Agenus Inc (AGEN) 2025 Q2 法說會逐字稿

Good afternoon. My name is Stefanie Nacar, and I'm the Chief Communications Officer here at Agenus. Welcome to our webcast where we'll be discussing topics related to patient care, their experiences, their needs, and the work that's required to bring new options to those impacted by cancer, specifically colorectal cancer.

午安.我叫 Stefanie Nacar，是 Agenus 的首席通訊長。歡迎收聽我們的網路廣播，我們將討論與患者護理、他們的經歷、他們的需求以及為受癌症（特別是結直腸癌）影響的人帶來新選擇所需的工作相關的話題。

Before we begin, a quick reminder that today's discussion includes forward-looking statements. These are subject to risks and uncertainties that could make actual results different. Please be sure to check our website for our SEC filings.

在我們開始之前，請快速提醒一下，今天的討論包括前瞻性陳述。這些都存在風險和不確定性，可能會導致實際結果有所不同。請務必造訪我們的網站以了解我們向美國證券交易委員會 (SEC) 提交的文件。

Joining us today are distinguished leaders from industry and medicine, each bringing deep expertise and shared commitment to advancing patient care. From Agenus, we will be joined with our host for today, Dr. Garo Armen, our Chairman and CEO; as well as Dr. Richard Goldberg, our Chief Development Officer; and Jennifer Buell, Chairman, Executive Counsel at Agenus and President and CEO of MiNK Therapeutics will be joining us.

今天與我們一起參加的是來自工業界和醫學界的傑出領袖，他們各自帶來了深厚的專業知識並共同致力於促進患者護理。來自 Agenus 的今天，我們將與主持人、董事長兼首席執行官 Garo Armen 博士以及首席開發官 Richard Goldberg 博士一起參加；Agenus 董事長、執行法律顧問兼 MiNK Therapeutics 總裁兼首席執行官 Jennifer Buell 也將加入我們。

We'll also have members of our executive team join us for our question-and-answer session: Robin Taylor, our Chief Commercial Officer; as well as Dr. Steven O'Day, our Chief Medical Officer. And I'm also excited to share that we'll have external thought leaders, Dr. Nicholas DeVito, the Assistant Professor of Medical Oncology at Duke University; as well as Dr. Chris O'Callaghan, the Senior Investigator from the Canadian Cancer Trials Group.

我們的執行團隊成員也將參加問答環節：我們的首席商務官 Robin Taylor；以及我們的首席醫療官 Steven O'Day 博士。我也很高興地告訴大家，我們將邀請外部思想領袖，杜克大學醫學腫瘤學助理教授 Nicholas DeVito 博士；以及加拿大癌症試驗組的高級研究員 Chris O'Callaghan 博士。

For the agenda, we'll specifically be discussing the growing colorectal cancer crisis, the spotlight on emerging data from BOT/BAL immunotherapy program and hear firsthand perspectives from leading clinicians. We'll also examine the systemic regulatory challenges that continue to delay access to potentially life-extending treatments. And finally, we'll answer your questions. (Event Instructions)

對於議程，我們將特別討論日益嚴重的結直腸癌危機、關注 BOT/BAL 免疫治療計劃的新興數據，並聽取領先臨床醫生的第一手觀點。我們還將研究持續延遲獲得可能延長生命的治療方法的系統性監管挑戰。最後，我們將回答您的問題。（活動須知）

And with that, I'll turn it over to Garo to start our webcast for today. Garo?

現在，我將把時間交給 Garo，開始我們今天的網路直播。加羅？

Thank you, Stefanie, and hello to all of you, patients, advocates, investors, truth seekers. I'm Garo Armen. At today's stakeholder briefing, we will cut through the noise and talk about what really matters to everyone, particularly to cancer patients.

謝謝你，史蒂芬妮，也向你們所有人問好，病人、倡議者、投資者、真理追求者。我是 Garo Armen。在今天的利害關係人簡報會上，我們將消除乾擾，討論對每個人，特別是癌症患者真正重要的事情。

Why are we here? Because colorectal cancer is not just another disease, it's a crisis, close to 900,000 deaths a year worldwide. In the US, it is on track to be the number one cancer killer for people under 50 by 2030. That's around the corner. And that's insane. For metastatic patients who failed first and second line, today's approved drugs give you 6 to 11 months. That's it, 6 to 11 months. These aren't numbers, they're lives, families broken, future stolen.

我們為什麼在這裡？因為大腸直腸癌不僅是一種疾病，更是一場危機，全球每年有近 90 萬人死於大腸癌。在美國，到2030年，它將成為50歲以下族群的頭號癌症殺手。就在附近。這太瘋狂了。對於第一線和第二線治療失敗的轉移性患者，目前核准的藥物可以提供 6 至 11 個月的治療時間。就這樣，6到11個月。這些不是數字，而是生命、破碎的家庭、被奪走的未來。

And here's the truth. The system is failing them. The current paradigm clings to paperwork. It rewards drugs that give weeks, but BAL is shown patients alive for as long as four years with no disease, living their lives with quality intact without toxic chemo, without mutilating surgeries in some cases.

事實是這樣的。系統讓他們失望了。目前的模式仍然依賴文書工作。它對那些只起效數週的藥物給予獎勵，但 BAL 療法卻可以讓患者存活長達四年且沒有疾病，無需毒性化療，甚至在某些情況下無需進行毀容性手術，就能過上高質量的生活。

Let's talk about who this disease is hitting, younger adults, even children. We had a compassionate use request for an eight-year-old child with metastatic colon cancer. That was unheard of. It was denied because of bureaucracy. Think about that. An eight-year-old and look around us, 20s, 30s, 40s, people with careers, young families with kids of their own, instead of raising families, they're thrown into chemoradiation, surgeries, colostomy bags, infertility, bankruptcies.

讓我們來談談這種疾病的受害者是誰，年輕人，甚至是兒童。我們收到了針對一名患有轉移性結腸癌的八歲兒童的同情用藥請求。這是聞所未聞的。由於官僚主義，該申請被拒絕。想一想。看看我們周圍，20 多歲、30 多歲、40 多歲的人，都有自己的事業，有孩子的年輕家庭，他們沒有養育孩子，而是被迫接受放化療、手術、結腸造口袋、不孕不育和破產。

Now I want to show you a story millions have seen. Andy, please play the video of Tanner.

現在我想向你們展示一個數百萬人都看到的故事。安迪，請播放坦納的影片。

(video playing)

（影片播放）

Wow, this was Tanner Martin, who died in June at the age of 30. Millions followed his plight online, brutal treatments, endless suffering, as you saw, and now a wife and a daughter left behind. That's the potential of delays. Chadwick Boseman, James Van Der Beek, famous names, yes, but they are just the tip of the iceberg. This disease is everywhere.

哇，這是坦納馬丁 (Tanner Martin)，他於 6 月去世，享年 30 歲。數百萬人在網路上關注他的遭遇，如你所見，他遭受殘酷的對待，承受著無盡的痛苦，現在他還留下了妻子和女兒。這就是延遲的可能性。查德維克·博斯曼、詹姆斯·范德比克，是的，這些都是著名的名字，但他們只是冰山一角。這種疾病隨處可見。

You can see it. You read it in papers all the time. So common that they lowered the screening age from 50 to 45, still not enough. CRC is exploding as we speak. Why don't we drop the screening age to 40 or 35 or even 20? Would that be enough to end the current epidemic of CRC? Because we lack effective treatments today, effective chemo-free treatments today, people will still be suffering with no viable solution, no matter how early diagnosis is.

你可以看到它。你經常在報紙上讀到它。這種現象十分常見，因此他們將篩檢年齡從 50 歲降低到 45 歲，但這還不夠。正如我們所說，CRC 正在爆炸式增長。為什麼我們不將篩檢年齡降低到 40 歲或 35 歲甚至 20 歲？這足以結束目前的 CRC 流行嗎？由於我們目前缺乏有效的治療方法，缺乏有效的非化療治療方法，因此無論診斷多麼早期，人們仍然會遭受痛苦而沒有可行的解決方案。

At Agenus, we don't settle for a few more months. We have our eyes on much bigger outcomes. We have the fortitude to fight for cures, patients alive for years and living better and ultimately, all patients cured. Ultimately, we're not quite there yet. No more bags, no more infertility, no more mutilating surgeries, no more toxic treatments that rub patients of their quality of life. Patients don't live on bureaucratic time. They live on cancer time. We need all recognizable facts that move this to the highest sense of urgency.

在 Agenus，我們不會滿足於短短幾個月的時間。我們著眼於更大的成果。我們有毅力為治癒疾病而奮鬥，讓患者活得更久、生活得更好，最終讓所有患者都得到治癒。最終，我們還沒有到達那裡。不再有袋子，不再有不孕不育，不再有痛苦的手術，不再有影響病人生活品質的毒性治療。病人的生活並不依賴官僚的時間。他們靠癌症時間生活。我們需要所有可識別的事實來使這個問題達到最高緊迫性。

Now here are the other side of the story. What happens when we unleash the immune system? Andy, if you could please pull the breakthrough IO therapy slide.

現在讓我們來看看故事的另一面。當我們釋放免疫系統時會發生什麼事？安迪，請你放出突破性的骨內治療幻燈片。

When strictly regulatory-minded people may call these slides anecdotes. Let's be clear that these are not anecdotes, these are real people, real patients. We know some of them. These are real families. We have treated over 1,200 patients across colorectal, breast sarcoma, lung melanoma, ovarian cancers. These outcomes are simply representative patients, the ones that you see on these slides. To be clear, not all patients respond, and most side effects are transient, and they don't last.

當嚴格監管的人可能將這些幻燈片稱為軼事時。我們要明確一點，這些都不是軼事，而是真實的人、真實的病人。我們知道其中一些。這些都是真正的家庭。我們已經治療了超過 1,200 名患有大腸癌、乳癌、肺黑色素瘤和卵巢癌的患者。這些結果只是代表性患者，就是您在這些投影片上看到的那些。需要明確的是，並非所有患者都有反應，而且大多數副作用都是暫時的，不會持續。

As we go from late-stage patients that have failed everything, where the response rates are 20% plus or minus, but we go to earlier-stage patients like Stage III cancers, responses go up dramatically, as you see in these pictures, the outcomes are black and white, and they're not anecdotes, as I said. They are real patients. Take a look, one dose of BOT and two doses of BAL, tumor is gone in seven weeks, and the patient kept her or his quality of life. That's not chemo. That's the immune system doing its job. It is the miracle of the immune system, an absolutely miracle.

對於所有療法都失敗的晚期患者，其反應率為 20% 左右，而對於 III 期癌症等早期患者，反應率急劇上升，正如您在這些圖片中看到的那樣，結果是黑白分明的，正如我所說的，它們不是軼事。他們是真正的病人。看一下，一劑 BOT 和兩劑 BAL，腫瘤在七週內消失，患者的生活品質保持不變。那不是化療。這就是免疫系統在發揮作用。這是免疫系統的奇蹟，絕對的奇蹟。

That's why we built BOT/BAL with that in mind. That's why we're here to show what happens when you prime and unleash the immune system. And today, you'll hear from people who know this fight inside out: advocates, physicians, patients and my colleagues at Agenus who push the science forward every day.

這就是我們建造 BOT/BAL 的原因。這就是為什麼我們在這裡展示當你啟動和釋放免疫系統時會發生什麼。今天，您將聽到那些對這場鬥爭瞭如指掌的人的聲音：倡導者、醫生、患者以及我在 Agenus 的同事，他們每天都在推動科學進步。

One last point before I hand it off. If you keep the current paradigm, we're not punishing companies like Agenus, we're punishing patients, and that should never be the role of any health care system. The good news is that we now have an FDA commissioner in Dr. Makary, who has laid out a reformist agenda. We hope to work with him and with his colleagues and reform-minded people at the FDA and outside of the FDA to align regulatory science with medical science.

在我結束討論之前，還有最後一點。如果保持目前的模式，我們就不會懲罰像 Agenus 這樣的公司，而是懲罰患者，而這絕不應該是任何醫療保健系統的職責。好消息是，我們現在有一位 FDA 專員 Makary 博士，他制定了一項改革議程。我們希望與他以及 FDA 內部和外部的同事和具有改革意識的人士合作，使監管科學與醫學科學保持一致。

We have an opportunity today to do the right thing for patients because the truth is science has moved so fast and regulation has kept poorly with pace of rapidly moving science. And that gap is costing lives. And that's a very sad thing, as you saw with Tanner's video and Tanner's plight.

今天我們有機會為患者做正確的事情，因為事實是科學發展如此之快，而監管卻跟不上快速發展的科學步伐。這種差距正在造成生命損失。正如你在坦納的影片和坦納的困境中看到的那樣，這是一件非常悲傷的事情。

So now let me introduce Dr. Richard Goldberg. Let me bring you in, Richard, you've treated thousands of colorectal patients over the years. You know the toll of this disease and how it really punishes patients and our limited options. So my first question to you is what's the real cost to patients of waiting on bureaucracy, while a therapy like BOT/BAL are sitting right in front of us?

現在讓我來介紹理查‧戈德堡博士。讓我帶你進來吧，理查德，這些年來你已經治療了數千名結直腸患者。您知道這種疾病的危害以及它如何真正懲罰患者和我們有限的選擇。因此，我要問您的第一個問題是，當 BOT/BAL 等療法就在我們面前時，患者在官僚主義中等待的真正成本是多少？

Thanks, Garo. So over my 40 years in practice, just like the epidemiologists who track trends in cancer incidents, I've seen the heartbreaking rise in the number of young people like Tanner with colorectal cancer. I've also both observed and contributed to the standard of care changes that we've seen in colorectal cancer.

謝謝，Garo。因此，在我 40 年的從業經歷中，就像追蹤癌症事件趨勢的流行病學家一樣，我看到像坦納一樣患有結直腸癌的年輕人數量令人心碎地上升。我也觀察並促進了大腸直腸癌治療標準的改變。

When I began, we had one drug. We then went to multiple chemotherapy drugs. We then developed targeted therapies that apply to some patients with colorectal cancer. And most recently, the immuno-oncology revolution has changed the lay of the land and the treatment of colon cancer. Today's immuno-oncology, or IO, effects can be seen in patients with immunologically hot tumors.

當我開始工作時，我們只有一種藥物。然後我們開始嘗試多種化療藥物。然後我們開發了適用於某些大腸直腸癌患者的標靶治療方法。最近，免疫腫瘤學革命改變了結腸癌的模式和治療。當今的免疫腫瘤學（IO）效應可以在免疫熱腫瘤患者身上看到。

In the colorectal cancer population, this is about 5% to 15% of all patients. For the other 85% to 95% of patients, those with cold tumors, immunotherapies have been ineffective to date and no approaches have yet been FDA approved. There's a clear unmet need here. Patients are clamoring for an IO approach that will bring the benefits seen in the few CRC cases with the hot tumors to the majority of cases with the cold tumors. And that's what Agenus is trying to do with BOT/BAL.

在大腸直腸癌族群中，這一比例約佔所有患者的 5% 至 15%。對於另外 85% 至 95% 的冷腫瘤患者，免疫療法迄今無效，且尚未有任何療法獲得 FDA 批准。這裡顯然存在著未滿足的需求。患者迫切需要一種能夠將少數熱腫瘤 CRC 病例所見的益處帶到大多數冷腫瘤病例中的IO方法。這就是 Agenus 試圖透過 BOT/BAL 所做的事情。

Thank you. So Richard, if you look at the current landscape, we talked about younger and younger people coming down with this disease. And I know I'm asking you a question, which is impossible to answer. But why do you think this is? Why do you think we're seeing an explosion of CRC in the young people today?

謝謝。理查德，如果你看看現在的狀況，你會發現罹患這種疾病的年輕人越來越少。我知道我問了你一個無法回答的問題。但您認為這是為什麼呢？您認為為什麼我們今天看到年輕人中 CRC 激增？

Well, the answer to that question is the subject of intensive research, but we really don't know. We think that it may be childhood exposures to potential things like high fat, low-fiber diets. It may be things were breathing in the air or drinking in the water, but we really don't know. And the advances that we're making in colorectal cancer apply to all patients, fortunately, whether they're young and old. And therefore, the research that we're doing can help to combat this epidemic.

嗯，這個問題的答案是深入研究的主題，但我們真的不知道。我們認為這可能是由於兒童時期接觸了高脂肪、低纖維飲食等潛在因素所造成的。可能是有東西在呼吸空氣或喝水，但我們真的不知道。幸運的是，我們在結直腸癌治療方面取得的進展適用於所有患者，無論年齡大小。因此，我們正在進行的研究可以幫助對抗這場流行病。

And if you look at the composition of responses that we have seen, first of all, your decision to become our Chief Development Officer, that was a big leap for you, of course. And what was the tipping point of that decision? Because I know that before you joined us, you immersed yourself with a lot of data. You cut it in all ways and what happened that really tipped you off to something that is worthwhile pursuing here?

如果你看一下我們所看到的回應的構成，首先，你決定成為我們的首席發展官，這對你來說當然是一個巨大的飛躍。這個決定的轉捩點是什麼？因為我知道，在您加入我們之前，您已經沉浸在大量的數據中。您從各個方面都做到了這一點，那麼究竟發生了什麼事情讓您真正意識到這是值得追求的事情呢？

Well, for one thing, I joined the Board of colorectal cancer advocacy group called Fight Colorectal Cancer and had the opportunity to interact with patients differently, not as their doctor, but as their advocate. And that made clear to me the unmet need we're seeing for those 85% of patients with cold tumors.

首先，我加入了大腸直腸癌倡導組織「對抗大腸直腸癌」的委員會，有機會以不同的方式與患者互動，不是作為他們的醫生，而是作為他們的倡導者。這讓我清楚地認識到，85% 的冷腫瘤患者存在尚未滿足的需求。

Then I had the opportunity to evaluate many of the new drugs and technologies that are in development across the spectrum of the biomedical community and had an opportunity to see what was happening, not just with BOT/BAL, but with other companies who are advancing other drugs. And the most promising combination in my mind was what I was seeing with BOT/BAL. And when I got inside the company, had an opportunity to look under the hood my conviction that this is a strong combination that will ultimately save lives, not just of colorectal cancer patients but of many kinds of cancer patients. I made the decision to put away my fly rod and go back to work.

然後，我有機會評估生物醫學界正在開發的許多新藥和新技術，並有機會了解正在發生的事情，不僅是 BOT/BAL，還有其他正在推進其他藥物的公司。而我心目中最有希望的組合就是 BOT/BAL 的組合。當我進入公司，有機會深入了解時，我堅信這是一個強大的組合，最終將挽救生命，不僅是結直腸癌患者，而且是許多類型癌症患者的生命。我決定收起我的飛釣竿並回去工作。

Well, we're delighted to have you with us because I cannot envision an expert in the field that has seen it all, has done drug development, and can objectively evaluate the plight of the patients and the benefit that our combination BOT/BAL is bringing to them. But on another note, if you look at, for example, the field that we're in, and it's confusing because as more scientific developments take hold, confusion really spreads more. We have hot cancers and cold cancers. And within the label of hot and cold cancers, we have cancers like colorectal cancer that are largely cold. But there's a segment of them that behave differently.

好吧，我們很高興您能加入我們，因為我無法想像該領域的專家能夠見識過一切，做過藥物開發，並且能夠客觀地評估患者的困境以及我們的組合 BOT/BAL 為他們帶來的好處。但另一方面，如果你看看我們所處的領域，你會發現它很令人困惑，因為隨著越來越多的科學發展，混亂確實會蔓延得更加廣泛。我們有熱癌症和冷癌症。在熱癌症和冷癌症的標籤中，像大腸直腸癌這樣的癌症大多屬於冷癌症。但其中一部分人的行為有所不同。

For example, we call it MSI-high, which is some of the so-called hotter versions of colorectal cancer. But unfortunately, it affects only about 5% of the colorectal cancer patients. And then we have the MSS patients, which is what BOT/BAL is going after.

例如我們叫它MSI-high，也就是一些所謂的比較熱門的大腸癌版本。但不幸的是，它只影響約5％的大腸直腸癌患者。然後我們有 MSS 患者，這就是 BOT/BAL 所針對的。

Now there's been confusion about MSI-high because we've seen drugs like PD-1 drugs or PD-L1s that have shown very high efficacy as much as 100%. And in fact, you were remarking in a different conversation that we had yesterday about how these drugs are changing the paradigm, the treatment paradigm. And so how do you extrapolate from that, simplify some of these definitions and show what BOT/BAL is doing in a portion of the cancers that are not being touched by the first-generation IO products?

現在人們對 MSI-high 感到困惑，因為我們已經看到 PD-1 藥物或 PD-L1 等藥物顯示出高達 100% 的非常高的療效。事實上，您在我們昨天的另一場談話中談到了這些藥物如何改變範式、治療範式。那麼，您如何從中推斷、簡化其中一些定義並展示 BOT/BAL 在第一代 IO 產品未涉及的部分癌症中發揮的作用？

Well, so BOT is not just another drug targeting CTLA-4. It's been engineered for deeper immune activation and also to avoid side effects. So it's a second-generation CTLA-4. And we studied it, as you mentioned, across more than 1,200 patients with nine different tumor types, including colorectal cancer. And recently, we updated our data from our Phase I study of 123 patients with MSS colorectal cancer.

那麼，BOT 不僅僅是另一種針對 CTLA-4 的藥物。它經過精心設計，可以更深層地激活免疫力，同時避免副作用。所以它是第二代 CTLA-4。正如您所說，我們對 1,200 多名患有九種不同腫瘤類型（包括結直腸癌）的患者進行了研究。最近，我們更新了 123 名 MSS 大腸直腸癌患者的 I 期研究數據。

And these are late-stage patients. They've either had three lines of therapy or four lines of therapy. And in the cases of those with four lines of therapy, there's nothing more to do other than best supportive care. And despite that, in this patient population, we're seeing a 42% two-year survival rate, which is really unprecedented, seeing a median overall survival and the data are still maturing of 21 months. And this is way more than the 10 to 14 months that has been the best case reported in the current standard of care regimens.

這些都是晚期患者。他們要么接受過三線療法，要么接受過四線療法。對於接受過四種療法的患者，除了最佳支持性治療外，沒有其他方法了。儘管如此，在這群患者中，我們看到了 42% 的兩年存活率，這確實是前所未有的，中位總存活期為 21 個月，而且數據仍在不斷成熟。這遠遠超過了目前標準治療方案所報告的最佳治療時間 10 至 14 個月。

And then we also are seeing manageable and largely reversible side effects in contrast to the profiles that we see with many chemotherapy regimens. Many of these patients, even though they are years past getting oxaliplatin still have the sensory neuropathy that's the scourge of treatment with that drug. And it saves lives in some cases, it extends lives in others, but you're always reminded of it if you have that side effect of neuropathy. And even though we're going for approval first in late-line therapy, the application that seems even more exciting to me is the application in early-stage cancers.

而且，與許多化療方案相比，我們也看到了可控且很大程度上可逆的副作用。許多患者即使已經接受奧沙利鉑治療多年，但仍患有感覺神經病變，這是該藥物治療的弊端。在某些情況下它可以挽救生命，在某些情況下它可以延長生命，但是如果您有神經病變的副作用，您就會一直想起它。儘管我們首先尋求的是晚期治療的批准，但對我來說更令人興奮的應用是早期癌症的應用。

So when you give a medical treatment before surgery, we call that neoadjuvant therapy. And we have three studies, the NEST, UNICORN, and NEOASIS studies where we're treating early-stage cancers, not just early stage colon and rectal cancers, but many different kinds of cancers, including breast cancer and seeing that in patients with robust immune systems that haven't been damaged by exposure to cytotoxic drugs that the responses are even more dramatic.

因此，當您在手術前進行醫療時，我們稱之為新輔助治療。我們進行了三項研究，即 NEST、UNICORN 和 NEOASIS，在這些研究中，我們治療的是早期癌症，不僅是早期結腸癌和直腸癌，還包括許多不同類型的癌症，包括乳腺癌，並且發現免疫系統強大且未因接觸細胞毒性藥物而受損的患者的反應更為顯著。

Just like you saw in that patient's colonoscopy where the colon cancer disappeared with just three treatments. So the preliminary data that we're seeing with BOT/BAL, everywhere we look, it's active. And we hope that that will really translate into lives saved.

就像您在那位患者的大腸鏡檢查中看到的那樣，僅經過三次治療，結腸癌就消失了。因此，根據我們透過 BOT/BAL 看到的初步數據，無論我們看向何處，它都是活躍的。我們希望這能真正轉化為拯救生命。

So on that note, Rich, if we look at the landscape, and you remarked about the broader activity of BOT/BAL. And given the fact that we've treated over 1,200 patients, we have a pretty good sense of the toxicity profile and the transient nature of some of the toxicities that we're seeing. And jumping ahead, because you've worked in a regulatory environment pretty much all your career, what would be the risk of allowing BOT/BAL access by patients and doctors on a wider scale, more notably in a commercial setting, quicker rather than later because as you remark, if we do randomized trials in every single indication, patients will wait a long time for access, wide access?

因此，Rich，就這一點而言，如果我們看一下形勢，您會注意到 BOT/BAL 的更廣泛的活動。鑑於我們已經治療了超過 1,200 名患者，我們對毒性特徵以及我們所看到的一些毒性的短暫性有相當好的了解。再說下去，因為您幾乎整個職業生涯都在監管環境中工作，那麼允許患者和醫生更廣泛地使用 BOT/BAL 會有什麼風險呢？尤其是在商業環境中，越快越好，因為正如您所說，如果我們對每一個適應症都進行隨機試驗，患者將等待很長時間才能獲得廣泛的使用權？

So why do you think there is this hang up? And why also do you think or how do you think rather, can the regulatory system evolve so that the precedent setting blockages are not going to be the drivers of future decision making?

那你認為為什麼會出現這種問題呢？為什麼您會這樣認為，或者您如何認為，監管體系能否發展，以便先例障礙不會成為未來決策的驅動因素？

Well, that's a complicated question. Even when there are early indications of dramatic tumor shrinkage such as we're seeing with BOT/BAL, the regulatory environment is such that the FDA still requires proponents of new approaches to perform large Phase III trials with hundreds of patients, that randomize patients between a new therapy and the standard of care. Given the efficacy signals and the toxicity differences that we're seeing with the new IO approaches, patients considering these studies often hesitate before accepting randomization.

嗯，這是一個複雜的問題。即使有早期跡象表明腫瘤會急劇縮小，例如我們看到的 BOT/BAL，但監管環境是這樣的，FDA 仍然要求新方法的支持者對數百名患者進行大規模 III 期試驗，將患者隨機分配到新療法和標準治療之間。鑑於我們在新的 IO 方法中看到的療效訊號和毒性差異，考慮這些研究的患者在接受隨機化之前常常會猶豫。

Today, they hope for more time, for moderate time off treatment, for meaningful extension of their life expectancies, and they even dare to hope that they can be cured. Our ambitions and their hope to accomplish this with IO regimens without the side effects of traditional chemotherapy-based regimens is why BOT/BAL were developed and why we're moving forward with those drugs.

如今，他們希望有更多的時間，希望適度停止治療，希望有意義地延長他們的壽命，他們甚至敢於希望他們能夠被治癒。我們的野心和他們的希望是透過IO方案實現這一目標，而沒有傳統化療方案的副作用，這就是開發BOT/BAL的原因，也是我們推進這些藥物的原因。

When we had our last meeting with the FDA two months ago, they told us that you had to do a Phase III trial. And fortunately, as you'll hear from our colleagues from the Canadian Clinical Trials Group, they had approached us with an idea for a study for Phase III trial that the FDA accepted as necessary to show the efficacy of our drugs in the late-line setting.

兩個月前，當我們與 FDA 舉行最後一次會議時，他們告訴我們必須進行 III 期試驗。幸運的是，正如您從加拿大臨床試驗組的同事那裡聽到的那樣，他們向我們提出了進行 III 期試驗的想法，FDA 認為有必要進行這項試驗，以證明我們的藥物在後期治療中的療效。

When we met with them, we did present the strong activity signals that we presented at many international meetings. We informed the FDA team about the high level of enthusiasm among both oncologists and patients with experience using BOT/BAL, and their desire to get the combination into the clinics as soon as possible. Since then, we and our academic collaborators keep asking ourselves why the FDA isn't open to accelerating the approval, allowing us to save lives that will be lost in the interim.

當我們與他們會面時，我們確實表現出了在許多國際會議上所表現出的強烈活動訊號。我們向 FDA 團隊通報了腫瘤學家和有使用 BOT/BAL 經驗的患者的高度熱情，以及他們希望盡快將這種組合引入臨床的情況。從那時起，我們和我們的學術合作夥伴就不斷問自己，為什麼 FDA 不願意加快審批，讓我們挽救在此期間失去的生命。

Science is moving fast. Regulatory processes need to move at the same pace as the science. We believe that the regulators need to reflect upon and update the approval process.

科學正在快速發展。監管過程需要與科學同步發展。我們認為監管部門需要反思和更新審批流程。

Thank you. And we'll come back to you. But on this very important note, let's go to Dr. DeVito.

謝謝。我們會再回來找你。但在這個非常重要的問題上，我們來聽聽德維托博士的意見。

Dr. DeVito, your background as an immunologist turned oncologist is fascinating because that's not the usual progression that we see. How has this impacted your research and shaped the way you think about treatments and your patients? Just to start.

DeVito 博士，您從免疫學家轉行成為腫瘤學家的背景非常吸引人，因為這不是我們通常看到的進展。這對您的研究有何影響？又如何影響您對治療和病人的看法？剛開始。

That's a great question. So as Garo mentioned, I came into oncology from a background of immunology and an interest of cancer vaccines, which are obviously limited by immunosuppressive mechanisms that compromise their efficacy and has led to a lot of unfortunate failures. But I have always -- I have viewed the mere existence of a cancer inside someone's body as an immune failure, as immune surveillance that didn't happen.

這是一個很好的問題。正如 Garo 所提到的，我從事腫瘤學研究的背景是免疫學，並且對癌症疫苗感興趣，而癌症疫苗顯然受到免疫抑制機制的限制，從而損害了其功效，並導致了許多不幸的失敗。但我一直認為，如果人體內有癌症，就表示免疫功能失敗，免疫監視並沒有發揮作用。

I think when you reframe oncology like that and you come into this with that kind of mindset, you start to think about ways that you could alleviate immune suppression and develop immune elimination of tumors rather than treating them almost like an infection with antibiotics -- like antibiotics with chemotherapy or playing whack-a-mole with targeted therapies that inevitably lead to resistance, where you get these nice durable responses and tolerable therapies. And I think there's a real appeal to patients as well with immunotherapy is what I've always seen in clinic.

我認為，當你以這種方式重新建構腫瘤學，並以這樣的心態進入這個領域時，你就會開始思考如何減輕免疫抑制並發展免疫消除腫瘤，而不是像用抗生素治療感染一樣治療它們——比如用化療聯合抗生素或用靶向治療玩打地鼠遊戲，這不可避免地會導致耐藥性，而你會得到良好持久的反應和可耐受的治療。我認為免疫療法對患者也具有真正的吸引力，這也是我在臨床上一直看到的。

It is really resting back control by saying this is my immune system attacking the cancer. This isn't me surviving chemotherapy or something like that. And I think that's extremely meaningful to people. So I have found a lot of fulfillment in coming into this field as an immunologist and feel that it aligns really well with what patients want.

透過說這是我的免疫系統在攻擊癌症，這其實就是恢復控制。這不是我經受化療或類似情況的經驗。我認為這對人們來說非常有意義。因此，作為一名免疫學家進入這個領域讓我感到非常滿足，並且覺得它與患者的需求非常吻合。

And so you embarked on a very courageous, I should say, unorthodox trial because the standard way of thinking about things is that you have a standard of care, no matter how poorly that standard of care is performing, you need to use that as the first line of therapy before you can try something else. And of course, as we adhere to that practice, patients are getting sicker and sicker and sicker. And the more sick they get, the more difficult treatment becomes for them.

因此，你開始了一項非常勇敢的，應該說是非傳統的試驗，因為標準的思維方式是，你有一個護理標準，無論該護理標準的效果有多差，你都需要將其作為第一線治療方法，然後才能嘗試其他方法。當然，隨著我們堅持這種做法，患者的病情會越來越嚴重。他們的病情越嚴重，治療就越困難。

So can you tell us a little bit about your trial, and we don't want to jeopardize your ability to publish and present the data. But perhaps you can give some representative examples of patients as to why they decided to enroll in this trial and what --

那麼，您能否向我們介紹一下您的試驗情況，我們不想危及您發布和展示數據的能力。但也許你可以舉一些有代表性的患者例子，說明他們為什麼決定參加這項試驗，以及--

Happy to do it.

很開心能做到。

Yes. Thank you.

是的。謝謝。

Yes. So this is referring to BBOpCo or botensilimab and balstilimab optimization in colorectal cancer. And is a first-line trial in microsatellite stable colorectal cancer patients without liver, bone or brain metastasis, which we believe to be immunosuppressive sites that we still need to learn more about until we can overcome in the first line. But it's first-line BOT/BAL, no chemotherapy in Stage IV MSS CRC. We've almost completely recruited the trial in a year, which I think explains what the patient desire is and it speaks for itself.

是的。這指的是 BBOpCo 或 botensilimab 和 balstilimab 在結直腸癌中的最佳化。這是針對沒有肝臟、骨或腦轉移的微衛星穩定性結直腸癌患者進行的一線試驗，我們認為這些患者是免疫抑制位點，我們仍然需要了解更多信息，直到我們能夠在第一線克服這些免疫抑制位點。但它是 IV 期 MSS CRC 的一線 BOT/BAL，無需化療。我們在一年內幾乎完成了試驗的招募，我認為這解釋了患者的願望，並且不言而喻。

So that's sort of one metric that I would put out there is that we're going to be able to present that data, hopefully, early next year, which I'm very excited about. But this trial came purely from a place of empathy. I thought about what I would want if I was diagnosed with Stage IV colon cancer. I work on cars, I play music, I have two young boys, like I'm active. I don't want neuropathy from oxaliplatin. I don't want cytopenias from irinotecan. I wouldn't want any of those things.

所以，我想提出的一個指標是，我們將能夠在明年年初展示這些數據，對此我感到非常興奮。但這次審判純粹是出於同情。我想過如果我被診斷出患有 IV 期結腸癌我會想要什麼。我修車、玩音樂，有兩個兒子，我很活躍。我不想因奧沙利鉑而導致神經病變。我不希望因伊立替康而出現血球減少症。我根本不想要這些東西。

I would want at least a shot at immunotherapy to see if it was going to work and lead to a durable response. And that's exactly what one of our patients who's 30 years old came in with lung metastasis after not getting scans for a Stage II colon cancer because he was told that he didn't need them, but he really felt uncomfortable with that. He came to see us at Duke, and we started him on trial, and he's done amazingly well.

我希望至少嘗試一次免疫療法，看看它是否有效並產生持久的反應。這就是我們的一位 30 歲患者的情況，他因肺轉移而入院，因為他被告知不需要接受 II 期結腸癌掃描，但他對此感到非常不舒服。他來杜克大學見我們，我們對他進行了試訓，他的表現非常出色。

He says that I'm a celebrity in his house apparently because I came up with this trial, but it really like aligns with exactly what he wanted. He is like, let my immune system get a shot before I have to go down this road of FOLFOX and getting side effects that could derail all of my family plans and all the things that I'm normally doing in my day-to-day job. I'm the only one that's working right now. I need to be there for my family. And he's done great, and he's tolerated everything really, really well.

他說我顯然是他家裡的名人，因為這個試驗是我提出的，但它確實與他想要的完全一致。他說，在我必須接受 FOLFOX 治療並產生副作用之前，讓我的免疫系統得到一次注射，因為這些副作用可能會破壞我所有的家庭計劃以及我日常工作中通常做的所有事情。我是目前唯一一個在工作的人。我需要陪伴我的家人。他做得很好，而且他能很好地忍受一切。

And really, the side effects to BOT/BAL, I think, are so much more manageable once oncologists wrap their minds around them, and they say, okay, we're just trying to prevent autoimmunity and trying to educate patients and educate providers so we can act early. And that's what we do in this trial. We give patients steroids that they take home, if they develop diarrhea due to immune-mediated diarrhea and colitis, then they start the steroids, and they come in and get infliximab or another biologic, and we can turn them around.

事實上，我認為，一旦腫瘤學家了解 BOT/BAL 的副作用，它們就會變得更容易控制，他們會說，好吧，我們只是試圖預防自身免疫，並試圖教育患者和提供者，以便我們能夠儘早採取行動。這就是我們在這次試驗中所做的。我們給病人服用類固醇讓他們回家，如果他們因免疫介導性腹瀉和結腸炎而出現腹瀉，那麼他們就開始服用類固醇，然後他們來醫院接受英夫利西單抗或其他生物製劑的治療，我們就可以扭轉他們的病情。

That's a lot different than oxaliplatin reactions that in people in the hospital or where we have to do desensitization because it randomly at the ninth dose or something, it can happen any time, leads to a terrible infusion reaction or some of the other things like diarrhea during chemotherapy with irinotecan while it's infusing, it can even happen. So a lot of these things are very different with BOT/BAL.

這與奧沙利鉑的反應有很大不同，奧沙利鉑的反應發生在醫院裡，或者我們必須進行脫敏治療，因為它會在第九次劑量時隨機發生，或者在任何時候發生，導致可怕的輸液反應或其他一些反應，例如在輸注伊立替康化療期間出現腹瀉，甚至會發生。因此，很多這些事情與 BOT/BAL 非常不同。

And so that's why this trial was developed. And we hope that by giving BOT/BAL in the first line, we can transform this disease into something where patients have more options and that they have a shot at avoiding chemotherapy entirely like patients with melanoma and patients with microsatellite unstable colorectal cancers too.

這就是開展此項試驗的原因。我們希望透過在第一線使用 BOT/BAL 療法，將這種疾病轉變為一種讓患者擁有更多選擇的疾病，使他們有機會像黑色素瘤患者和微衛星不穩定型結直腸癌患者一樣完全避免化療。

And moreover, one thing that I think is really fascinating here and I think when we -- I hope that when we look back on this in 5 to 10 years, Garo, that we say like, look, MSS CRC, it's looking just like MSI CRC, where if you give the immunotherapy first, it works much better. If you look at some of the crossover arms and like the IPI/NIVO trials, the patients who got chemotherapy first and crossed over to IPI/NIVO still did worse. They still didn't have as high of a response rate.

此外，我認為有一件事非常有趣，我認為當我們——我希望當我們在 5 到 10 年後回顧這一點時，Garo，我們會說，看，MSS CRC，它看起來就像 MSI CRC，如果你先進行免疫療法，效果會更好。如果你看一些交叉組，例如 IPI/NIVO 試驗，你會發現先接受化療然後轉到 IPI/NIVO 的患者的情況仍然更糟。他們的回覆率仍然不高。

So immunotherapy early is better before there's tumor immune evolution in response to chemotherapy and resistance to chemotherapy and before patients are getting absolutely obliterated by some of these side effects from chemotherapy that just accumulate over time.

因此，在腫瘤對化療產生免疫反應和產生抗藥性之前，以及在患者因化療的某些副作用而完全喪失抵抗力之前，儘早進行免疫治療是更好的選擇。

Unlike BOT/BAL, where you're dealing with the side effects upfront, you're able to manage them. This is something with chemotherapy that just builds and builds. They just get worse as you go further along. And if you try to do things like FOLFOX reintroduction, you raise your risk of like oxaliplatin infusion reactions.

與 BOT/BAL 不同，您需要提前處理副作用，而您能夠管理它們。這是化療不斷累積的結果。隨著你進一步深入，情況只會變得更糟。如果您嘗試重新引入 FOLFOX 療法，則會增加奧沙利鉑輸注反應的風險。

So it's very important to me that patients have this option. And if they have it as early as possible, especially in a disease setting like Stage IV CRC, which we know is typically incurable, that may change. And in a population that's enriched for those that we've seen respond in later lines, like those with lung mets or peritoneal mets, only lacking liver metastasis.

因此，對我來說，讓患者擁有這個選擇非常重要。如果他們儘早接受治療，特別是在像 IV 期 CRC 這樣我們所知通常無法治癒的疾病環境下，情況可能會改變。在那些我們在後期有反應的腫瘤群體中，例如肺轉移或腹膜轉移的腫瘤群體，僅缺乏肝轉移。

So what you're basically saying in very simple terms, is, why not use the best option for the patient first. And if that fails, you can use some of the nasty things like chemotherapy later, which is, by the way, what Mike -- Dr. Atkins advocated at last year's SITC meeting because he said exactly what you're saying that it doesn't make sense to keep the best to last, when --

所以，用非常簡單的話來說，你基本上就是在說，為什麼不先為病人提供最好的選擇呢？如果失敗了，你可以稍後再用一些更糟糕的方法，比如化療，順便說一下，這也是 Mike 博士在去年的 SITC 會議上所提倡的，因為他說的和你完全一樣，把最好的留到最後是沒有意義的，當--

Yeah. Use your most durable, tolerable therapy first and let's get people into long-term remissions and spare them the toxicity of other regimens. And that's exactly right. That's exactly what Mike Atkins did with the DREAMseq trial in BRAF-mutant melanoma. You have patients that respond much longer and do much better. There's a 20% difference in overall survival, if you give immunotherapy first and if you give targeted therapy first. So right on the nose, completely agree.

是的。首先使用最持久、最可耐受的療法，讓我們讓人們獲得長期緩解，並使他們免受其他療法的毒性。確實如此。這正是 Mike Atkins 在 BRAF 突變黑色素瘤的 DREAMseq 試驗中所做的。您的患者反應更持久，並且恢復得更好。如果先進行免疫療法和先進行標靶療法，整體存活率會有 20% 的差異。完全正確，完全同意。

And yet another provocative question for you as I did with Dr. Goldberg. In spite of all of this, patients are being held back from being exposed to drugs that could be the best option for them.

正如我向戈德堡博士提出的那樣，這又是一個發人深省的問題。儘管如此，患者仍然無法接觸到對他們來說可能是最佳選擇的藥物。

Right.

正確的。

And, of course, Rich Goldberg said that the FDA requirement today is randomized trials that have four-, five-, six-year readouts. And, of course, we're trying to change that. And when we talk to Chris, we'll touch upon how we're going to do that.

當然，里奇‧戈德堡 (Rich Goldberg) 表示，FDA 目前的要求是進行隨機試驗，並進行四年、五年、六年的讀數。當然，我們正在努力改變這種狀況。當我們與克里斯交談時，我們會討論如何做到這一點。

But how do we -- I mean, if you were the FDA commissioner today, how would you practically change this archaic paradigm that really is based on precedence, based on an old generation of drugs rather than embracing new innovative drugs. How would you do that?

但是，我們該如何——我的意思是，如果您是今天的 FDA 局長，您將如何切實改變這種基於先例、基於老一代藥物而不是擁抱新型創新藥物的陳舊模式。你會怎麼做呢？

Yeah. Why are we so wed to the mustard gas, I guess, is the phrase that I always say. This is -- this chemotherapy, in my eyes, is the horse that got us to the car. And now we need to get in the car and drive. And the car is, obviously, immunotherapy here. So let's get going. Let's hit the gas.

是的。我常說的一句話是「為什麼我們對芥子氣如此著迷」。在我看來，這種化療就是把我們帶到車上的馬。現在我們需要上車開車。顯然，這款車就是免疫療法。那麼我們就開始吧。我們加大油門吧。

And the way we do that is we have to have an open mind. There are patients who present with colorectal cancer that are asymptomatic. They have a period of time where they could try certain drugs and the risk of a tumor pressing on something or causing them a problem is not that great.

我們做到這一點的方法是必須保持開放的心態。有些患有結腸直腸癌的患者沒有症狀。他們有一段時間可以嘗試某些藥物，而且腫瘤壓迫某些器官或引起問題的風險並不是那麼大。

And I think that there is a patient population that you can select for to try highly promising agents like botensilimab out as first line, obviously, under a consent and a protocol and with the plan like what we have for BBOpCo, which is where we give BOT/BAL, we scan at six weeks. We monitor circulating tumor DNA, et cetera. We monitor patient symptoms, and we can rescue with chemotherapy and add it on if we need to.

我認為，您可以選擇一個患者群體來嘗試像 botensilimab 這樣非常有前景的藥物作為一線治療，顯然，是在同意和協議下，並按照我們為 BBOpCo 制定的計劃，即給予 BOT/BAL，我們在六週後進行掃描。我們監測循環腫瘤DNA等等。我們監測患者的症狀，如果需要的話，我們可以採用化療來挽救患者的生命。

But what that does is it opens up the window. It gives us a foothold. It gives us that first rung on the ladder and helps us say, okay, who's responding first line and can really, really avoid chemotherapy entirely. And what are the resistance mechanisms in the absence of chemotherapy and other variables, thinking from like a very basic scientific standpoint, like we want clean outcomes here. We want clear answers.

但這樣做的目的是打開窗戶。它為我們提供了立足點。它為我們提供了第一步，並幫助我們判斷，好吧，誰對第一線治療有反應，誰真的可以完全避免化療。從非常基本的科學角度思考，在沒有化療和其他變因的情況下，抗藥性機制是什麼，我們想要的是明確的結果。我們想要明確的答案。

So if we want to learn our biomarkers, they're not going to be in the third and fourth line necessarily. They're probably going to be in the first line where there's less patient and tumor heterogeneity. There's more similarity between the diseases.

因此，如果我們想了解我們的生物標誌物，它們不一定會出現在第三行和第四行。它們可能會處於患者和腫瘤異質性較低的第一線。這些疾病之間存在著更多的相似性。

So if we can define those biomarkers by giving effective therapies first line, and we can like open that door up a little bit, we're only going to increase it from there and chemotherapy will start to become something that is really just like salvage when everything else has failed, and we know we still have more work to do on the research side.

因此，如果我們能夠透過提供有效的一線治療方法來定義這些生物標誌物，我們就可以稍微打開那扇門，我們只會從那裡增加它，當其他一切都失敗時，化療將開始成為一種真正的挽救手段，我們知道我們在研究方面還有更多的工作要做。

So when you came up with this idea of trying BOT/BAL as a first-line therapy in metastatic colorectal cancer, can you walk us through some of the challenges you encountered at your institution, at the FDA? And how did you resolve them?

那麼，當您提出嘗試將 BOT/BAL 作為轉移性大腸直腸癌的一線治療方法時，您能否向我們介紹您在您所在機構和 FDA 遇到的一些挑戰？您是如何解決這些問題的？

Yeah. It was incredibly difficult. I mean I know you've heard the story, but I'll repeat for everybody on the call is that in the 2022 SITC hot topic session, I saw the BOT/BAL data and like leapt out of my seat and I was like, why am I the only one standing up and looking around. I was just this man on an island, and I didn't really understand why people weren't as excited about the data as I was. I'm like, just give it first, give people a shot at it.

是的。這真是太難過了。我的意思是，我知道你已經聽過這個故事，但我要向電話中的每個人重複一遍，在 2022 年 SITC 熱門話題會議上，我看到了 BOT/BAL 數據，然後從座位上跳了起來，我想，為什麼只有我一個人站起來環顧四周。我就像一個孤島上的人，我真的不明白為什麼人們對這些數據並不像我一樣興奮。我想，先嘗試一下，讓別人也試試看。

And I immediately wrote the trial like after that, like on the plane home, just started like crafting it and my -- the knee-jerk response from almost everybody with a few select people is like, that's a really good idea, and you'll never pull it off. It just won't happen.

之後，我在回家的飛機上立即寫了試驗稿，開始構思，幾乎所有人和少數幾個人都下意識地表示，這是一個好主意，但你永遠不可能實現。這根本不會發生。

We develop drugs late line and then they slowly move back into the first-line, you combine them with chemotherapy, you don't mess what the stuff where you're giving it by itself. That doesn't make sense. FOLFOX has been given for 50 years, which brings on, of course, the most dangerous phrase in the English language, which is that's the way we've always done it.

我們在後期開發藥物，然後慢慢將它們移回一線，將它們與化療結合起來，你不會弄亂你單獨給予的藥物。這沒有道理。FOLFOX 療法已經實施了 50 年，這當然引出了英語中最危險的短語，即「我們一直都是這樣做的」。

So that being said, it's the stick-to-itiveness of like that's the way we've always done it was a real barrier, and I had to keep pounding the pavement and saying like, I guarantee this is something that patients would sign up for and that they would be interested in.

話雖如此，但我們始終堅持的做法才是真正的障礙，我必須不斷努力，並說，我保證這是患者願意報名參加並且會感興趣的事情。

So I received no internal funding. There's really not a lot of funding for investigator-initiated trials, which is a totally different issue for a different day about how we need to do more of that and let hopefully some physician-scientists like myself and others who are out there seeing patients, but also in the lab and understanding how we get from one side to the other.

所以我沒有得到任何內部資金。對於研究者發起的試驗，資金確實不多，這是一個完全不同的問題，我們需要做更多這樣的試驗，並希望讓一些像我這樣的醫師科學家和其他不僅在外面看病人，還在實驗室裡了解我們如何從一邊走到另一邊的人。

Let us run some of these trials and come up with these innovative ideas and appeal to our patients. And it really didn't happen. It languished for about 1.5 years, and we were extremely fortunate because I kept trying to apply for different opportunities and finding different grants and everything else.

讓我們進行一些這樣的試驗，提出這些創新的想法並吸引我們的患者。但事實並沒有發生。它停滯了大約一年半，我們非常幸運，因為我一直嘗試申請不同的機會，尋找不同的補助金和其他一切。

And Gateway, which is the clinical trial research foundation ended up funding us. And they were enthusiastic beyond my wildest dreams really because they said, we whittled this down to 32 trials and yours was the clear winner. This is what we will fund. They've been extremely involved since then, they have patient advocates as well who have said that this is what patients really would prefer is to at least have an option towards immunotherapy.

最終，臨床試驗研究基金會 Gateway 為我們提供了資助。他們的熱情超出了我的想像，因為他們說，我們把試驗範圍縮小到 32 次，而你的試驗顯然是贏家。這就是我們將要資助的。從那時起，他們就積極參與其中，他們也有患者倡導者，他們說，患者真正希望的至少是可以選擇免疫療法。

And then we hit the heartbreak of the FDA after that, where we are essentially told that you must scan these patients at six weeks or you cannot proceed with this trial. This raises trial costs tremendously. It doubled our diagnostic costs. And that was difficult when all of our money comes from a foundation and then we had to put some internal Duke money towards that, which was not easy.

然後我們又遭遇了 FDA 的嚴厲處罰，他們告訴我們必須在六週後對這些患者進行掃描，否則就不能繼續進行這項試驗。這大大增加了審判成本。這使我們的診斷費用翻了一番。當我們所有的錢都來自基金會時，這很困難，然後我們必須將一些杜克大學內部的資金用於此，這並不容易。

But frankly, we have an amazing GI oncology research group, nine physicians, and a great research team who really were all behind us and said, let's get this done, let's get this over the finish line. You got it this far, you got $0.25 million from Gateway. Let's go.

但坦白說，我們有一個出色的胃腸道腫瘤研究小組、九名醫生和一個偉大的研究團隊，他們都支持我們，並說，讓我們完成這件事，讓我們完成它。你已經走到這一步了，你從 Gateway 獲得了 25 萬美元。我們走吧。

And that's what happened in the entire trial of 15 patients is being executed at a pretty low cost, I think, and it's happening very fast. And again, recruiting as many patients as we have as fast as we have, that is testament to the demand. There's nothing I can say that beats that.

這就是在 15 名患者中發生的整個試驗，我認為，它以相當低的成本進行，並且進展非常快。再次強調，我們以最快的速度招募盡可能多的患者，這證明了需求。沒有什麼能比這更好了。

So it has been a long and difficult road, but it's 100% worth it. I would do it 10 times over again even if it took twice as long.

所以這是一條漫長而艱難的道路，但它絕對值得。即使要花兩倍的時間，我也會再做十次。

And Gateway is happy so far.

到目前為止，Gateway 一切順利。

They're thrilled. They just invited me to a gala to speak, and they're saying like we want to get some of the patients from the trial involved and giving their stories. So stay involved with looking at Gateway's website, you'll see things about BBOpCo start to pop up over time. And I think you'll see at least two or three of our patient stories show up on there, including the 30-year-old with lung metastasis, I mentioned before.

他們很激動。他們剛剛邀請我參加一個慶典並發表演講，他們說我們想讓一些參與試驗的患者參與並講述他們的故事。因此，請繼續關注 Gateway 的網站，您會看到有關 BBOpCo 的資訊逐漸出現。我想你會在那裡看到至少兩三個病人的故事，包括我之前提到的那位 30 歲肺轉移患者。

Wow. That's terrific. So I'm going to switch to Chris O'Callaghan and then, we'll come back with some questions for everybody as well. And of course, we have questions from the audience.

哇。太棒了。所以我要切換到克里斯·奧卡拉漢 (Chris O'Callaghan)，然後我們也會回來向大家提出一些問題。當然，我們也收到觀眾的提問。

Chris, you were exposed to BOT/BAL maybe about two years ago. And you have been after us to do a trial. Now if you can go back and recount what was it that drew you to us? Because you've done a lot of trials, and your business is not just to generate revenues because you're getting funded by also some government entities. But you wanted this trial for a reason. And if we can get into your heads and tell us that, then I have a couple of additional questions for you.

克里斯，大約兩年前你接觸過 BOT/BAL。而且您一直追著我們做審判。現在，如果您可以回顧一下是什麼吸引您來到我們這裡呢？因為你已經做了很多試驗，而且你的業務不僅僅是為了創造收入，因為你還得到了一些政府實體的資助。但你想要這次審判是有原因的。如果我們能夠了解你們的想法並告訴我們這一點，那麼我還有幾個問題要問你們。

Sure, Garo. Well, it's a pleasure to be here and to speak on behalf of the trial that we've proposed. I'm a member of the Canadian Cancer Trials Group, as you know, and we have a -- the group has been in existence for 45 years, but more importantly related to this particular subject, we've been doing colorectal cancer trials in an international collaborative environment for 25 years.

當然，Garo。嗯，我很高興來到這裡並代表我們提議的試驗發言。如你所知，我是加拿大癌症試驗小組的成員，該小組已經存在 45 年了，但更重要的是，與這個特定主題相關的是，我們已經在國際合作環境中進行了 25 年的結直腸癌試驗。

And we're a little bit different. We're on the back end of where Dr. DeVito was. I applaud him. I think it's incredibly exciting that his trial is taking immunotherapy to the front. But we also have to remember that there are patients who exhaust all available therapies out there and are still looking for options who are otherwise fit and ready to continue to take more treatment. And that's where we focused on.

我們有點不同。我們位於德維托博士所在位置的後端。我為他鼓掌。我認為他的試驗將免疫療法推向了前沿，這非常令人興奮。但我們也必須記住，有些患者已經用盡了所有可用的療法，但仍在尋找其他治療選擇，他們身體健康，願意繼續接受更多治療。這就是我們關注的重點。

And we've done a number of trials in that patient population of colorectal cancer patients who literally are at the end of their ropes and have exhausted all other lines of therapy. And one of those trials in the early days of the immuno-oncology revolution was a study in which we took two agents that targeted similar receptors as BOT and BAL and we combined them.

我們對那些已經走投無路、用盡了所有其他治療方法的結腸直腸癌患者群體進行了多項試驗。在免疫腫瘤學革命的早期，我們進行了一項試驗，其中研究了兩種針對類似受體的藥物 BOT 和 BAL，並將它們結合起來。

And our feeling was that in the microsatellite stable population or the cold tumor population, as you've noted, that there was still a possibility that we could overcome that coldness, if you will, by synergy with different approaches to stimulating the immune system.

我們認為，在微衛星穩定群體或冷腫瘤群體中，正如您所說，我們仍然有可能透過協同不同的方法來刺激免疫系統，從而克服這種冷漠。

And that trial was a Phase 2 trial. It was positive. And I have to admit that I was a little bit surprised at the time, it was a bit of a Hail Mary pass for us. The trial came out positive for overall survival, for quality of life benefit. And we were excited by that. And serendipitously, we became aware of your work with BOT and BAL around that time. And quite frankly, your results look even more impressive for those agents.

該試驗是第二階段試驗。這是積極的。我必須承認，當時我有點驚訝，這對我們來說就像是孤注一擲。試驗結果顯示，整體存活率和生活品質都有所提升。我們對此感到非常興奮。偶然的是，我們在那時了解到您在 BOT 和 BAL 的工作。坦白說，您的結果對於那些代理商來說看起來更加令人印象深刻。

And so we were looking for an opportunity to continue our work and to demonstrate proof of principle in a Phase 3 study where we could answer the question definitively that doublet IO therapy works in these patients and that's the reason we approached Agenus. And we are very excited as we embark on opening up our CO.33 or BATTMAN trial.

因此，我們正在尋找機會繼續我們的工作，並在第 3 階段研究中證明原理，以便我們可以明確回答雙藥 IO 療法對這些患者有效的問題，這就是我們聯繫 Agenus 的原因。當我們開始啟動 CO.33 或 BATTMAN 試驗時，我們感到非常興奮。

And when you talked about the other trial, Chris, I suspect the reason that it worked, but it wasn't blowing you away, is it because the molecule didn't have the turbo charging capabilities that BOT perhaps brings to the party?

克里斯，當您談到另一項試驗時，我懷疑它之所以有效，但卻沒有讓您驚嘆，是因為該分子不具備 BOT 可能帶來的渦輪增壓能力嗎？

Well, I think that is our -- that is certainly our hope on the basis of what we're seeing with the results that you are producing. They -- the Phase 1 and Phase 2 studies that you have done really outstrip the results that we saw in our combination trial.

嗯，我認為這是我們的——根據我們所看到的你們所取得的成果，這當然是我們的希望。您進行的第一階段和第二階段研究確實超出了我們在聯合試驗中看到的結果。

And so I think that it's one of these really great positions where we think that there's been a proof of concept for our trial that has demonstrated that immunotherapy can work. And now the question is if we use the best immunotherapies that we can get our hands on, can we show that, that works even better.

因此，我認為這是真正偉大的立場之一，我們認為我們的試驗已經證明了免疫療法是有效的。現在的問題是，如果我們使用我們所能獲得的最好的免疫療法，我們能否證明其效果更好。

Thank you. Now a couple of days ago, when we were talking, you mentioned we were talking about logistical steps towards enrolling patients. Of course, we have finalized our agreement with you, and we are now ready to go, so to speak, to enroll patients.

謝謝。幾天前，當我們交談時，您提到我們正在討論招募患者的後勤步驟。當然，我們已經與您達成了最終協議，現在我們就可以開始招募患者了。

And you told me because I always push as you're well aware. And the push is since we've got everything in order, why don't we enroll patients tomorrow, and of course, I know that is not possible, but why not?

你告訴我是因為我總是努力，你很清楚這一點。而且既然我們已經把所有事情安排好了，為什麼我們不明天就招募病人呢？當然，我知道這是不可能的，但是為什麼不呢？

And -- but you gave me a couple of pieces of news that reflected the level of enthusiasm and engagement by the participating centers and physicians. If you can talk about that, what is happening, why are the people excited about this? And then another follow-up question for you after that.

而且——但你給了我一些消息，反映了參與中心和醫生的熱情和參與程度。如果您可以談論這個，那麼到底發生了什麼，為什麼人們對此感到興奮？之後我也會問您另一個後續問題。

Sure. So the first thing I should say to you is that we're putting together an international collaboration. Ourselves in Canada, we have experience and decades, quite frankly, of history and collaborating with other groups like ourselves around the world, most notably in Australia, New Zealand, and France. And so when we came to you, we had put together this triumvirate, if you will, of three regions around the world that want to enroll patients on this study. That said, Canada will lead the way. We will be the first off the mark.

當然。所以我要告訴你們的第一件事就是我們正在進行一項國際合作。坦白說，我們在加拿大有經驗和數十年的歷史，並與世界各地的其他類似團體合作，最著名的是澳洲、紐西蘭和法國。因此，當我們來找您時，我們已經組建了這個三巨頭，如果您願意的話，指的是來自世界各地的三個地區，他們想要招募患者參與這項研究。儘管如此，加拿大仍將發揮領導作用。我們將率先行動。

And I'm delighted to let you know that we have submitted our clinical trial application to our regulatory authority Health Canada already. Health Canada will require a 30-day review period, after which we will be what we call, centrally activated and ready to go.

我很高興地告訴大家，我們已經向監管機構加拿大衛生部提交了臨床試驗申請。加拿大衛生部將需要 30 天的審查期，之後我們將進入所謂的集中啟動和準備狀態。

But notably, the enthusiasm around this trial is such that at least two of our lead investigators in provinces, the major provinces in Canada, in Ontario and British Columbia, got their ethics submissions in within six days of our submission to Health Canada. That is utterly unprecedented. And like Dr. DeVito said, it's a clear reflection of investigator enthusiasm to trial these agents.

但值得注意的是，人們對這項試驗的熱情如此之高，以至於我們在加拿大主要省份安大略省和不列顛哥倫比亞省的至少兩名首席研究員在我們向加拿大衛生部提交報告後的六天內就提交了倫理意見書。這是史無前例的。正如德維托博士所說，這清楚地反映了研究人員試驗這些藥物的熱情。

So when we go through with this, we've talked about enrollment timelines. And of course, one of the attractive aspects of working with you was not just your team, but your ability to work with the centers in Canada, France, Australia and bring on patients very quickly and do this.

因此，當我們完成此事時，我們會討論入學時間表。當然，與您合作的吸引力之一不僅在於您的團隊，還在於您與加拿大、法國、澳洲的中心合作並迅速接收患者的能力。

Of course, the quicker you enroll trials, the more economic the costs are plus subsidies that are also available to you. So with all of that and with the initial signals that you're getting, what can you say about enrollment timelines?

當然，您越早報名參加試驗，費用就越經濟，還可以獲得補貼。那麼，根據所有這些以及您收到的初步信號，您能對入學時間表說些什麼嗎？

So let me tell you that the trial that I mentioned to you previously, which we call our CO.26 trial, the Phase 2 trial, we enrolled 180 patients over 10 months. And month on month, our accrual was better. In the final month of that trial, we enrolled 39 patients from Canada only, which I think was, again, as Dr. DeVito had noted, is it was a real reflection of an unmet need, a patient desire to attempt to benefit from immunotherapy and investigators' willingness and belief in the use of immunotherapy.

所以讓我告訴你，我之前提到的試驗，我們稱之為 CO.26 試驗，即第 2 階段試驗，我們在 10 個月內招募了 180 名患者。而且我們的業績逐月成長。在該試驗的最後一個月，我們僅招募了 39 名來自加拿大的患者，我認為這再次反映了未滿足的需求、患者希望嘗試從免疫療法中受益的願望以及研究人員對使用免疫療法的意願和信念。

So if you think that we can put 39 or 40 patients a month on in Canada, our population base of about 35 million to 40 million, and we triple that or more than triple that by engaging Australia, New Zealand, and France, our -- I think our legitimately conservative target is that we average over the life of the trial, 60 patients a month. And so in the context of 834 patient sample size, that is a pretty expeditiously recruiting trial.

因此，如果您認為我們可以在加拿大每月接收 39 或 40 名患者，我們的人口基數約為 3500 萬至 4000 萬，並且通過與澳大利亞、新西蘭和法國合作，我們可以將這個數字增加兩倍甚至三倍以上，那麼——我認為我們合理保守的目標是，在整個試驗期間，我們平均每月接收 60 名患者。因此，在 834 名患者樣本量的情況下，這是一項相當迅速的招募試驗。

Thank you. Thank you for that. And it's really a privilege to work with like-minded internal experts and external experts like you and Dr. DeVito, and of course, our very own Dr. Goldberg, Dr. O'Day, and our Chief Commercial Officer, who is here as well, Robin Taylor, who is -- who might as well be a physician. He's a scientist, but he knows the field of CRC inside out based on his previous experience at Genentech and Seagen.

謝謝。謝謝你。能夠與志同道合的內部專家和外部專家（如您和 DeVito 博士）一起工作真的是一種榮幸，當然，還有我們自己的 Goldberg 博士、O'Day 博士，以及我們的首席商務官 Robin Taylor（他也在這裡，他也可能是一名醫生）。他是一名科學家，但根據他在 Genentech 和 Seagen 的先前工作經驗，他對 CRC 領域瞭如指掌。

So it's really a wonderful outcome for patients because we want to get to the finish line as soon as possible. But more importantly, we will also explore the more expeditious ways forward, meaning potentially pressuring the system to accept our accelerated approval application when that decision is made. And of course, we know we've hit some resistance on that in the past year, although that resistance seem to be a bit more moderate when we encountered the FDA this year. But we can talk about that separately.

所以這對患者來說真的是一個很好的結果，因為我們希望盡快到達終點。但更重要的是，我們還將探索更快捷的前進方式，這意味著在做出決定時可能會向系統施壓，要求其接受我們的加速批准申請。當然，我們知道在過去的一年裡我們遇到了一些阻力，儘管今年我們遇到 FDA 時阻力似乎有所減弱。但我們可以單獨討論這個問題。

Now let me switch gears a little bit and go to Dr. Jennifer Buell, and if we can bring Jennifer Buell here. As you know, we started as an immunotherapy company a long time ago, that is for the audience to know. It's been 31 years. And as the Irish say, this is not for the faint hearted, no pun intended because you're Irish Dr. Buell, not by birth, but by heritage.

現在讓我稍微轉換一下話題，談談 Jennifer Buell 博士，我們是否可以請 Jennifer Buell 來這裡。如你所知，我們很久以前就成立了一家免疫療法公司，這是觀眾都知道的。已經31年了。正如愛爾蘭人所說，這不適合膽小的人，這不是雙關語，因為你是愛爾蘭人，布埃爾博士，不是因為出生，而是因為血統。

But if you look at what we've done, how we expanded our immunotherapy armamentarium because I say to people like the military system, it's silly to expect that a single agent or a single pathway is going to get the job done because the immune system is like the military fighting an enemy. In this particular case, the enemy is cancer.

但是如果你看看我們所做的，看看我們如何擴展我們的免疫療法設備，因為我對像軍事系統這樣的人來說，期望單一藥劑或單一途徑能夠完成工作是愚蠢的，因為免疫系統就像軍隊與敵人作戰一樣。在這個特殊情況下，敵人就是癌症。

And some time ago, we expanded our efforts to cell therapies. And as you go from molecules to cell therapies, I always say and sometimes you all ridiculed the fact that you're getting into a more and more intelligent system. Cells are more intelligent than molecules. And of course, our own invariant NKT cells are the most intelligent cells of all of the immune system.

不久前，我們將努力擴展到細胞療法。當你們從分子療法轉向細胞療法時，我總是說，有時你們也會嘲笑你們正在進入一個越來越聰明的系統。細胞比分子更聰明。當然，我們自己的不變的 NKT 細胞是整個免疫系統中最聰明的細胞。

And so there are -- we did this, and we segregated the companies because the manufacturing model is different, of course, going from molecules to cells. And we did it also because there are synergies between cell therapy and our molecules that constitute the immuno-oncology armamentarium.

所以——我們這樣做了，我們將公司分開，因為製造模式當然是不同的，從分子到細胞。我們這樣做也因為細胞療法和構成免疫腫瘤學設備中的分子之間存在協同作用。

And then, you also took the concept to another level by getting into an engagement with the government and government's interest in all of this. So if you can give us a flavor about the synergy in cancer and also the capabilities of these cells beyond cancer.

然後，您也透過與政府接觸以及政府對這一切的興趣將這一概念提升到了另一個層次。因此，如果您能向我們介紹癌症中的協同作用以及這些細胞在癌症之外的能力。

I'm so happy to. And what a perfect segue, given what you've just heard from Dr. DeVito and Chris, the immune system, as we observed following, chemotherapy does become somewhat incompetent. It's unable to actually do its job. And what we identified early on is that there are certain cell types that actually do the job far better than other cell types.

我很高興。這是一個完美的過渡，根據您剛從 DeVito 博士和 Chris 那裡聽到的，免疫系統，正如我們觀察到的，化療確實變得有些無能。它實際上無法完成其工作。我們很早就發現，某些細胞類型實際上比其他細胞類型表現得更好。

And that's what brought out MiNK Therapeutics. So the invariant natural killer T cells, as you've mentioned, they're rare cells. They are one of the most highly conserved cells in immunity historically, they've been around identified for the longest period of time. But they are the rarest, they make up less than essentially 0.1% of your circulating lymphocytes, and that's because they're so potent. They act like first responders.

這就是 MiNK Therapeutics 誕生的原因。因此，正如您所提到的，不變的自然殺手 T 細胞是稀有細胞。它們是歷史上免疫中保守性最高的細胞之一，發現的時間最長。但它們是最稀有的，它們佔循環淋巴細胞的不到 0.1%，這是因為它們非常有效。他們就像第一個響應者一樣。

These are -- on one hand, they can kill dangerous cells directly. And on the other, they're waking up the immune system to fight back. So your immune system has two major branches for those who aren't immunologists, and that's innate immunity, which provides broad and rapid defense, as well as adaptive immunity, which we came to know far better during pandemic.

一方面，它們可以直接殺死危險的細胞。另一方面，它們正在喚醒免疫系統進行反擊。因此，對於那些不是免疫學家的人來說，你的免疫系統有兩個主要分支，那就是先天免疫，它提供廣泛而快速的防禦，以及適應性免疫，我們在大流行期間對適應性免疫有了更深入的了解。

That immune -- that part of your immune system mounts a bit slower, but it's highly specific and it's somewhat long lasting directly against a particular threat. So most immune cells specialize in one branch or the other, innate or adaptive immunity.

免疫系統的這一部分發展得比較慢，但它具有高度的特異性，並且可以長期直接對抗特定的威脅。因此，大多數免疫細胞專注於一個分支或另一個分支，即先天免疫或適應性免疫。

The uniqueness of iNKT cells is that they actually are unusual because they bridge both arms of immunity, both innate and adaptive, and they're really unique in doing so. So they respond quickly like innate cells, they release cytokines, different chemicals that effectively can operate within minutes. They can kill or lyse cancer cells. They could also clear infections.

iNKT 細胞的獨特之處在於它們實際上很不尋常，因為它們連接了免疫系統的兩個方面，包括先天性和適應性，並且它們在這方面確實是獨一無二的。因此，它們像天然細胞一樣快速做出反應，釋放細胞因子和可以在幾分鐘內有效發揮作用的不同化學物質。它們可以殺死或溶解癌細胞。它們還可以清除感染。

At the same time, they influence adaptive immunity like T cells that you hear so much about or B cells, shaping the memory, that long-term memory response is what is necessary for long-term durable anticancer or antitumor immunity or anti-infectious immunity.

同時，它們影響適應性免疫，例如我們經常聽到的 T 細胞或 B 細胞，塑造記憶，而長期記憶反應是長期持久的抗癌或抗腫瘤免疫或抗感染免疫所必需的。

So these make iNKTs really powerful coordinators. As you've mentioned, they are intelligent. What we've seen is data in cancer, which I'll speak to in just a moment as well as in severe inflammatory or infectious diseases, including pulmonary diseases. And that's where the immune system is really disorganized.

因此，這些使得 iNKT 成為真正強大的協調員。正如你所提到的，他們很聰明。我們看到的是癌症數據（我稍後會談到），以及嚴重發炎或傳染病（包括肺部疾病）的數據。這就是免疫系統真正混亂的地方。

So MiNK, as an entity, launched as an independent company in 2021, and it does work together with Agenus as well as independently. It's one of the most clinically advanced companies developing iNKT cells. So unlike T cells, which you hear about, or NK cells, which you also hear more about, iNKT cells operate through a very specific, essentially, it's called the glycolipid antigen. I don't want to be too technical, but it's an antigen that's really common in all of us.

因此，MiNK 作為一個實體，於 2021 年作為一家獨立公司成立，它既與 Agenus 合作，也獨立開展工作。它是開發 iNKT 細胞方面臨床最先進的公司之一。因此，與您聽說過的 T 細胞或 NK 細胞不同，iNKT 細胞透過一種非常特殊的、本質上稱為醣脂抗原的物質發揮作用。我不想講得太專業，但它是我們所有人身上都很常見的抗原。

So we could deliver these cells. I could take them from me and give them to you, you won't reject them. It's essentially an invariant T cell receptor. So the cells recognize this antigen. It enables the cells in cancer to essentially infiltrate tumors and reprogram the microenvironment. And it's essentially this dual mechanism that directly kills plus the orchestration to modulate different cells in immunity.

所以我們可以傳遞這些細胞。我可以把它們從我身上拿走並給你，你不會拒絕它們。它本質上是一種不變的 T 細胞受體。所以細胞辨識這種抗原。它使癌細胞能夠滲透到腫瘤並重新編程微環境。本質上，這是一種直接殺死細胞的雙重機制，加上對免疫系統中不同細胞進行調節的協調機制。

Now these are naturally resistant to graft-versus-host disease, and that's another area where we are working with the government as well as with an institution with non-dilutive grant financing to advance these cells in these disease settings.

現在，這些細胞對移植物抗宿主疾病具有天然的抵抗力，而這也是我們正在與政府以及一家擁有非稀釋性贈款融資的機構合作的另一個領域，以在這些疾病環境中推進這些細胞的發展。

Thank you for that. And so why is the government specifically now, as opposed to 10 years ago, although I might add 20 years ago, when 9/11 happened, we were relatively an unknown quantity as a company at the time, but we had an agent called QS-21, which we still have with a new means of producing it in large quantities.

謝謝你。那為什麼政府現在要這麼做呢？與 10 年前不同，儘管我得補充一下 20 年前，當 9/11 事件發生時，我們當時作為一家公司還是一個未知數，但我們有一種名為 QS-21 的代理，我們仍然擁有這種代理，並且採用新的方式大量生產它。

And we were contacted by the government because they considered QS-21 as a -- potentially a biodefense agent because then the country came under attack and the concern was that we may next encounter things like anthrax and other means. So what is happening right now that is generating interest particularly now?

政府聯繫了我們，因為他們認為 QS-21 是一種潛在的生物防禦劑，因為當時我們的國家受到了攻擊，他們擔心我們接下來可能會遇到炭疽病和其他病毒。那麼現在發生了什麼特別引起人們興趣的事情呢？

Well, I'll tell you. When we launched the cells in clinical trials, we effectively started it in 2020, and it was at the time when the pandemic was really just becoming identified in February of 2020 in the United States, and it very quickly overwhelmed the ICUs.

好吧，我會告訴你的。當我們在臨床試驗中啟動這些細胞時，我們實際上是在 2020 年啟動的，當時疫情才剛剛在 2020 年 2 月在美國被發現，並且很快就讓重症監護室不堪重負。

We talked to the FDA about the preclinical data we had that showed that these cells actually prolonged survival in influenza, in pneumonia models, and actually restored immune function and improved oxygenation in the lungs by repairing cells within the lungs.

我們與 FDA 討論了我們掌握的臨床前數據，這些數據表明這些細胞實際上延長了流感和肺炎模型中的存活時間，並且透過修復肺內的細胞實際上恢復了免疫功能並改善了肺部的氧合。

So the agency cleared in our ability to start a clinical trial, we did so. We published these data in Nature Communications, and they're really quite exciting for us and part of the reason why they can -- we believe that they can be very important, particularly in protecting our nation from different infectious threats or biologic threats.

因此，該機構批准了我們開始臨床試驗的能力，我們就這麼做了。我們在《自然通訊》上發表了這些數據，它們確實讓我們感到非常興奮，這也是為什麼我們相信它們非常重要的原因之一，特別是在保護我們的國家免受各種傳染病威脅或生物威脅方面。

So what we showed is that in our clinical trial now published that we -- that when you administer just a single dose of about 1 billion iNKT cells, they very quickly reset the immune system. They help the body fight opportunistic or resistant infections, and they protect against secondary infections.

因此，我們在現在發表的臨床試驗中表明，當你只注射一次劑量的約 10 億個 iNKT 細胞時，它們很快就會重置免疫系統。它們有助於身體抵抗機會性或抗藥性感染，並防止繼發性感染。

And patients in the ICU, they're intubated, undergoing procedures, blood draws, they're vulnerable to infections, they're quite sick. And in that setting, we've shown not only that we can clear primary infections and restore oxygenation to the lungs, getting patients off of ventilators very quickly, we've shown that we can also prevent secondary infections.

加護病房的病人需要插管、接受手術、抽血，他們容易受到感染，病情非常嚴重。在這種情況下，我們不僅證明我們可以清除原發性感染並恢復肺部的氧合，使患者能夠很快脫離呼吸機，而且還證明我們還可以預防繼發性感染。

And those secondary infections are generally what causes the high death rate in patients in the ICU. So there were two opportunities for us in those settings that show that not only can we help patients immediately with the threat that they're dealing with and the pathogens that they're exposed to and fighting, but also we can prevent secondary infections and that was really illuminating for us.

這些繼發性感染通常是導致 ICU 患者死亡率高的原因。因此，在這些環境中，我們有兩個機會表明，我們不僅可以立即幫助患者應對他們所面臨的威脅以及他們所接觸和對抗的病原體，而且我們還可以預防繼發感染，這對我們來說真的很有啟發。

So when we think about the types of threats that we demonstrated in our clinical trial, we saw that patients who had either recovered from COVID or were infected with COVID, we could address that complication not only in patients that were on mechanical ventilation, but also those patients who are on the most severe form of life support called VV ECMO.

因此，當我們思考我們在臨床試驗中證明的威脅類型時，我們發現，對於那些已經從 COVID 中康復或感染 COVID 的患者，我們不僅可以解決使用機械通氣的患者的併發症，還可以解決那些已經使用最嚴重的生命支持形式（稱為 VV ECMO）的患者。

And we could administer the cells, and they do not plug the oxygenator, which is a problem with other immune cell types. So they're really broadly active, and they can be broadly used in an ICU setting on top of steroids.

我們可以管理這些細胞，而且它們不會堵塞氧合器，而這是其他免疫細胞類型所面臨的問題。因此，它們的活性非常廣泛，並且可以在 ICU 環境中與類固醇一起廣泛使用。

That was -- that is of great interest, not only as we face our annual threats of influenza and pneumonia in our country, but also as we contemplate preparedness for other threats that may be imposed upon us or biowarfare. We have shown and will be publishing relatively soon some very important data on the effect of the iNKT cells in a typical pneumonia.

這是非常有趣的，不僅因為我們國家每年都要面臨流感和肺炎的威脅，而且我們也在考慮如何應對可能對我們造成的其他威脅或生物戰。我們已經展示並將很快發布一些關於 iNKT 細胞在典型肺炎中的作用的非常重要的數據。

And these are pneumonias that are generally caused by fungal infections, and those are of high concern for potential biologic threats. So we have been talking certainly with clinicians who are quite interested but also with government agencies who would like to see these cells advancing relatively quickly.

這些肺炎通常是由真菌感染引起的，對潛在的生物威脅有很高的關注度。因此，我們一直在與非常感興趣的臨床醫生進行交流，同時也與希望看到這些細胞相對快速發展的政府機構進行交流。

And again, Garo, I think it's important to note that these cells can be delivered without HLA matching, which is unique as well as no lymphodepletion. Typically, when you're administering a cell therapy, the cells could be rejected if you don't administer high doses of chemotherapy to deplete a patient's immune system. And in those settings, you're killing the actual cells that you need.

再說一次，Garo，我認為需要注意的是，這些細胞可以在沒有 HLA 匹配的情況下輸送，這是獨一無二的，而且不會引起淋巴細胞耗竭。通常，當您進行細胞療法時，如果不使用高劑量的化療來消耗患者的免疫系統，細胞可能會被排斥。在這些情況下，你殺死的是你需要的實際細胞。

In the way that we could use the iNKT cells and because they have a common receptor, common in all of us, we can administer them without depleting a patient's embedded immune system, their active immune system, which is such an important feature of these cells, not only for infections, but also for the disease setting that I mentioned, GVHD. It's very important.

我們可以使用 iNKT 細胞，因為它們具有共同的受體，在我們所有人體內都是共同的，所以我們可以在不消耗患者嵌入式免疫系統（他們的主動免疫系統）的情況下使用它們，這是這些細胞的一個重要特徵，不僅適用於感染，而且適用於我提到的疾病環境，即 GVHD。這非常重要。

And I know that there are other logistical advantages that may accrue shortly in terms of both storage and transport of these cells. We don't want to let it out just yet, but I think you're working on some very exciting developments here and the government could become increasingly a major stakeholder in all of this in driving some of this progress forward.

我還知道，這些細胞在儲存和運輸方面可能很快就會出現其他物流優勢。我們現在還不想透露，但我認為你們正在努力實現一些非常令人興奮的發展，政府可能會越來越成為推動這些進展的主要利害關係人。

Now of course, we, as Agenus, are delighted that you've taken the company to these exciting territories. And not only do we have the synergistic benefit of iNKT cells in connection with potentially using as combination treatment for cancer patients, but the standalone opportunity in areas outside of cancer is also very exciting.

當然，作為 Agenus，我們很高興您帶領公司進入這些令人興奮的領域。我們不僅擁有 iNKT 細胞在癌症患者聯合治療方面的潛在協同優勢，而且在癌症以外領域的獨立機會也非常令人興奮。

And we're very, very delighted that we're a major stakeholder in here, both from a synergistic perspective, but also it is an owner of this entity. Agenus owns about 48% of MiNK. And we don't want to use that as leverage. But on the other hand, it is a major benefit for both companies for us to be intertwined in that way.

我們非常高興我們是這裡的主要利益相關者，不僅從協同的角度來看，而且也是該實體的所有者。Agenus 擁有 MiNK 約 48% 的股份。我們不想利用這一點作為籌碼。但另一方面，我們以這種方式合作對兩家公司來說都是非常有利的。

But thank you very much. So we're now pushing 5:05 actually. So we can choose to show Jennifer's, not this Jen, but one of our patients' video, if you will. This is a very touching video, and it speaks to Dr. Nick DeVito's point about life with chemotherapy in the same patient versus life with an immunotherapy. So if we can roll that video, Andy, that would be --

但還是非常感謝。所以我們現在實際上正在推進 5:05。因此，如果您願意的話，我們可以選擇播放 Jennifer 的視頻，不是這個 Jen，而是我們的一位患者的視頻。這是一個非常感人的視頻，它表達了 Nick DeVito 博士關於同一患者接受化療和接受免疫療法治療的生活的觀點。所以如果我們可以播放那個視頻，安迪，那將是--

(video playing)

（影片播放）

So with that note, I think it's all of our moral responsibility to work collaboratively, particularly with the new leadership in Washington, in the health agencies, the FDA, with Dr. Makary to make sure that patients are -- do their best treatment options as quickly as possible. I mean, waiting four or five years for randomized trial readout before patients get widely access to drugs like BOT and BAL is really not an acceptable outcome for us and for patients, it's not just for us. It's not acceptable for patients.

因此，我認為我們所有人都有道義上的責任去合作，特別是與華盛頓的新領導層、衛生機構、FDA 以及 Makary 博士合作，以確保患者能夠盡快得到最好的治療。我的意思是，等待四到五年的隨機試驗結果出來後，患者才能廣泛使用 BOT 和 BAL 等藥物，這對我們和患者來說確實是一個不可接受的結果，這不僅對我們有意義。這對於患者來說是不可接受的。

So in my closing remarks before we take on questions, I know that in everybody's mind, as a company, we've had challenges being around for 31 years is not an easy undertaking and 31 years with unwavering commitment to the belief that immuno-oncology would be the holy grail to curing cancer.

因此，在我們回答問題之前的結束語中，我知道在每個人心中，作為一家公司，我們面臨著 31 年的挑戰，這並非易事，31 年來，我們始終堅定不移地相信免疫腫瘤學將是治愈癌症的聖杯。

And it has come with its financial challenges; we have persisted. It has come with its regulatory challenges, we have persisted. And here we are. Here we are at a point where I think we're seeing the light at the end of the tunnel on all fronts. And I'm delighted that, for example, in our recent undertaking with Zydus Corporation, that we will be given the opportunity on all fronts because there's a sharing of some of the burden in terms of our manufacturing burden to be transferred to Zydus and for them to explore other opportunities with other clients because we have a state-of-the-art manufacturing facility in Emeryville that will become a facility of Zydus with us having access to it for our own needs.

儘管它也帶來了財務挑戰，但我們堅持了下來。儘管它帶來了監管挑戰，但我們一直堅持下去。現在我們就在這裡。現在，我認為我們已經看到了各方面隧道盡頭的光。我很高興，例如，在我們最近與 Zydus 公司的合作中，我們將在各個方面獲得機會，因為我們將分擔一些製造負擔，將其轉移到 Zydus，並讓他們探索與其他客戶合作的其他機會，因為我們在埃默里維爾擁有一個最先進的製造工廠，它將成為 Zydus 的一個工廠，我們可以使用它來滿足我們自己的需求。

That transaction is slated to close soon, and I'll tell you what soon is because this is a point of question among investors and others. There are so many bureaucracies like in anything else to overcome. And when we entered into this collaboration towards the closing, the first challenge was Hart-Scott-Rodino clearance. I'm very, very delighted to announce that we have cleared HSR just in the last couple of weeks.

該交易預計很快就會完成，我會告訴你「很快」是什麼，因為這是投資者和其他人的疑問點。就像其他事情一樣，還有很多官僚主義問題需要克服。當我們在接近尾聲時開始合作時，第一個挑戰是 Hart-Scott-Rodino 的批准。我非常非常高興地宣布，我們在過去幾週內已經完成了 HSR 的通關。

And the next hurdle is a hurdle that I wasn't even aware that existed. And that will be a hurdle with the treasury department that is particularly concerning companies that get into business with US companies. And that hurdle is expected to clear in the next two to three weeks. And after that, we should very expeditiously be able to close the transaction.

而下一個障礙是我甚至不知道存在的障礙。這對財政部來說是一個障礙，特別是對於與美國公司有業務往來的公司。預計這一障礙將在未來兩到三週內消除。此後，我們應該能夠非常迅速地完成交易。

So I will end my talk, and I want to thank our participants because they have been the real stars of this session. If there are questions for me and our participants, all four participants, please do so. Stefanie Nacar is going to be moderating the question-and-answer period. So go ahead, Stefanie.

我的演講就此結束，我要感謝我們的參與者，因為他們是這次會議的真正明星。如果有任何問題想問我以及我們的參與者，所有四位參與者，請提出來。史蒂芬妮·納卡 (Stefanie Nacar) 將主持問答環節。所以繼續吧，史蒂芬妮。

Great. Thank you very much, Garo. And thank you all for your continued engagement throughout the webcast today. It's been fantastic.

偉大的。非常感謝，Garo。感謝大家今天在整個網路直播中的持續參與。太棒了。

And we've had a number of questions already come in. (Operator Instructions)

我們已經收到了許多問題。（操作員指示）

But we do already have a couple of questions come in. So let me go ahead and get started with that. Some of the questions, Garo, actually did have to do with the status of the Zydus collaboration. And so thank you very much for addressing the state of that transaction and the next steps there.

但我們確實已經收到了幾個問題。那麼就讓我繼續開始吧。Garo，有些問題其實與 Zydus 合作的狀態有關。非常感謝您解決交易的狀態以及後續步驟。

We do have some questions here related to the Phase III study. The first question, I will ask Chris to go ahead and answer. And you did provide us a great background, Chris, of the collaboration and the interest that CCTG had in conducting this study with BOT/BAL.

我們確實有一些與第三階段研究相關的問題。第一個問題，我請克里斯來回答。克里斯，你確實為我們提供了很好的背景信息，說明了 CCTG 與 BOT/BAL 合作進行這項研究的興趣。

The question here is related to, can you share some additional resources that CCTG provides the partnership? And what does the monetary commitment look like in order to execute the study?

這裡的問題是，您能否分享 CCTG 為合作夥伴提供的一些額外資源？為了完成這項研究，需要投入多少資金？

Sure. Thank you very much, Stefanie. So the CCTG has a long history of executing clinical trials. As I mentioned to Garo, we've been around for 45 years. As an academic cooperative group, we are capable of doing everything from Phase I to Phase III. We don't limit ourselves to colorectal cancer. We research all types of cancers. We research all modalities of therapy.

當然。非常感謝你，史蒂芬妮。因此，CCTG 有著悠久的臨床試驗執行歷史。正如我向 Garo 提到的，我們已經存在 45 年了。作為一個學術合作小組，我們有能力完成從第一階段到第三階段的所有工作。我們的研究範圍並不限於大腸直腸癌。我們研究所有類型的癌症。我們研究所有治療方式。

We are really a clinical trials organization, and we are renowned for our excellence and our ability to get those trials done. That said, a large Phase III trial like we have proposed and Agenus has agreed to support of 834 patients really requires an international effort. And thankfully, we have cultivated a long-standing and productive collaboration with other groups like ourselves around the world, specifically the Australasian Gastro-Intestinal Trials Group in Australia and New Zealand.

我們是一個真正的臨床試驗組織，我們因卓越的品質和完成試驗的能力而聞名。話雖如此，像我們提議的、並且 Agenus 已同意支持的 834 名患者的大型 III 期試驗確實需要國際上的努力。值得慶幸的是，我們與世界各地的其他類似組織建立了長期而富有成效的合作關係，特別是澳大利亞和紐西蘭的澳洲胃腸道試驗小組。

We have done multiple trials successfully in this same patient population. We've done other GI trials with our Unicancer colleagues who are a federation of French cancer centers over the years. And bringing all three of our organizations together in the context of demonstrated abilities to recruit patients from this population really provides an assurance that we can get this study done, and we should be able to get it done in a quite timely way.

我們已經在同一患者群體中成功進行了多次試驗。多年來，我們與法國癌症中心聯合會 Unicancer 的同事們一起進行了其他胃腸道試驗。在擁有從這一人群中招募患者的能力的前提下，將我們三個組織聚集在一起，確實保證了我們能夠完成這項研究，而且我們應該能夠及時完成它。

I know it's never fast enough. It is a requirement for regulatory authorities around the world that we demonstrate these positive Phase III studies. So we have to do it, but we need to do it quickly.

我知道它永遠不夠快。世界各地的監管機構都要求我們證明這些積極的第三階段研究。所以我們必須這麼做，但需要盡快行動。

In terms of the financial support for the organization, the Canadian Cancer Trials Group is funded in our core funding from the Canadian Cancer Society. We are a major program grant of them and have been for 45 years. And we leverage funding -- core funding from the Canadian Cancer Society from a variety of other sources, academic grants are one, pharma support -- unrestricted pharma support is another, but it works out to about 10:1.

在組織資金支持方面，加拿大癌症試驗組的核心資金來自加拿大癌症協會。我們是他們資助的一個主要項目，已有 45 年歷史。我們利用資金——核心資金來自加拿大癌症協會，還有來自其他各種來源的資金，學術補助是其中之一，製藥支持——無限制製藥支持是另一個，但比例約為 10:1。

So we are a solid, stable organization able to conduct and fund the trials that we do.

因此，我們是一個堅實、穩定的組織，能夠進行並資助我們所做的試驗。

And do you see any gating steps in actually initiating the Phase III study this year? And you already shared a little bit about the number of patients that we anticipate enrolling, but maybe you could share a little bit more about the scheme of the study design itself and what the control arm will be?

您是否認為今年啟動第三階段研究會採取任何限制措施？您已經分享了一些我們預計招募的患者人數，但也許您可以分享更多關於研究設計方案本身以及對照組的資訊？

Yes. So the study is about as far away from the patients that Dr. DeVito was describing as possible. So the typical patient that we would be considering for our study is a patient who has undergone the full trajectory, the full gamut of the treatments that are available for their colorectal cancer, progressively their disease has become resistant to one after the other.

是的。因此，這項研究與德維托博士所描述的患者相距甚遠。因此，我們研究中考慮的典型患者是已經經歷了完整的治療過程、接受了針對其結腸直腸癌的所有治療的患者，但其病情逐漸對一種又一種療法產生了抗藥性。

And there's a large proportion of these patients who end up in a situation where there are no standard available treatments for them. And those patients are usually still fit and healthy and looking for treatment options, looking for options to extend their lives. And so that is the population that our trial will target.

其中很大一部分患者最終陷入無法獲得標準治療的情況。這些患者通常仍然身體健康，並且正在尋找治療方案，尋找延長生命的選擇。這就是我們試驗的目標族群。

They will be patients who have microsatellite stable disease. So that's what would have normally have been considered a cold tumor. And we will enroll those patients in a one-to-one randomization so that half of the patients will receive BOT and BAL according to the same treatment regimens that you have been using on your Phase I and II studies.

他們將是患有微衛星穩定疾病的患者。這就是通常被認為是冷腫瘤的東西。我們將以一對一隨機的方式招募這些患者，以便一半的患者將按照您在 I 期和 II 期研究中使用的相同治療方案接受 BOT 和 BAL 治療。

And the other 50% of the patients on our trial will be patients who will proceed with what are known as best supportive care measures. And that is -- actually, it sounds terrible, but it is appropriate in the context of patients who have exhausted all other lines of therapy. There really is no available therapy left for those patients.

我們試驗中的另外 50% 的患者將接受所謂的最佳支持性治療措施。事實上，這聽起來很可怕，但對於那些已經用盡所有其他治療方法的患者來說，這是合適的。對於這些患者來說，確實沒有可用的治療方法。

So that trial will recruit, as I said, 834 patients. We're projecting that recruitment to occur over a period of approximately 20 to 24 months. There will be a period of follow-up as we mature -- wait for the data to mature, and then there will be an analysis. And we're confident and cautiously optimistic that it will be supportive for registration of BOT and BAL internationally.

正如我所說，該試驗將招募 834 名患者。我們預計招聘將持續約 20 至 24 個月。隨著我們逐漸成熟，將會有一段時間的追蹤——等待數據成熟，然後進行分析。我們有信心並謹慎樂觀地認為，這將支持 BOT 和 BAL 在國際上的註冊。

Thank you very much, Chris. Wonderful. And stay tuned because I may call you for additional questions as they come in.

非常感謝，克里斯。精彩的。請繼續關注，因為一旦有其他問題，我可能會打電話給您。

But still on the topic of the Phase III, Garo, I have a question here for you. I know that there's been a lot of work that the organization has done certainly even as we've announced recently with the outcomes of the regulatory and the FDA meeting just in July.

但仍然關於第三階段的話題，Garo，我有一個問題想問你。我知道該組織已經做了很多工作，正如我們最近宣布的 7 月監管和 FDA 會議的結果一樣。

But there was a question that came in that -- why the delay? Why has the study since the completion of the Phase II been delayed by approximately 18 months? So maybe can you share some light on that, please?

但有一個問題出現了──為什麼會延遲？為什麼第二階段的研究自完成以來被推遲了大約18個月？那麼，您能否就此分享一些見解呢？

Well, first of all, at last year's FDA meeting, about a year ago and change, the FDA was still insisting on doing a three-arm trial. And even though we had brought in some of the experts that had experience with BOT/BAL and patients that had experienced with BOT/BAL to submit that doing a three-arm trial would not be ethical based on the data that was generated. And it would not be able to accrue patients expeditiously.

首先，在去年的 FDA 會議上，大約一年前，FDA 仍然堅持進行三組試驗。儘管我們請來了一些有 BOT/BAL 經驗的專家和有 BOT/BAL 經驗的患者，但他們表示，根據產生的數據，進行三組試驗是不道德的。而且它也無法迅速地累積病人。

It took the FDA about a year with some minor additional data to come to the conclusion that a three-arm trial was not necessary, that a two-arm trial would be the way to go. And so that delayed us by at least a year. And at this year's meeting with the FDA, one concession, an important concession they made was the fact that they agreed to a two-arm trial.

FDA 花了大約一年的時間，並根據一些額外的數據得出結論：三組試驗沒有必要，雙組試驗才是可行的方法。這導致我們至少耽誤了一年的時間。在今年與 FDA 的會議上，他們做出的讓步，一項重要的讓步，就是同意進行雙臂試驗。

They agreed to the fact that contribution of the components were demonstrated. And so there was no real reason to probe that any further in spite of the fact that they formally had engaged with us to tell us prior to that, the contribution of the elements was not reached or was not satisfactorily demonstrated.

他們同意組件的貢獻已經得到證明。因此，儘管他們之前已經正式與我們接洽並告知我們，但這些元素的貢獻尚未達到或沒有得到令人滿意的證明，因此沒有真正的理由進一步探究。

And I might add that all of this is happening with not a lot more data that was presented to the agency. So there was a change of hearts in a favorable fashion, and we're delighted with that outcome, actually.

我想補充的是，所有這一切都是在向該機構提交的數據並不多的情況下發生的。因此，人們的想法發生了積極的變化，事實上，我們對這個結果感到非常高興。

Yes. Thank you for that further explanation. I know that nobody other than us would like to initiate this trial as quickly as possible with the hopes of getting this combination treatment to patients. But the longer-term follow-up, as you mentioned, was essential for making it easier for patients in this study and to show the evidence for the contribution of components. So thank you.

是的。感謝您的進一步解釋。我知道，除了我們之外，沒有人願意盡快啟動這項試驗，希望將這種聯合治療方法應用於患者。但是，正如您所提到的，長期追蹤對於讓本研究中的患者更容易接受治療以及顯示各成分貢獻的證據至關重要。所以謝謝你。

We actually are going to pivot a little bit from the Phase III late line study. We've been receiving a lot of questions regarding our neoadjuvant strategy. So I'd like to bring Steven O'Day on to perhaps answer some of those questions.

實際上，我們將從第三階段後期研究中稍微轉變。我們收到了很多有關新輔助治療策略的問題。因此我想請 Steven O'Day 來回答其中的一些問題。

So firstly, we've done a lot of neoadjuvant studies with some of our partnerships and investigators. And one of the questions is, what else are we doing in the neoadjuvant setting? And are there additional investigator-sponsored trials that are planning or initiating near term? And are there any other data reads out that were expected for the remainder of the year as well?

首先，我們與一些合作夥伴和研究人員進行了大量新輔助研究。其中一個問題是，我們在新輔助治療中還能做些什麼？是否有其他研究者發起的試驗正在規劃或啟動？今年剩餘時間是否還有其他預期的數據讀數？

Thank you, Stefanie. It's great to participate in this. Rich Goldberg has really brought this high, high level of GI understanding from a clinical and a patient and a regulatory perspective. And he's had nine months to look at the data. I've actually had eight years to look at the data and come from the perspective of the -- really the first revolution in melanoma.

謝謝你，斯蒂芬妮。能夠參與這個活動真是太好了。Rich Goldberg 確實從臨床、患者和監管的角度帶來了高水平的胃腸道理解。他有九個月的時間來查看這些數據。我實際上花了八年的時間來研究這些數據，並從黑色素瘤的第一次革命的角度來看待它。

And it's really remarkable to see BOT/BAL perform in over 1,200 patients in many different settings. And I think what's clear is there is a late-line setting across multiple solid tumors of patients having deep durable responses that we know. And then it takes sort of brave courageous trials to move earlier line, just like we did in melanoma from late-line to early-line metastatic that Nick has described, and we're looking forward to watching this really exciting data emerge in the next year.

看到 BOT/BAL 在不同的環境下對超過 1,200 名患者發揮作用，真是令人驚嘆。我認為，很明顯的是，我們所知的針對多種實體腫瘤的晚期治療方案對患者俱有深度持久的反應。然後需要進行一些勇敢的試驗來將治療轉移到早期，就像尼克所描述的那樣，我們將黑色素瘤從晚期轉移到早期轉移，我們期待在明年看到這些真正令人興奮的數據。

But obviously, all of our hearts, and I speak for the melanoma community and the IO community in general, SITC and others, the neoadjuvant space where you have an intact tumor that has not yet metastasized and that serves as the education center for the T cells is phenomenal in terms of its ability to drive memory and tumor eradication. And we learn that in melanoma in the neoadjuvant setting.

但顯然，我們所有人，包括我代表黑色素瘤社區和整個 IO 社區、SITC 和其他人，都認為新輔助治療領域是一個完整的腫瘤，尚未轉移，並且可作為 T 細胞的教育中心，就其驅動記憶和腫瘤根除的能力而言，它具有驚人的效果。我們在新輔助治療中了解到了黑色素瘤的情況。

And what we also learned that what Garo brought up is the rapidity of these neoadjuvant responses is remarkable. People said it took -- would take forever for the immune system to really reignite. When you have good drugs, like in melanoma with first-generation molecules, it happens within four to eight weeks, dramatic.

我們也了解到，正如 Garo 所提到的，這些新輔助治療的反應速度非常驚人。人們說免疫系統要真正重新活化需要很長時間。當你擁有好的藥物時，例如治療黑色素瘤的第一代分子藥物，它會在四到八週內發生，非常顯著。

What we're seeing with BOT/BAL in a setting with tumors that have historically not responded, we're seeing that an intact tumor in the early neoadjuvant setting. We're seeing the same kind of responses quick, deep and durable. And now we've explored in multiple ISTs, one in the US, the NEST trial in colorectal cancer, a second multicenter Italian study with colorectal cancer with one dose of BOT and two doses a BAL, and we're seeing remarkable 40%-plus of patients within four to eight weeks are having complete or near complete responses.

我們在歷史上沒有反應的腫瘤環境中使用 BOT/BAL 所看到的是，我們在早期新輔助環境中看到了完整的腫瘤。我們看到了同樣的反應，快速、深入且持久。現在，我們已經在多個 IST 中進行探索，一個在美國，即針對結直腸癌的 NEST 試驗，另一個在意大利的多中心研究中，針對結直腸癌患者使用一劑 BOT 和兩劑 BAL，我們發現 40% 以上的患者在四到八週內獲得了完全或接近完全的反應。

And then finally, Myriam Chalabi has taken the same approach at the Netherlands Cancer Institute across multiple solid tumors. And at AACR, she presented the first patients there, similarly high response rates, almost tumor agnostic. And this includes breast cancer, triple-negative ER-positive sarcomas. It's sort of mimicking the trajectory of our late-stage pan-tumor data.

最後，荷蘭癌症研究所的 Myriam Chalabi 對多種實體腫瘤採取了同樣的方法。在 AACR，她向第一批患者展示了同樣高的反應率，幾乎與腫瘤無關。其中包括乳癌、三陰性 ER 陽性肉瘤。這有點像是模仿我們後期全腫瘤數據的軌跡。

So the data is consistent. It gets better as you go earlier, and when you have effective IO drugs, they work. And then finally, the rectal cancer space is hugely important for all the reasons Garo and others have talked about, the organ preservation, the infertility, the chronic toxicities that patients undergo with locally advanced rectal cancer.

所以數據是一致的。越早開始，情況就會越好，而且當您有有效的骨內注射藥物時，它們就會起作用。最後，直腸癌治療領域極為重要，原因如 Garo 和其他人所述，包括器官保存、不孕症以及局部晚期直腸癌患者所經歷的慢性毒性。

And most of our neoadjuvant data today has been in colon cancer that Andrea Cercek has launched a neoadjuvant rectal study with BOT and BAL really to mimic the MSI-high cohort that she and others have had paradigm shifting treatments. So we look forward to watching BOT/BAL perform in a number of neoadjuvant settings in the coming 6 to 12 months and ongoing reporting of the data.

我們今天的大部分新輔助治療數據都來自結腸癌，Andrea Cercek 已啟動一項新輔助直腸癌研究，使用 BOT 和 BAL 來模擬她和其他人進行過範式轉變治療的 MSI 高患者群。因此，我們期待在未來 6 到 12 個月內觀察 BOT/BAL 在多種新輔助治療中的表現並持續報告數據。

Yes. Thanks, Steven. And related to that studies and other neoadjuvant studies, are we doing anything specifically to identify patients that have MSS disease? Certainly, we've also -- a lot of our focus is certainly on filling that unmet need in the MSS tumor types. But there's also data certainly that we have in MSI-high as well.

是的。謝謝，史蒂文。與該研究和其他新輔助研究相關，我們是否採取了任何具體措施來識別患有 MSS 疾病的患者？當然，我們的重點也集中在滿足 MSS 腫瘤類型中未滿足的需求。但我們肯定也擁有 MSI-high 的數據。

But one of the questions is, what are we doing with biomarkers otherwise to help identify those patients with MSS disease?

但問題之一是，我們用生物標記做什麼來幫助識別那些患有 MSS 疾病的患者？

Yes. So this is the holy grail, right, of MSS disease. In warm or hot tumors, we have some sort of okay biomarkers, not great, TMB, PD-L1 in some setting. These are very still suboptimal markers to really enrich for dramatic IO responses. But in the cold tumor settings, we've really struggled mightily.

是的。所以這就是 MSS 疾病的聖杯。在溫腫瘤或熱腫瘤中，我們有一些還可以的生物標記物，但不是很好，在某些情況下是 TMB、PD-L1。這些仍然是次優標記，無法真正豐富戲劇性的 IO 反應。但在冷腫瘤環境中，我們確實遇到了巨大的困難。

What's interesting about BOT/BAL is this 20%-plus deep durable response in an end-stage sitting and maybe 40% to 50% as we move further as this neoadjuvant data, it would be wonderful to enrich even further to MSI-high type approaches. And so we are actively working both internally as well as external collaborations to really find ways to deeply enrich MS stable tumors so that more and more patients can have these long-term benefits.

BOT/BAL 的有趣之處在於，在末期治療中這種深度持久反應可達 20% 以上，而隨著我們進一步研究這種新輔助治療數據，這種反應可能會達到 40% 到 50%，如果能進一步豐富 MSI 高類型的方法，那就太好了。因此，我們正在積極進行內部和外部合作，真正找到深度豐富 MS 穩定腫瘤的方法，以便越來越多的患者能夠獲得這些長期益處。

Thank you, Steven, for that clarification. And while I have you on the line still, what's coming next at the end of -- between now and the end of 2025? ESMO is coming up. Can you reiterate some of the data that we'll be sharing at ESMO? And anything else that we can anticipate for the rest of the year?

謝謝史蒂文的澄清。當我還在跟你通話的時候，從現在到 2025 年底，接下來會發生什麼事？ESMO 即將到來。您能重申一下我們將在 ESMO 上分享的一些數據嗎？對於今年剩餘的時間我們還能期待什麼呢？

Yes, we're very excited about ESMO. We're going to be launching our BATTMAN trial in terms of investigators from around the world, in terms of getting that ready for the end of year launch. We're also going to be presenting more data in the refractory setting, not just colorectal cancer, but many other tumor types.

是的，我們對 ESMO 感到非常興奮。我們將與來自世界各地的研究人員一起啟動 BATTMAN 試驗，為年底啟動做好準備。我們還將提供更多關於難治性腫瘤的數據，不僅是大腸癌，還包括許多其他類型的腫瘤。

And I think what is so compelling to me and the reason I'm here and deeply invested is when you see -- when IO therapy works, we know what good looks like. And Rich has talked about it. I've talked about it through my career, Nick is now in his emerging career seen it.

我認為對我來說如此引人注目的原因以及我來到這裡並投入大量精力的原因是——當IO療法起作用時，我們知道什麼是好的。Rich 也曾談論過此事。我在我的職業生涯中談論過這一點，尼克現在在他新興的職業生涯中也看到了這一點。

These deep durable responses, even if it's 20% of patients, that is a game changer for those 20% when you don't have other good options. And when immunotherapy works, you can have short durations of treatment with reversible side effects. And the real advantage is long-term survival without the need for additional treatment. We call it treatment-free survival.

這些深度持久的反應，即使只適用於 20% 的患者，但當你沒有其他好的選擇時，對於這 20% 的患者來說，也是一個改變遊戲規則的機會。當免疫療法起作用時，您可以進行短時間的治療，並且副作用是可逆的。真正的優勢是無需額外治療即可長期生存。我們稱之為無治療存活期。

So we're going to see more of that data in our refractory setting and then obviously more neoadjuvant data in the coming year.

因此，我們將在難治性治療中看到更多此類數據，然後在未來一年顯然會看到更多新輔助治療數據。

Great. Thank you. And another question just came in, Steven, that I think would be great for you to answer. So related to the BATTMAN Phase III study, there's a question that has arisen. A lot of our studies has been in non-liver met patients. Can you describe any sort of stratification or inclusion in the Phase III trial related to those patients?

偉大的。謝謝。史蒂文，剛才有另一個問題，我認為你很適合回答。因此，關於 BATTMAN 第三階段研究，出現了一個問題。我們的許多研究都是針對非肝轉移患者進行的。您能否描述與這些患者相關的 III 期試驗的任何分層或納入情況？

So certainly, Chris can also answer this. I think the short answer to this is in the original first-generation CTLA-4 PD-L1 study that the Canadian Group did, they saw a positive study in all comers. And obviously, non-liver mets are even more enriched for IO response, but there was a survival benefit across all comers, meaning liver and non-liver, and we have better drugs.

所以當然，克里斯也可以回答這個問題。我認為這個問題的簡短回答是，在加拿大小組進行的最初的第一代 CTLA-4 PD-L1 研究中，他們看到了各方面的正面結果。顯然，非肝臟轉移瘤對免疫治療反應更為敏感，但無論肝臟或非肝臟轉移瘤，均具有生存益處，而且我們有更好的藥物。

Obviously, they had a 1% objective response rate in that trial with durva and treme with -- so 1% response rate, but still had a survival benefit, and we obviously have 20% or thereabouts deep durable responses in ours. So you can just imagine why we would want to look at all comers as well as our subgroups. And we think it will win on those.

顯然，他們在使用 durva 和 treme 的試驗中獲得了 1% 的客觀反應率 - 因此反應率為 1%，但仍然具有生存優勢，而我們顯然在我們的試驗中獲得了 20% 左右的深度持久反應。所以你可以想像為什麼我們要關注所有人以及我們的子群體。我們相信它會取得勝利。

Great. Thank you very much, Steven. Wonderful.

偉大的。非常感謝，史蒂文。精彩的。

I have a couple of questions for Garo related to some additional financing and some additional partnerships. One of the questions here is so much is going on within the government and at DC almost on a daily basis. One of the questions was just related to the India tariffs that were just announced.

我有幾個問題想問 Garo，涉及一些額外的融資和一些額外的合作關係。這裡的一個問題是，政府內部和華盛頓特區幾乎每天都發生很多事情。其中一個問題與剛剛宣布的印度關稅有關。

Did any of that impact our cost of goods with the Zydus deal or for the Phase III development? And could you give any background on where you see that impacting or not impacting at all?

這些是否影響了我們與 Zydus 交易或第三階段開發的商品成本？您能否提供一些背景信息，說明您認為這會產生什麼影響或根本不會產生什麼影響？

I think the impact is a positive impact on us because while I'm not an economist, it's common sense that if there are tariffs on various countries like India, that means that anything that they ship from that country to the US will be subject to a tariff or taxation.

我認為這種影響對我們來說是正面的影響，因為雖然我不是經濟學家，但常識是，如果對印度等各國徵收關稅，那就意味著從該國運往美國的任何商品都將被徵收關稅或徵稅。

Now by Zydus purchasing this facility, they'll be able to have a means of producing biomolecules in this particular case, in a facility that is a US facility, that will not be subject to tariffs. So it's a big advantage. And so we're delighted with that outcome for our collaborator partner with Zydus.

現在，透過 Zydus 購買該工廠，他們將能夠擁有一種生產生物分子的方法，在這種特殊情況下，該工廠是美國工廠，不會受到關稅的影響。所以這是一個很大的優勢。因此，我們對與 Zydus 的合作夥伴所取得的成果感到非常高興。

Now in terms of financing, you asked, Stefanie, of course, Zydus was the first step. We're currently engaged in multiple discussions with one particular discussion that is closer to maturity, if you will, that will result in a significant infusion of also cash into the company.

現在就融資而言，你問，史蒂芬妮，當然，Zydus 是第一步。我們目前正在進行多項討論，其中一項討論已經接近成熟，這將為公司帶來大量現金注入。

We haven't released the details of that. But all I can tell you is that the details are such that we will keep the rights to BOT/BAL, which is right now, is a most valuable molecule for us for the major territories. That includes US, Europe, Japan, and South America. Those territories will still be with us with this potential transaction coming to a head soon.

我們尚未公佈相關細節。但我可以告訴你的是，具體細節是這樣的，我們將保留 BOT/BAL 的權利，對於我們目前的主要地區來說，它是最有價值的分子。其中包括美國、歐洲、日本和南美洲。隨著這項潛在交易即將達到高潮，這些地區仍將屬於我們。

Now if you let me, I know we're coming to our finale here in terms of timing. Let me first thank you all of the participants on this call for your time. We allotted an appropriate amount of time to cover all bases here. I want to thank our participating experts, internal and external experts, very much for your insights.

現在，如果你讓我知道，從時間上來說，我們即將迎來結局。首先，我要感謝參加本次電話會議的所有參與者的時間。我們分配了適當的時間來涵蓋這裡的所有基礎。我要非常感謝我們與會的專家，包括內部和外部專家，感謝你們的真知灼見。

I'd also like to thank our collaborators, many of whom are on this call. And also our colleagues that are not just in science and medicine, but in all divisions of the company, they have worked very hard throughout. They have been dedicated believers in our mission. So I want to thank the entire Agenus team for making all of this possible.

我還要感謝我們的合作者，他們中的許多人都參加了這次電話會議。還有我們的同事，不僅在科學和醫學領域，而且在公司的所有部門，他們一直都非常努力地工作。他們始終堅信我們的使命。所以我要感謝整個 Agenus 團隊，是他們讓這一切成為可能。

We are yet to reach our final endgame here, but I think we're getting closer. And I'm delighted that our external environment, including our regulatory environment, maybe moving in the right direction, and that will be a big, big advantage for a company that has dedicated its efforts to make sure that patients benefit and patients benefit in a meaningful fashion, not in terms of days and weeks extension in life, but in a manner that is going to be transforming their lives and the families' lives in every way possible.

我們還沒有到達最後的結局，但我認為我們正在接近它。我很高興我們的外部環境，包括我們的監管環境，可能正朝著正確的方向發展，這對於一家致力於確保患者受益並以有意義的方式受益的公司來說是一個巨大的優勢，這種受益不是通過延長幾天或幾週的生命來實現，而是通過盡可能地改變他們和家人的生活的方式。

So thank you very much.

非常感謝。