have you announced?

你们在这次三期试验中看到了什么？

What have you seen in this Phase three trial?

然后我确实想深入了解一下Moderna在癌症方面的工作。

And then I do wanna dig in into what Moderna is doing in cancer.

太好了，Jorge，非常感谢你再次邀请我们，我们很高兴能和你在一起。

Wonderful, so Jorge, thank you so much for having us back, we're very happy to be with you.

所以，确实，上周我们和默克的同事分享了消息，经过十年时间用mRNA技术研究针对癌症的个体化治疗，三期试验结果是阳性的，这是众多成果中的第一个，也是第一次有一种药物在黑色素瘤上比单独使用Qetidra效果更好，所以这对黑色素瘤患者来说当然是个大消息。

So indeed, last week now, we shared the news with our colleagues at Merck that after working ten years on an individualized treatment against cancer using mRNA technology, that the Phase three was positive, it's a first of many, it's the first time that there is an agent in melanoma that is better than Qetidra alone, so it's a big deal for patients of course with melanoma.

这是第一次有癌症疫苗起作用，你知道这个领域已经做了二十多年，我想有超过一千个临床试验都失败了。

Here it's the first time there is a cancer vaccine working, the field as you know has been doing that for twenty plus years, I think more than a thousand clinical trials that have all failed.

如果你看二期数据，因为我们上周宣布的是我们达到了研究的主要终点，也就是无复发生存期，我。

And if you look at the phase two data, because what we announced last week is that we met the primary endpoint of a study, which was recurrence free survival, I.

也就是说，

E.

人们癌症复发或死亡，我们达到了这个终点，然后让我们自己都惊讶的是，因为这是第一次中期分析，不是研究结束，而是研究的第一次中期分析，让我们惊讶的是我们达到了次要终点，也就是无远处转移生存期，这当然需要更长时间才能成熟，因为它意味着从原发肿瘤有远处转移，我们也达到了这个终点，这很棒，再次强调，这是我们没想到的，但也说明效果真的很好。

People having the cancer back or dying, that we met, and then to our own surprise, because this was the first interim analysis, this is not the end of a study, it's a first interim analysis of a study, and what was a surprise event to us is we met the secondary endpoint, which was distant metastasis free survival, which is of course takes more time to mature, because it means that you have distant metastasis from your primary tumor, and we also made that endpoint, which was great, again, unexpected from our side, but again, means it is really good.

我们很快会在一个大型医学肿瘤学会议上分享数据，这是这个领域的惯例，为了给你一个方向感，我们在ASCO，也就是今年春天的大型肿瘤学会议上，展示了我们的二期研究，也是随机对照单独使用ketidra，所以是同样的研究类型，显示大约百分之五十的人无复发生存，而只接受Qetidra的人，这是治疗后五年。

We will share the data very soon at a big medical oncology conference, which is what the field does, just to give you a sense maybe to orient kind of directionally, we showed at ASCO, the big oncology conference in the spring of twenty twenty six, a few months ago, that our Phase two study, which was also randomized against ketidra alone, so the same type of study, showed that around fifty percent of people had recurrence free survival versus people only getting Qetidra, and this is five years after treatment.

而且你知道，在肿瘤学中，五年被医生认为是治愈，所以这是非常非常大的事情。

And as you know, in oncology, five years is considered by a doctor like a cure, and so it's a big, big deal.

如果你看organ的二期数据，大约百分之八十的人在黑色素瘤手术和治疗后五年无病生存。

And if you look at the data from organ that's Phase two, had around eighty percent of people that's where disease free five years after their treatment and their surgery of melanoma.

所以我们对于这对整个领域意味着什么感到非常兴奋。

And so we're very excited about what it means for the field.

我们已经在和监管机构紧密合作，准备提交申请，以便药物能尽快惠及患者，我们希望能在2027年实现，而且我们会尽最大努力加快进度。

We are working very hard already with regulators to file, so the drug can be available to patients as soon as possible, and we hope in 2027, and we're gonna try to make it as fast as we can.

马萨诸塞州的工厂已经准备好了，但我们已经解决了如何为每个人生产和扩大产品规模的问题。

The factory is ready in Massachusetts, but we have figured out how to make and scale a product for every human being at this at the time.

我觉得这里有很多值得探讨的内容。

I mean, there's so much to unpack here.

所以，这是针对黑色素瘤治疗的一个进步，希望随着时间推移，也能更广泛地应用于其他癌症。

So I this is an advance for the treatment of, in this case, melanoma, and hopefully over time, cancers more broadly.

那么，让我们来深入探讨一下这些内容吧，斯特凡。

So let's unpack some of this if we could, Staphane.

第一个问题，对于那些不太熟悉癌症治疗的人来说，什么是可瑞达？为什么单独使用可瑞达还不够？

The first one, for folks that are less familiar with cancer treatment, what is Keytruda, and why is Keytruda alone not sufficient?

为什么需要这种特定的mRNA癌症疫苗与可瑞达联合使用？

Why was this particular mRNA cancer vaccine necessary in conjunction with Keytruda?

当然可以。

Sure.

说到Keytruda，它其实是

So if you look at Keytruda, which is

一种大家可能听说过的领先免疫疗法。简单来说，如果让我给非生物学背景的人打个比方，它就像是一个分子，打开了免疫系统的闸门，让那些‘狗’——也就是免疫细胞——去攻击你的癌细胞。

kind of one of the leading immunotherapy that people might have heard of, is basically, if I oversimplify for non biologists, it's basically a molecule that basically open the gates for letting the dogs out, that are gonna go and attack your cancer, from your immune system if you want.

检查点抑制剂的问题是，当它们有效时效果非常好，因为那些患者治疗后五年就痊愈了，也就是说体内没有残留的疾病。但根据KEYTRUDA的三期临床数据，只有60%的人在五年后没有疾病。

The thing about checkpoints is when they work, they are fantastic, because those people five years after treatment are cured, in the sense they have no remaining disease, but only sixty percent of people are disease free after five years, if you look at the Phase three published data of KEYTRUDA.

所以，对于那60%的人来说，这确实很神奇，但这也意味着有40%的人，即使接受了治疗，努力对抗癌症，治疗对他们来说却没什么效果。

So again, for those sixty percent of people, it's amazing, but it means that there's forty percent of people where you go through a treatment, you're fighting for cancer, and the treatment doesn't really work for you.

而且困难的是，这些治疗虽然很好，但很多时候会带来非常严重的副作用，和化疗或放疗完全不同。

And also what is difficult is those treatments are wonderful, but they, a lot of time come with very serious side effects, very different from chemotherapy or radiotherapy.

免疫疗法的副作用主要是免疫系统相关的疾病。

The side effect of immunotherapy are mostly immune disease.

所以你会看到，如果你看药品说明书或者临床研究，接受检查点抑制剂的患者，无论是Keytruda还是其他公司的类似药物，最终可能会出现1型糖尿病、狼疮、克罗恩病这类疾病。

So you see people, if you look at the label or the clinical studies, people that get checkpoints, whether it's ketudra or any other type of checkpoints from other companies, they end up having type one diabetes, lupus, Crohn's disease, these type of things.

当然，得这些病总比死于癌症要好，所以它们才成了标准疗法。

Of course, it's better to have those disease than of course being dead from your cancer, which is why those have become standard of care.

但想想那百分之四十对检查点抑制剂没反应的人，他们大多会得自身免疫病，却得不到药物的疗效。

But think about those forty percent of people who don't respond to checkpoint, they get an autoimmune disease most of the time, and they don't get the benefit of a medicine.

所以我们和默克合作时，其实这项技术是2015、2016年从Moderna实验室出来的，当时我们和默克合作，想找一家最好的免疫疗法公司来互补。

And so what we try to do with Merck, and it's really a technology that emerged from Moderna labs back in 2015, 2016, when we did a partnership with Merck, we're looking for one of the best company in immunotherapy to partner and to have a compliment approach.

我们当时利用传染病疫苗的经验，对免疫系统和mRNA如何相互作用了解了很多，我们想开发一种完全不同的作用机制，和免疫疗法不同，因为你可以从你的肿瘤序列出发，设计一个产品来教那些狗，回到狗的比喻，教它们非常具体地找什么。

The idea that we have at the time using our infectious disease learning from our infectious disease vaccine, we learned a lot about the immune system and how mRNA interact with the immune system, we thought we could develop a mechanism of action that was totally autogonal, different from immunotherapy, because you will be able to start from a sequence of your tumor, so that we could design a product to basically teach, if I go back to the dog analogy, to teach those dogs what to look for, very specifically.

这就是我们技术的妙处，如果你想想Keytruda，它基本上是放开狗，但有时候它们有点乱跑，那是你的免疫系统；而我们的产品是在分子层面，在免疫系统内部，非常具体地教你的T细胞，这就是你要找的。

And that's really the beauty of about our technology is, if you think about ketoglutarate, basically unleash the dogs, but they go a bit randomly sometime, it's your immune system, whereas monoproduct is about, they bought at the molecular level inside the immune system to very specifically teach your T cell, this is what you need to look for.

而且那个东西其实就在你的癌细胞上。

And that thing is actually on your cancer cell.

这样那些T细胞就会去攻击你的癌细胞。

So that those T cells go and basically attack your cancer cells.

好的。

Okay.

所以现在，个性化癌症疫苗技术将对黑色素瘤的治疗产生重大影响。

So now that's where the personalized cancer vaccine technology will make a big impact on treatment of melanoma.

我们稍后再回到个性化这个话题，因为我觉得这不仅在技术层面，而且在操作层面都非常吸引人。

We'll come back to the personalized piece, because I think that's just fascinating, not only from a technological standpoint, but just from an operational standpoint.

所以我确实想再回到这个话题。

So I do wanna come back to that.

但让我们先聚焦在“疫苗”这个词上。

But let's focus on the word vaccine.

通常，提到疫苗，大家想到的是预防疾病。

So typically, when you think of the word vaccine, it is to prevent a disease.

但在这里，这些患者已经患有癌症。

Here in this context, these patients already have cancer.

所以从某种意义上说，你是在预防某种东西。

So in a sense, you are preventing something.

你预防的不是癌症本身。

You're not preventing the cancer.

你预防的是癌症的复发，这本身就是从治疗干预的角度来看，一个非常了不起的想法。

What you're preventing is the return of the cancer, which is in and of itself an extraordinary thing to think about from a therapeutic intervention perspective.

所以第一点，这个说法是否准确？

So number one, is that a fair characterization of

这个说法是否准确，以及为什么这个领域用“疫苗”这个词，其实不是我们发明的，我们只是跟随这个领域的惯例，就像我提到的，在一千多项临床试验中，因为核心是训练你的免疫系统。

how you a fair characterization, and the reason the field has used the word vaccine, it was not us using it, we just followed the field, as I mentioned, that in a thousand plus clinical trial, is because it's about teaching your immune system.

想想新冠疫苗或流感疫苗，你是在病毒侵入身体之前，先训练你的免疫系统。

If you think about a COVID or flu shot, you teach your immune system before you get the virus infecting your body.

而在这里，你训练免疫系统不是针对病毒，而是针对你的免疫系统之前忽略的癌症信号。

Here, you teach your immune system not about the virus, but about basically the cancer signal that your immune system missed.

因为我们现在在这个领域了解到，我们体内其实一直都有癌细胞，无论是外部因素导致的，还是细胞复制过程中出现的错误，导致DNA突变，从而产生癌细胞。

Because what we know today in the field is that we all have cancer cells all the time in our body, whether it's outside factors, or just as you have cell replication and you have mistakes that happen that create mutation of DNA that are cancer cells.

我们的免疫系统非常擅长在早期发现这些癌细胞，并清除它们。

Our immune system is very well trained to basically notice those cancer cells very early, and get rid of them.

但如果癌症发展起来，问题就是，你如何重新训练你的免疫系统？

But if your cancer grows, then the question is how can you reteach your immune system?

所以我觉得这就是为什么这个领域也用疫苗这个词来形容这种方法，即使像你说的，这是癌症确诊后的治疗方法，核心还是在于训练免疫系统。

So I think that's why the field use the word vaccine for that approach as well, even as you said, it's a therapeutic treatment approach post cancer, it's about the teaching of the immune system.

好的，正如你所说，这个领域之前已经尝试过很多次了。大约有一千项临床试验测试过这个理论。

Okay, and so, as you point out, the field has tried this many times before, A thousand on the order of a thousand clinical trials have tested this theory.

但都失败了。

They've all failed.

你和Moderna、默克这次成功了。

You and Moderna and Merck have succeeded here.

这次有什么不同？

What was different this time?

mRNA技术有什么特别之处，能让免疫系统以其他方法无法成功的方式学习？

What is it about mRNA technology that enables the immune system to learn in a way that other approaches were unable to be successful?

是的，我觉得有

Yeah, I think there's, there

两个关键因素。

are two components.

一个是mRNA技术，另一个我觉得是个性化，就是为每个病人单独设计产品。

One is the mRNA technology, and I think the other one is individualization by designing a product for one human at a time.

那我分别说说这两点。

So let me go through those two.

在mRNA技术方面，我们已知并发表过的，其实和卡罗林斯卡学院合作过，你知道，就是瑞典那个2015年颁发诺贝尔医学奖的机构，我们证明了，用我们的技术——我不能代表其他mRNA公司，它们有不同的mRNA、不同的脂质等等——但用我们的技术，当我们把mRNA注射到肌肉里，不管是新冠疫苗、流感疫苗还是这个癌症治疗，mRNA基本上会进入淋巴结，然后进入APC，也就是抗原呈递细胞，你知道，这是免疫细胞的关键组成部分，mRNA就进入APC内部。

On the technology of mRNA side, what we have known and published, actually with Karolinska, as you know, the institute in Sweden that gave the novel Brassal medicine back in 2015, is that with all technology, I cannot speak about other mRNA companies that have different mRNAs, different lipids and so on, but with all technology, when we inject our mRNA in a muscle, whether it's a COVID shot or flu shot or this cancer treatment, basically the mRNA goes down to your lymph node and enters the APCs, the antigen presenting cell, which as you know, are key component of your immune cells, and the mRNA gets inside the APCs.

这个我们在卡罗林斯卡的时候就已经证明过了，然后你基本上就在APC内部，也就是免疫细胞内部，翻译mRNA携带的信息，并从内部呈递出来。

This we've demonstrated and proven at the time of Karolinska, and then you basically translate the message contained in the mRNA inside the APCs, inside your immune cells, and present it from within.

所以我们认为这是

So we think it's a

一个非常重要的区别，和之前大多数癌症疫苗不同，那些疫苗是用蛋白质或多肽做的，基本上是在反应器里生产，注射到病人体内后，它们会进入血液，因为你知道，重组蛋白或蛋白质，注射后就直接进入血液，然后循环。

very important differentiation from most of the previous vaccine in cancer in the field that were made by protein or peptide, that basically are made in reactors, are injected in the patient, but they basically turn into the blood because as you know, recombinant or protein, when you inject them, they just go into your blood and they turn around.

所以免疫系统能看到它们，但和mRNA这种从内部呈递的方式不一样。

So your immune system sees them, but not in the same manner from within as it's done with the mRNA.

所以我们认为这是免疫呈递的一个非常重要的组成部分，不知道这样说是否清楚。

So we think that's one very important component of immune presentation, if that makes sense.

另一个关键点就是个体化。

The other component is really the individualization.

过去，很多时候人们尝试过非mRNA的，嗯，

In the past, a lot of time people have tried with non mRNA, I.

蛋白质技术或者肽，但我们也试过共享抗原。

Protein technology or peptide, but also we tried a shell antigen.

而在这里，我们说的是，因为癌症是DNA的疾病，所以我们打算这样做：由于过去二十年测序成本大幅下降，我们会取你的肿瘤活检样本，读取其DNA的所有字母，也就是那三十亿个基因，然后对你的健康细胞做同样的事情，然后我们逐字母、逐核苷酸地比较，接着用算法从你的数百或数千个突变中，根据当前癌症免疫学领域的知识，识别出哪些突变最相关，我们选出我们认为最相关的34个，把它们拼接成一个大的mRNA分子，大约三十天内为你制造出来，然后在医院肌肉注射。当这个被注射到你体内时，它基本上教会免疫系统识别它之前漏掉的你的癌细胞的签名。

Whereas here what we said is because DNA is a disease, sorry, cancer is a disease of DNA, what we're gonna do here, because the cost of sequencing have dropped so much in the last twenty years, is we're gonna basically take a biopsy of your tumor, we're gonna read all the letters of its DNA, the three gigabyte of its genes, and then we're gonna do the same things with the healthy cell of your body, and we're gonna literally compare letter by letter, nucleotide by nucleotide, and then we're gonna use an algorithm to identify of your hundreds or thousands of mutations, which one, based on the current knowledge of a field of immunology in cancer, which one of those mutations are the most relevant, we select the 34 that we believe are the most relevant, and we stitch them together into one big mRNA molecule, which we make in thirty ish days for you, that is injected then in a hospital intra muscularly, and so when this is injected in your body, basically it teaches the immune system the signature of your cancer cell that it missed.

不是每个其他患者共享抗原的签名，而是你的癌细胞非常特异的签名。我们在ASCO上展示并从二期研究中发表的数据，我们相信在三期研究中也是一样的，因为这是机制性的，大约90%的抗原在不同患者之间是不同的。

Not the signature of every other patient with a shared antigen, but the very specific signature of your cancer cell, and what we showed at ASCO and we published from a Phase two study, but we believe it's the same thing in the Phase three, because it's mechanistic, is that around 90% of the antigen are different patient to patient.

因为我们刚开始时完全不知道，因为领域来自共享抗原。

Because when we started, we had no idea, because again, field came from shared antigen.

所以当我们开始时，我们想，我们完全不知道，我们会得到2%、5%还是90%的相同抗原在所有患者中，实际上，90%的抗原在人与人之间是不同的。

So when we started, we're like, we have no idea, we're gonna get 2%, 5%, 90% of of same antigen across all the patient, actually, 90% of antigen are different from a human to another one.

哇。

Wow.

所以这只能靠个性化来实现。

So the only way this can work is through personalization.

我们就是做个性化，没错。

We just individualize, exactly.

你知道，假设这能延续下去。

You know, assuming that carries over.

那么在这方面，比如说，如果你做这种正常细胞和肿瘤基因组的对比，你就能找到差异。

And so in that regard, you know, if you're doing, let's say, this normal to tumor comparison of the genome, you find the differences.

我很好奇你们是怎么得出34这个数字的，最多34个，为什么是这么多。

I'm curious how you arrive at 34, up to 34 as the right number.

我相信这背后肯定有很好的理由。

I'm sure there's a very good reason for that.

但你们是用什么算法来做到这一点的？

But what is the algorithm that enables you to do that?

这是Moderna的专有技术吗？

Is this something that's proprietary to Moderna?

这是业内已知的东西吗？

Is this something that is known within the field?

帮我们理解一下，帮我们看看那个黑箱里面是什么。

Help us understand, like, help us look into that black box.

当然可以。

Sure.

我想稍微分享一下黑箱的情况，但不会说太多，因为里面有很多技术诀窍，对我们来说非常机密。

So I wanna share a little bit about the black box, not too much because there's a lot of know how, things are very confidential to us.

基本上，我们一开始当然是从业内已知的东西出发。

Basically we started with, of course, what is known in the field?

我们用了很多数据库和出版物，还有很多科学家和医生，都是免疫学和肿瘤学领域顶尖的专家，然后从这个起点出发，我们利用了大量自己长期积累的内部数据。

And so we basically use a lot of database and publication, and a lot of scientists and doctors, kind of best in class in immunology and in oncology, and then from that starting point, we use a lot of internal data that we generated over time.

我们还和一些公司合作，因为他们做诊断，或者做细胞治疗和其他肿瘤学领域，他们能接触到大量数据，比如T细胞图谱之类的，所以对学习很有帮助。

We also partner with some companies that because they are in the diagnostic space, or they are, let's say, cell therapy and other space in oncology, had access to a lot of data, a lot of T cell mapping and so on, that's why they were useful for the learning.

上周我们分享的数据有意思的地方在于，我认为这是mRNA-1.0，因为三期临床试验的算法和二期一样，和一期也一样。

The thing that is interesting about the data we shared last week is this is what I consider in this mRNA-1.0, because the algorithm from a Phase three was the same from a Phase two, was the same from a Phase one.

但是因为我们做这个已经十年了，这个算法已经用了十年。

But because we've been doing this for ten years, it's a ten year old algorithm.

所以你看数据，效果其实挺好的，对吧？

So as you look at the data, it works pretty well, right?

就像我们说的二期数据，五年后百分之八十的人没有疾病，对病人来说很了不起，但还有百分之二十的病人没有反应。

As we said about the Phase two data, eighty percent of people are disease free after five years, it's amazing for those patients, but there's still twenty percent of patients that don't respond.

所以我们现在有了三期病人的数据和样本，接下来要做的一件事就是回去挖掘这些数据，弄清楚为什么有些病人有反应，有些没有，因为我们有他们所有的血样、序列，什么都有。

And so one other thing we're gonna be doing now that we have access to a Phase three patient data and samples, is to go back and mine that data, to figure out why some patient responded, and why some of our patient did not respond, because we have access to all their blood sample, the sequence, everything.

然后他们试着看看，能不能改进算法。

And when they try to see, can we improve the algorithm?

如果我们找到科学依据，说明为什么要从1.0算法升级到2.0算法，我们就会去找FDA，然后进行更改。

And we will go to see FDA if we find scientific reason why we should change the algorithm to go from, let's say, 1.0 to a 2.0 algorithm, and then change it.

当然，我们必须以非常可控的方式进行，以确保不会失去疗效，这是很明显的。

Of course, we have to do that in a very controlled way to ensure we don't lose efficacy, very obviously.

但我的想法是，就像我们谈论AI时，我们总是开玩笑说，当前版本的AI是我们这辈子能见到的最差版本，但intismarin也是一样，Moderna现在的intismarin版本，是你在整个医学史上能见到的最差版本。

But the way I think about it is really like when we talk about AI, it's just, we always joke that the current version of AI is the worst we're gonna see in our lifetime, but it's exactly the same for intismarin, which is the current version of intismarin that Moderna is the worst version of intismarin you're gonna see for the rest of medical history.

所以这给了我很大的希望，不仅是对黑色素瘤中那百分之二十没有反应的患者，而且可能对领域里一直很难攻克的肿瘤，比如胰腺癌和其他免疫疗法无效的癌症，我们也希望能利用这项技术学到很多，同时借鉴过去十年领域里积累的经验，因为你知道，这个领域已经学到了很多。

And so that gave me a lot of hope, not only in melanoma for those twenty percent of patients that don't respond, but also for potentially over tumors that have been really hard in the field, you know, pancreas cancer and others where immunotherapy doesn't work, we want to be able to learn a lot about the technology, using also what the field has learned in the last ten years, because the field has learned a lot as you know.

这甚至还不是Intisperan 1.0版本，所以我对接下来要发生的事情感到非常兴奋。

This is even not in Intisperan 1.0, so that's why I'm so excited about what's coming next.

那太棒了。

That's fantastic.

回顾过去，你和我认识已经很久了。

So looking back, you and I have had we've known each other for a very long time.

我就不说具体多少年了，免得让你我都不开心。

I won't depress you or me by saying how long.

但你还在上幼儿园呢。

But you haven't you're in kindergarten.

所以我有幸从Moderna最早期的阶段就看到了它的发展。

So I've had the benefit of seeing the Moderna from the earliest days.

是的。

Yes.

有一件事是真的，过去是真的，现在也是真的，那就是你，首先，你骨子里是个工程师。

And one thing that is true, that was true then, is true today, is you are Well, first of all, you are an engineer at heart.

而且你从一开始就非常执着于流程、运营和效率。

And you have, from the very, very beginning, been obsessed with process, with operations, with being efficient.

如果你想做你在这里尝试做的事情，也就是个性化癌症疫苗，为每个病人量身定制药物，那么这些特质绝对是必需的，因为百分之九十的情况下，抗原之间没有重叠。

And those things need to be absolutely true if you're going to attempt to do what you're trying to do here with personalized cancer vaccines and make a medicine for each individual patient precisely because in ninety percent of the cases, there's no overlap in terms of the antigens.

你能给我们讲讲这里需要的运营工作吗？你已经为了运行试验做了很多，但如果最终商业化这个产品，你还需要做哪些工作？

Can you walk us through a bit the operational lift that is required here that you've already had to do to even run the trial, but that you would have to do if you eventually commercialize this product?

当然可以。

Sure.

也许可以这样来理解，我想很多人会想到癌症领域另一种大型个性化疗法，那就是CAR T细胞疗法。

Maybe one way to frame it is, I think a lot of people think about the other big personalized therapy that exists in cancer is CAR T cell therapy.

对于可能不熟悉的人来说，CAR T细胞疗法是这样的：你取出病人的肿瘤，然后取出病人的免疫细胞。

And in that case, thing that and CAR T cell therapy, for folks that may not be familiar, is this idea that you take a patient's tumor, and then you take the patient's immune cells.

你把它们从体内取出，基本上重新编程免疫细胞，重新设计它们使其对肿瘤有反应，然后再把它们放回病人体内。

You take them out of the body, and you essentially reprogram the immune cells and re engineer them to be reactive to the tumor and put them back into the patient.

当然，我这是说得太简单了，但CAR T细胞疗法大概就是这么回事。

I'm oversimplifying, of course, but that's CAR T cell therapy in very sort of in a simple nutshell.

而在这个案例中，我们在某些方面做的事情非常相似。

In this case, you're doing, in some ways, things that are very similar.

对吧？

Right?

你取一块肿瘤组织，大概是通过活检得到的，然后对肿瘤进行测序，来生成一种针对该患者肿瘤非常特异的疫苗。

You're taking a piece of the tumor, and that you have in the form of a biopsy presumably, you're sequence trying the tumor to generate a vaccine that is very specific to that patient's tumor.

你如何看待从静脉到静脉的时间？

How do you think about essentially the vein to vein time?

也就是说，从你见到病人、获取肿瘤组织的那一刻，到病人接受个性化疫苗的那一刻，需要满足什么条件？

Like what needs to be true from the moment you, you know, sort of see a patient and get access to the tumor to the moment that patient receives their personalized vaccine?

好的。

Sure.

现在的时间大约是四十二天，从取活检到疫苗在医院准备好给你，也就是从针到针的时间。

So the time is around forty two days now, needle to needle, so from taking biopsy to getting the vaccine in the hospital ready for you.

我觉得我们还能把这个时间缩短，因为我们在自动化和机器人方面还有很多可以提高效率的地方。

I think we're gonna be able to improve that as we still have a lot of efficiencies to work on in automations and robotics.

这和CAR T疗法很不一样的地方在于，我们不需要提取你的免疫细胞，在体外、在工厂里、在我们的工厂里，用反应器来编程它们，然后再送回你的医院。

The place where this is very different from CAR T is that we don't have to take your immune cells, we program them ex vivo in a reactor, in a factory, in our factory, and send them back to your hospital.

我们只需要信息。

The only thing we need is the information.

你和我之前聊过mRNA的美妙之处，它是一种信息分子，所以基本上我们从实验室得到的就是你健康细胞的序列和你癌细胞的序列。

You and I the talked beautiful thing of mRNA, it's an information molecule, and so basically what we get from the lab is the sequence of your healthy cells and the sequence of your cancer cells.

所以我们只是拿到一个文件，然后用这些信息来制造DNA，但现在我们不是用质粒培养大肠杆菌来生产。

So we just get a file, and then we use that information to basically make the DNA, but now we don't make it with plasmid growing E.

我们完全用合成的方法，整个过程都是酶促反应，在液体、水里进行，然后从模板合成RNA，再用脂质包裹起来。正因为这是一个合成过程，它更像小分子药物，而不是大分子药物。

Coli or whatever, we make it all synthetic, so it's all enzymatic in liquid, in water, then we make the RNA from the template, then we put the lipid around it, and because of that, and that it's a synthetic process, it's much more like small molecule than the large molecule.

你想想CAR T，对我来说，它的类比是重组蛋白领域。

You think about CAR T, for me the analogy is the recombinant world.

那里有细胞、大型反应器，还有很大的体积，因为你知道，生物技术行业之所以需要大体积，是因为如果细胞压得太紧，它们就会死。

Where you have, you know, cells and big reactors, and you have big volumes, because as you know, the reason you have big volumes in biotech industry is if you compress the cells too much, they die.

CAR T也有同样的问题，所以一切都是大规模的。

You have the same issue with CAR T, so it's all, everything is big.

而在这里，因为整个过程都在水里进行，而且是酶促反应，也就是说催化效率很高，反应器非常非常小。

Whereas here, because it's all in water and it's all enzymatic, meaning it just, it's very catalytic, the reactors are very, very tiny.

所以我们在进入临床之前就开始做这件事了，因为正如你所说，为了做一期研究，我们得先把技术开发到能针对每个人定制，对吧，所以我们把一切都缩小了。

And so what we've been doing since before the clinic, because as you said, we had to start developing the technology to individualize it one human at a time to even do a phase one study, right, is we shrunk everything down.

第一版机器看起来像个大号的美式冰箱，有点大而且不太稳定，因为我们跟团队说，先做到质量好就行，但暂时不考虑效率，因为如果临床效果不好，花五年时间去做一个漂亮又优化的机器人又有什么意义呢，对吧？

So the first version of a machine that looks like a big American fridge was a bit big and cranky, because we told the team, make it good enough so you have good quality, but we're not solving for efficiencies yet, because if it doesn't work in the clinic, what's the point of wasting five years making a beautiful, amazing optimized robot if the science doesn't work, right?

所以我们跟团队说，先做好质量，确保没有质量问题，也不要在临床上出现假阴性，因为如果你造了个机器人，看起来能用但实际上不行，然后你做了研究，结果说科学上不成立，那你就完了，但如果本来应该有效的，那对全人类来说都是灾难，对吧。

So we told the team, make it good so that we have no quality issue, and we don't have a false experiment, a false negative in the clinic, because it would be terrible for patients if you build a robot kind of working, but not working, you run the study, and it tells you the science doesn't work, and you're done, if it should have worked, right, that would be a disaster for humanity obviously.

团队也确实这么做了，他们开发了一个质量上没问题但效率不高的机器人。当我们拿到二期数据，发现这个方案有效时——二期第一次中期数据才两年，现在我们已经有了五年的数据，疗效持续时间表现很好——我们就跟团队说，好了，现在我们落后了，而且我们知道如果成功的话这种情况会发生，这是个让人高兴的问题。所以我们投入了很多非常聪明的工程师去思考，现在怎么造一个非常高效的机器，甚至能把机器的体积都压缩，因为重要的因素之一当然是时间，就像你提到的，从采血到回输的周期时间，还有成本。

And so the team did exactly that, they developed a robot that was good in terms of quality, but it was not very efficient, and when we got the phase two data, that this was working, the first interim of phase two data at only two years, now we have five years of data maturing beautifully for duration of efficacy, we told the team, okay, now we are behind, and knew this was gonna happen in case of success, which is a happy program, and so we dedicate a lot of very smart engineers to think about, okay, now how do you make a very efficient machine that you can compress even the volume of a machine, because one of the important vector of course is time, as you mentioned, cycle time from needle to needle, but also cost.

降低成本的一个方法就是减少占地面积，因为如果你的洁净室设施是固定的，而你能在同样的面积里放两倍甚至十倍多的机器，那当然能获得更大的吞吐量，固定成本也会低很多。

And so one way to reduce the cost is reduce the footprint on the floor, because if you have a fixed envelope of a clean room facility, and you can put as 2x or 10x more machines in that surface area, of course you're gonna get the bigger throughput and a much lower price on your fixed cost.

所以我们非常关注周期时间，因为周期时间越短，你就能在一年内让你的资产周转更多次。

And so we are obsessed about cycle time, because the more, I mean, the more you can reduce cycle time, the more you can get a turnaround, let's say in a year on your assets.

我特别在意的第二个方面就是占地面积。

And the second vector I'm obsessed about is square inches.

说实话，我去工厂的时候总是很烦人，抱歉，我会看所有能节省的空间，怎么发挥创意，甚至把一些计算设备搬出洁净室，尽量缩小一切，这对最终产品成本影响巨大。

Literally, I'm always a pain in the butt, sorry, when I go to the factory to look, you know, at all the space we can save, how we can be creative, how even we can move some compute out of the clean rooms, just to shrink things as much as you can, got a huge impact on cost of the product at the end of the day.

那在大规模生产时，大概需要多少剂量？我们只关注黑色素瘤，一年要生产多少剂量才能满足需求？

And at scale, how many, roughly how many, for let's just focus on melanoma, how many doses would you need to produce in a given year to accomplish?

因为正在进行非临床研究，我们已经有了数千剂量的产量。

We've already got thousands of doses because of the non clinical studies that are ongoing.

位于马萨诸塞州马尔伯勒的设施将能生产数万剂量，随着技术不断改进，同一设施内的产量还会增加，之后我们可能还需要建几个其他设施。但如果你看黑色素瘤的发病率，数万剂量就足以轻松覆盖黑色素瘤市场了。

The facility will be able to make the one in Marlborough, Mass, tens of thousands of doses, and then as we keep improving the technology, that number is gonna go up in the same facility, and then we might need to build several other facilities, But if you look at the incidence of melanoma, if you're in tens of thousands of doses, you're gonna cover, you're gonna easily the melanoma market.

是的，我相信这一点。

Yeah, I can believe that.

你们有没有公开过关于生产成本和定价的想法，还是说这还在计划中？

Have you disclosed how you think about COGS and price, or is that something that

我们还没有公开，首先需要和默克的同事分享数据，然后一旦能分享数据，就要和支付方沟通，讨论带来的价值等等，但这些目前还没有讨论过。

We have not disclosed yet, we need first to disclose the data with our Merck colleagues, we need to engage with our payers once we can share the data with them in terms of what is the value being driven there and so on, but this hasn't been discussed yet.

所以也许一个可以关注的点就是个性化这个概念。

So maybe one place to focus is on this concept of personalization.

我相信你肯定听说过GitLab创始人的故事，他亲自下场研究自己的骨肉瘤。

I'm sure you've seen the story of the GitLab founder who went founder mode on his own osteosarcoma.

第一，未来那些像SIDS这样的患者会来找Moderna吗，还是说你觉得这种单例现象会自然发生，并且和你们并行存在？

Number one, do the future SIDS of the world come to Moderna, or is this end of one phenomena something that you think will just happen and exist in parallel?

我觉得他们大多数都会来找Moderna，因为这样会更简单、更安全。

So I think they will come most of them to Moderna because it will just going to be easier and safer.

因为你知道，生产注射类产品总是有污染的风险，如果你给病人注射的产品里哪怕只有一个细菌，都可能导致败血症。而且多步骤工艺中总有可能出错，但如果是在工业化、经过验证的GMP和FDA标准下生产，出错的概率就小得多。

Because as you know, making an injectable product always carry risk of contamination of a product, if you inject to somebody a product that has even one copy of bacteria, you might give the patient sepsis, then you always have a question of quality, because when you have a multi step process, a mistake can happen, and of course if it's industrialized and has been validated in terms of good manufacturing practice, of FDA standard, you have much less chance of this happening.

这就像生活中的各种工具一样，比如你在山洞里，没有刀具店，还得养家糊口，你会不会自己打第一把刀？

So it's a bit like every tools in life, which is, you know, do you make your first knife because there's no knife store and you are in a cave and you need to feed your family?

当然会，因为你得养家糊口，对吧？

Yes, of course you make your first knife because you have to feed your family, right?

但要是街角就有一家店卖高质量刀具，你肯定会把时间花在别的事情上。

But when you have a store making high quality knives down the street, you're gonna use your time to do something else.

所以我觉得这有点像同样的现象，就像任何技术一样，当你有工业规模的高质量产品时，你作为人类就会用你的时间去做别的事情，对吧？

So I think it's a bit of a same phenomenon, which is like in any technology, which is when you have industrial scale of high quality product, you use your time as a human to do something else through your time, right?

在那个世界里，监管机构在这里是怎么运作的？

And in that world, how does the regulatory apparatus function here?

换句话说，你之前提到，你和默克很快会准备提交监管申请。

So in other words, you mentioned earlier, you, along with Merck, will prepare a regulatory filing soon.

这里到底监管的是什么？

What gets regulated here?

因为每一剂都不一样，所以显然不是每一剂都获批。

Because every dose is different, so obviously every dose doesn't get approved.

显然，是合成mRNA的过程吗？

Is it obviously the process for synthesizing mRNA?

是算法吗？

Is it the algorithm?

还是整个系统的组合？

Is it a combination of the entire system?

帮我们理解一下，也让我们有个直观感受，你觉得未来这类个性化药物会怎么被监管？

Help us understand that and build intuition around how we think that these kinds of personalized medicines will be regulated in the future.

是的。

Yes.

好消息是，有先例可循。就像你提到的CAR T，CAR T当初获批的方式，和我们认为intismaran会获批的方式是一样的，都是作为工艺BLA，而不是产品BLA。

So the good news is there are precedents, as you mentioned, CAR T, CAR T was also approved in the same way as we believe intismaran will be, which is as a process BLA, not a product BLA.

你知道，Moderna已经有五个产品获批了，那些都是真正的产品审批。

So as you know, Moderna has five products approved, so that's really product approval.

但针对这个，从我们开始临床试验起，整个流程就是工艺IND，因为我们必须问FDA：我们能不能进入临床？

On this one, the whole process since we started in the clinic, the IND was a process IND, because we had to ask the FDA, can we go to the clinic?

你们觉得安全吗？

Do you think it's safe?

你们觉得我们对工艺有很好的控制，能安全地进行一期研究吗？

And do you think we have a good control of a process so we can do safely a phase one study?

所以几年前，我们为了进入临床，就已经进行过这样的讨论了。

So we already had that discussion just to go into the clinic years ago.

而且在我们启动每个三期试验之前，我们都需要开二期结束会议，和FDA达成一致，包括研究设计和生产方案。

And then before we started every phase three, we need to have end of phase two meeting, and agree with design of a study, the manufacturing protocol with the FDA.

这些讨论已经进行了好几年，所以我们并不是过去十年都没和FDA沟通过，然后突然跑到他们门口，告诉他们这是个新产品，他们会觉得莫名其妙。

So those discussions have happened for years, and so it's not like we have not talked to FDA for the last ten years, I'm gonna show up at their, you know, front door, you know, in a week or two, and tell them, this is a new product, and they're gonna like, why is this?

我们进行了很多讨论和互动，好几次在生产方面遇到技术问题，我们都主动要求额外开会，去请教指导，也向他们介绍我们的技术，分享我们学到的东西等等。

There's been a lot of discussion, a lot of engagement, several times we've had technical question on the manufacturing front, where we basically requested additional meetings to ask the guidance, to also educate them on the technology, what we've learned and so on.

所以其实已经有很多讨论了，而且审批整个流程的监管路径非常清晰。

So there's already been a lot of discussions, and there's a very clear regulatory pathway in terms of approving the entire process.

基本上，Jorge，FDA想知道的是，这个要求很合理，我自己为了家人也会这么要求，就是如果你拿到的是同一个样本，但血液里的量更多，最后从那个大黑箱里出来的产品是不是一样的？

Basically, Jorge, what the FDA wants to know, which is very legitimate, which I would want for my own family's sake obviously, which is if you get the same sample at the beginning, but you're more and the blood, do you get the same product make at the end of a big black box?

这就是我们首先要向自己证明的，然后用数据向FDA证明，确保整个流程的稳健性。

And that's what we have to demonstrate first to ourself, and then with the data to the FDA, so that we have really robustness of the whole process.

所以只要输入相同，我们就能得到相同的输出，给到患者，作为个体化药物。

So if we have the same input, we're gonna get the same output going to patient as an individualized medicine.

我们怎么考虑超越黑色素瘤，或者说你们怎么考虑超越黑色素瘤？

How do we think about moving beyond, or how do you all think about moving beyond melanoma?

这种方法是不是能适用于多种癌症？

Is this an approach that's going to be applicable to a broad range of cancers?

有没有哪些癌症更可能适用这种方法，而其他癌症就不太适用？

Are there cancers that are much more likely where this is going to be a viable option versus others?

还有，怎么说呢，我想用这个词。

And sort of what's your I'll use the word.

这里的雄心是什么，癌症疫苗能带来什么样的影响？

What's the ambition here for where cancer vaccines can have an So

雄心很大，因为我们相信我们已经证明了，至少对我们自己，然后我们希望向世界证明，总会有怀疑者，但这是常态，我们能够从头教育T细胞，这一点我们甚至在今年的ASCO上也展示了，我们取了治疗前和治疗后的黑色素瘤癌症患者的血液，用我们的技术，我们展示了，不仅仅是T细胞的扩增，而是从头，也就是新的T细胞被创造出来，识别我们在mRNA中编码的东西，这在治疗前并不存在于患者体内。

the ambition is pretty big because we believe we have demonstrated, at least to ourselves, and then we hope to the world, there's always will be skeptics, but that's always true, that we are able to create de novo education of T cell, and this we showed it even at ASCO this year, where we took the blood before treatment, after treatment of cancer patient melanoma with our technology, and we showed that don't think we have an expansion of the T cells, but we have de novo, so new T cells being created that recognize what we code in the mRNA, that was not in the patient's body before the treatment.

所以，在我看来，我们已经向自己和临床界证明了，Moderna的mRNA技术能够开发、教导免疫系统产生新的T细胞去攻击你的癌症。

So we already, in my book, have proven to ourselves and to the clinical community that Moderna's mRNA technology can develop, teach the immune system to develop new T cell to go attack your cancer.

基于这一点，基本上，我认为我们正在从黑色素瘤扩展，有三个不同的方向。

So based on that, they are basically, I would say three different vectors we're going after in term of expansion from melanoma.

这项研究，提醒大家，是招募了二期、三期和四期癌症患者，他们参加了那个三期研究。

So this study, to remind people, was a cancer patient in stage two, stage three, and stage four, that were enrolled in that Phase three study.

所以我们现在的做法是，先去所有KEYTRUDA有效的地方，因为就像我说的，我们认为PD-1的作用机制和现代的抗Tismarin是完全正交的，所以我们觉得这样能产生协同效应，提高患者的疗效。所以我们在肺癌上做三期临床，在肾癌、膀胱癌上做二期临床，我们有一大堆研究正在进行中，因为大家都知道KEYTRUDA在那里有效，它已经获批了。

So what we are doing is we are going first everywhere where KEYTRUDA works, because as I told you, we believe the mechanism of action of a PD-one and modern anti Tismarin are totally orthogonal, so we think these allow to have synergistic element and performance of efficacy for the patients, and so we are in Phase three for lung, we're in Phase two for kidney cancer, bladder cancer, so we have a whole slew of studies ongoing, where the world knows that ketoglutar works because ketoglutar has been approved there.

我们相信你会看到比单用KEYTRUDA有实质性的改善。

And we believe you're gonna see a material improvement versus ketoglutar alone.

在临床试验开始之前，不可能知道你会得到百分之五十的效果，就像我们在黑色素瘤二期看到的那样，还是百分之三十、百分之四十，或者别的数字，我们必须得做研究才能知道。

Before you run the clinical experiment, it's impossible to know are you gonna get fifty percent like we saw in the phase two of melanoma, or are going get thirty percent or forty percent or another number, we have to run the study.

所以这些研究很多都在进行中。

So these are, a lot are ongoing.

第二个方向是往疾病早期走，在检查点药物有效的地方。最好的例子是我们在2026年春天宣布，启动一项针对一期肺癌患者的三期研究，但用的是Intismaran，也就是Moderna的产品，作为单药治疗，不加检查点抑制剂。

The second vector is to go early in disease where checkpoints work, And the best example is we announced in the spring of twenty twenty six, starting a Phase three study for patients with stage one lung cancer, but as Intismaran, so Moderna's product, as a monotherapy without checkpoint.

哇。

Wow.

我们这么做是因为我们相信，在疾病早期，检查点药物因为副作用而不被使用。

And we are doing that because we believe when you go early in disease, checkpoints are not used because of the side effect that they bring.

嗯。

Mhmm.

因为如果你得了一期癌症，医学界认为监测你的癌症比给你用检查点抑制剂更合适，因为不是每个人都会有效，但每个人都会面临严重的终身副作用，比如自身免疫疾病。

Because if you have stage one cancer, the medical field thinks it's worth monitoring your cancer versus giving you a checkpoint, because not everybody's gonna respond, but everybody's gonna get pretty serious lifelong side effects, like autoimmune disease.

但是，如果能为患有肺癌一期、且容易通过X光发现的癌症患者，比如戒烟者这个最容易筛查的人群，定期用X光筛查，你就能从看不到癌症到看到癌症，然后给他们用mRNA药物呢？

But what if you could have an mRNA made for cancer patient that has lung disease stage one, which you can find easily with x-ray, let's say, in former smokers is the easiest target population, just screen regularly with x-ray your former smokers, and if you do it regularly, you're gonna go from not seeing the cancer to seeing the cancer.

然后想法是，你做手术，这是标准治疗，然后给患者用intismaran单药治疗，副作用类似疫苗，你可能累一天，但仅此而已，在癌症治疗中这种副作用算很不错的了，对吧？

And then the idea is, do you do a surgery, which is to the standard of care, and you give intismarine monotherapy, which the side effect is similar to a vaccine, you know, you might feel tired for a day, but that's it, so in cancer it's a pretty cool type of side effect, right?

这是我们在临床研究中的另一个方向，目前检查点抑制剂在这些领域还不可用。

And that's another approach we have in terms of clinical studies, where checkpoints are not available today.

第三个方向是检查点抑制剂无效的领域，当然风险最高，但因为作用机制不同于检查点，我们和默克认为有很好的科学依据去尝试。

The third vector is where checkpoints don't work, so of course it's where you have the highest risk, but because the mechanism of action is different from a checkpoint, we and Merck believe that there's a very good scientific rationale to go try.

我们现在尝试的两个领域是胰腺癌和胃癌，这两种癌症类型中，检查点抑制剂和KEYTRUDA都无效，过去的临床研究结果都是阴性的，但我们认为，因为作用机制不同于检查点，而且我们现在已经证明可以产生新的T细胞，所以这个实验值得做。

So two places we're trying right now is pancreas cancer, and also gastric cancer, those two cancer type checkpoints and ketirrhod do not work, the clinical studies have been run-in the past and they were negative, but we think because again, the mechanism of action is different from checkpoint, and we know now that we have approved that we can create de novo T cell, we think it's an experiment worth running.

如果我们看到好的信号，我们会考虑联合用药，你知道，就在昨天，Revolution Medicine刚批准了一种治疗胰腺癌的新药，利用KRAS突变。

If we have good signal, we'll think about combination, as you know, literally yesterday, you know, Revolution Medicine had a wonderful new medicine approved for pancreas cancer using the KRAS mutation.

如果能将那种药物和intismaran联合使用，它们的作用机制是互补的。

What if you could combine that medicine and intismaran, those are very autogonal mechanism of action.

对我来说，如果英特斯马兰有效，而且我们应该很快就能在儿科，抱歉，在胰腺癌单独治疗中看到结果，当然革命医药在胰腺癌生存率方面取得了巨大改善，那么这两种药联合使用在科学上说不通。

For me, it makes no scientific sense that if intismaran work, and we should know soon in pediatric, sorry, in pancreas cancer by itself, and of course the revolution medicine does great improvement of survival in pancreas cancer.

如果联合使用这两种药，我们相信应该会有益处，当然，你需要进行临床试验来看看效果有多大，但这就是我们接下来想做的事情。

If you combine those two things, we believe it should have benefit, again, you need to run the clinical experiment to see how much, but that's the type of things we're gonna want to do.

所以如果你想想英特斯马兰，现代医学将会与凯特卓联合使用，它会在疾病早期与凯特卓一起使用，而且它可能会在凯特卓无效的情况下与其他药物联合使用。

So if you think about intismaran, the modern medicine is gonna be used with a ketidra, it's gonna be used early in disease with ketidra, and it might be used in places where ketidra doesn't work, but with over agents.

这给了癌症患者及其家属很多理由，让他们对这个领域新型疗法的未来充满希望。

Well, gives a lot of reason for, I think, cancer patients and their families to have a lot of hope for the future of novel therapies in this field.

是的，而且在我们刚才说的基础上，

Yes, and on top of what we've

记住，这是英特斯马兰1.0版本。

just said, remember, this is intismaran 1.0.

所以我看到的东西非常强大，我一直在推动我们的团队跳出思维定式，进行大量分析，并利用人工智能来审视我们拥有的那组庞大数据，也就是我们能从临床试验中学到什么，以了解那些没有反应的患者的情况。

So what I saw is very powerful, and I'm really pushing our team to think really outside the box, and to do a lot of analysis, and to use AI to look at that gigantic set of data that we have, which is what are the things we can learn from the clinical studies to understand about the people that did not respond?

因为我认为你总是能从不起作用的事情中学到更多，而不是从起作用的事情中，所以我想专注于那百分之二十五年后没有反应的患者，这样我们就能理解他们为什么没有反应，以及我们能否在算法或技术上做出调整来帮助他们。

Because I think you always learn more from things that don't work, and things that work, so I want to obsess about the twenty percent of patients that do not respond five years out, so we can understand why they did not respond, and can we tweak anything in the algorithm or in the technology to be able to help them.

哇，这真是太了不起了。

Wow, that's remarkable.

最后我想说，看到你们把一个原本不是为疫情设计的技术平台，用来应对疫情，为成千上万的人研发出疫苗，然后在十年后又把它转回最初想治疗的疾病上，这真的很了不起。是的，

And I, just to wrap, I think it's remarkable to see how you were able to take a technology platform that originally wasn't built for a pandemic, pointed at a pandemic, create a vaccine for millions and millions and millions of people, and essentially pointed back towards treating some of the diseases that you had originally intended ten years later, as you Yeah,

这确实非常了不起。豪尔赫，最后我想说一个令人兴奋的消息，就是在今年年底之前，我们应该会公布我们的关键性研究结果，也就是针对患有罕见遗传性肝病的儿童进行的后期临床试验，这是我们技术平台的另一个应用方向。

that's very remarkable, and the piece that's gonna be exciting, Jorge, maybe to close, is before the end of the year, we should have our pivotal study, so late stage study for rare genetic disease, for kids that have rare genetic disease of the liver, so it's another vertical which we're pointing the technology.

一期和二期试验显示，孩子们用药三年后情况非常好，所以我们等着看最终数据。另外，在六月份我们的年度科学日上，我们宣布了mRNA平台的下一座要攀登的高峰，那就是自身免疫性疾病。因为你想，我们在传染病方面学到了很多，这些疾病是由免疫系统介导的，癌症方面我们刚刚也谈了很多关于免疫系统的话题，所以我们对免疫系统有了很多了解，我们认为我们有一些非常新颖的方法来治疗自身免疫性疾病的根本原因，而不是像制药行业一直做的那样只治疗症状。

The Phase one, two have shown kids three years on drugs doing fantastic, so we'll see when we get that data, and in June we had our annual science day, and we announced that the next mountain where we're pointing mRNA platform is autoimmune disease, because if you think about it, we've learned a lot for infectious disease, which are, you know, mediated by the immune system, cancer, we've just been talking a lot about immune system, so we learned so much about the immune system that we think we have some very novel approach on how to treat the root cause of autoimmune disease, not the symptoms, which is what the pharma industry has been doing.

当然，治疗症状对患者来说非常有帮助，可以提高生活质量，但那并不能解决根本问题。

It's of course very helpful to patient to treat the symptoms, so we can have a higher quality of life, but it doesn't treat the root cause.

我们觉得我们可能找到了利用免疫系统来治疗自身免疫性疾病根本原因的方法。

And we think we might have find ways to use the immune system to treat the root cause of autoimmune disease.

所以这个平台还有很多可以应用的方向。

So there's still a lot of ways to point the platform.

我们对未来充满期待。

So we're quite exciting about what's what's to come.

那这里的理论是不是说，会有个性化的自身免疫调节剂？这会是产品还是更像一种流程？

Would the theory in there be that you'd have personalized autoimmune modulators, would this be product or more process?

所以我们两个都在做。

So we're doing both.

春天我们展示的是一个对所有人都一样的产品，但我最兴奋的，还在实验室里的，是个性化的自身免疫治疗，就是直接针对那些在自身免疫疾病中攻击你身体的免疫细胞，让免疫系统的一部分去攻击那些失控的免疫细胞，这样就能消除免疫疾病的症状。

So what we presented in the spring was a product that would be the same for everybody, but what I'm the most excited about, which is in the lab still, is the ability to do individualized autoimmune treatment where you target directly to the immune cells that are attacking your body as self when you have an autoimmune disease, and to have basically part of the immune system going, attacking those immune cells that are part of order so that you are able to take the symptom of the immune disease out.

当然，现在还处于早期阶段，但这就是我今天感到兴奋的事情。

Again, it's still early days, but that's what I'm excited about today.

好，从传染病到癌症，再到最终的自身免疫疾病，我们很希望你能再次来到播客，录制第三集，完成三部曲，当你

Well, going from infectious disease to cancer to eventually autoimmune disease, we would love to have you back on the podcast to film episode three and complete the trilogy when you're

准备好了。

ready.

太好了。

Wonderful.

Stéphane，非常感谢你参加a16z播客。

Staphane, thank you so much for joining us on the a 16 z podcast.

一如既往，见到你真的很高兴。

It's always as always, it's great to see you.

恭喜你。

And congratulations.

见到你。

To see you.

感谢收听本期a16z播客。

Thanks for listening to this episode of the a16z podcast.

如果你喜欢这期节目，记得点赞、评论、订阅，给我们评分或留言，并分享给你的朋友和家人。

If you like this episode, be sure to like, comment, subscribe, leave us a rating or a review, and share it with your friends and family.

更多节目，请前往YouTube、Apple Podcast和Spotify。

For more episodes, go to YouTube, Apple Podcast, and Spotify.

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Follow us on x at a16z, and subscribe to our Substack at a16z.substack.com.

再次感谢收听，我们下期再见。

Thanks again for listening, and I'll see you in the next episode.

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