Allogene Therapeutics Inc (ALLO) 2024 Q3 法說會逐字稿

Hello, and thank you for standing by. Welcome to Allogene Therapeutics' third quarter 2024 conference call. (Operator Instructions) Please be aware that today's conference call is being recorded.

您好，感謝您的支持。歡迎參加 Allogene Therapeutics 2024 年第三季電話會議。（操作員指示）請注意，今天的電話會議正在錄音。

I would now like to turn the call over to Christine Cassiano, Chief Corporate Affair and Brand Strategy Officer. Ms. Cassiano, please go ahead.

現在，我想將電話轉給首席企業事務和品牌策略長 Christine Cassiano。卡西亞諾女士，請繼續。

Thank you, operator, and welcome to all who have joined this call. After the market closed today, Allogene issued a press release that provides a business update and financial results for the third quarter of 2024. This press release and today's webcast are available on our website.

謝謝接線員，歡迎所有參加本次通話的人。今天收盤後，Allogene 發布了一份新聞稿，提供了 2024 年第三季的業務更新和財務表現。本新聞稿和今天的網路廣播可在我們的網站上查閱。

Following our prepared remarks, we will host a Q&A session. We recognize that historically questions have been multifaceted but note that we will endeavor to keep this call to under an hour. Joining me today are Dr. David Chang, President and Chief Executive Officer; Dr. Zachary Roberts, Executive Vice President of Research and Development and Chief Medical Officer; and Geoff Parker, Chief Financial Officer.

在我們準備好的發言之後，我們將舉辦問答環節。我們認識到歷史上的問題是多方面的，但請注意，我們將盡力將本次通話時間控制在一小時以內。今天與我一起出席的還有總裁兼執行長 David Chang 博士；研發執行副總裁兼首席醫療官 Zachary Roberts 博士；以及財務長傑夫·帕克（Geoff Parker）。

During today's call, we will be making certain forward-looking statements. These may include statements regarding the success and timing of our ongoing and planned clinical trials, data presentations, regulatory filings, future research and development efforts, manufacturing capabilities, the safety and efficacy of our product candidates, commercial market forecasts, and 2024 financial guidance, among other things.

在今天的電話會議中，我們將做出某些前瞻性的陳述。這些可能包括有關我們正在進行和計劃中的臨床試驗的成功和時間表、數據展示、監管備案、未來研發工作、製造能力、我們候選產品的安全性和有效性、商業市場預測和 2024 年財務指導等的聲明。

These forward-looking statements are based on current information, assumptions, and expectations that are subject to change. A description of the potential risks can be found in our press release and latest SEC disclosure documents. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements.

這些前瞻性陳述基於當前資訊、假設和預期，可能會發生變化。在我們的新聞稿和最新的 SEC 揭露文件中找到有關潛在風險的描述。請注意不要過度依賴這些前瞻性陳述，Allogene 不承擔任何更新這些陳述的義務。

I'll now turn the call over to David.

現在我將電話轉給大衛。

Thank you, Christine, and welcome to those on the call today. Today, I'm excited to share our recent progress and upcoming milestones as we continue our mission to redefine cell therapy for both cancer and autoimmune disease.

謝謝你，克莉絲汀，歡迎今天參加電話會議的各位。今天，我很高興與大家分享我們最近的進展和即將到來的里程碑，我們將繼續我們的使命，重新定義癌症和自體免疫疾病的細胞療法。

In the third quarter, our groundbreaking achievements include, one, in heme malignancy, we continue to activate sites and advance the pivotal Phase 2 ALPHA3 trial of cema-cel for large B cell lymphoma. This trial marks a significant step forward as cema-cel could become the first CAR T therapy integrated into the first line treatment. With its focus on patient at high risk for relapse and the ability to potentially predict, who those patients might be, this trial could transform first line treatment and set a new standard for patient outcomes.

第三季度，我們所取得的突破性成果包括：一是在血液腫瘤領域，我們繼續活化站點並推進cema-cel針對大B細胞淋巴瘤的關鍵性2期ALPHA3試驗。這次試驗標誌著向前邁出的重要一步，因為 cema-cel 可能成為首個融入第一線治療的 CAR-T 療法。該試驗重點關注復發風險高的患者，並能夠預測這些患者可能是誰，因此它可能會改變第一線治療方法，並為患者治療結果樹立新的標準。

Solid tumors ALLO-316 is showing unprecedented efficacy in solid tumors through the Phase 1 TRAVERSE trial for renal cell carcinoma, achieving a confirmed response rate of 33% and best overall response rate of 50% in heavily pretreated patients with high CD70 expression. We define high CD70 expression as tumor proportion score greater than 50%, which represents the majority of patients. This breakthrough led to the RMAT designation from the FDA positioning ALLO-316 as a promising treatment for advanced renal cell carcinoma.

實體瘤 ALLO-316 在針對腎細胞癌的 I 期 TRAVERSE 試驗中顯示出對實體瘤前所未有的療效，在 CD70 表達高的、接受過大量治療的患者中實現了 33% 的確認反應率和 50% 的最佳總體反應率。我們將高 CD70 表現定義為腫瘤比例評分大於 50%，這代表了大多數患者。這項突破使 FDA 獲得了 RMAT 認證，將 ALLO-316 定位為治療晚期腎細胞癌的有希望的療法。

Pipeline. Our pipeline innovation extends into autoimmune diseases with ALLO-329, the first dual CD19/CD70 CAR designed to target CD19 positive B cells and CD70 positive T cells, both key drivers of autoimmune dysfunction. By addressing both B cells and activated T cells, we are tackling a broader spectrum of autoimmune mechanisms, which could significantly enhance therapeutic outcomes and expand the range of autoimmune diseases we can address. But what really differentiates ALLO-329 is our proprietary Dagger Technology. This technology, now clinically validated via the ALLO-316 program, could enable ALLO-329 to overcome one of the biggest anticipated barrier to cardiotherapy in autoimmune disorders, lymphodepletion.

管道。我們的產品線創新延伸至自體免疫疾病，包括 ALLO-329，這是首個雙重 CD19/CD70 CAR，旨在靶向 CD19 陽性 B 細胞和 CD70 陽性 T 細胞，這兩者都是自體免疫功能障礙的關鍵驅動因素。透過解決 B 細胞和活化 T 細胞的問題，我們正在解決更廣泛的自身免疫機制，這可以顯著增強治療效果並擴大我們可以解決的自身免疫疾病的範圍。但 ALLO-329 的真正與眾不同之處在於我們專有的 Dagger 技術。該技術目前已透過 ALLO-316 計畫進行臨床驗證，它可以使 ALLO-329 克服自體免疫疾病心臟治療中預計面臨的最大障礙之一——淋巴細胞耗竭。

We believe this unique feature of ALLO-329 will allow us to reduce or eliminate the need for lymphodepleting chemotherapy, which we believe is a significant barrier to advance CAR T beyond severe cases of autoimmune disorders.

我們相信 ALLO-329 的這一獨特特性將使我們能夠減少或消除對淋巴細胞清除化療的需求，我們認為這是 CAR T 在治療嚴重自體免疫疾病以外的領域取得進展的重大障礙。

Beyond its technical strength, ALLO-329 is designed as an off-the-shelf and once-and-done solution, which differentiates ALLO-329 from Autonomous CAR T or bispecific T cell engagers and allow us to potentially reach these larger patient population more efficiently. We anticipate an IND filing in first quarter 2025 with proof-of-concept data by year end 2025. A sneak peek at the potential of ALLO-329 in preclinical models will be presented at the American College of Rheumatology Convergence on November 18th, 2024.

除了技術優勢之外，ALLO-329 還被設計為一種現成的、一次性的解決方案，這使得 ALLO-329 與自主 CAR-T 或雙特異性 T 細胞接合器有所區別，並使我們能夠更有效地接觸到更大的患者群體。我們預計將於 2025 年第一季提交 IND 申請，並在 2025 年底提供概念驗證資料。2024 年 11 月 18 日，美國風濕病學會大會將展示 ALLO-329 在臨床前模型中的潛力。

Looking ahead to 2025, this development reflects a potential paradigm shift, highlighting the AlloCAR T platform's unique ability to address diverse patient needs. This journey is not without challenge as each trial brings its own level of complexity in a highly competitive field. It's for this reason, we crafted each program with a long-term vision in mind.

展望 2025 年，這一發展反映了潛在的範式轉變，凸顯了 AlloCAR T 平台滿足不同患者需求的獨特能力。這趟旅程並非沒有挑戰，因為在競爭激烈的領域，每一次試驗都有其自身的複雜程度。出於這個原因，我們在製定每個計劃時都考慮到了長遠的眼光。

As Wayne Gretzky famously said, skate to where puck is going to be, not where it has been. That's precisely our approach. By pursuing what we believe are best-in-class therapies with differentiated development approaches to maximize the key attributes of AlloCAR T, we are confident that this strategy of anticipating future needs will yield remarkable outcomes. Each of these programs has the potential to revolutionize the application of CAR T therapy in treating disease and shaping the future of medical practice.

正如 Wayne Gretzky 的名言，滑向冰球將要到達的地方，而不是它曾經到達過的地方。這正是我們的方法。透過追求我們認為一流的治療方法和差異化的發展方法來最大限度地發揮 AlloCAR T 的關鍵屬性，我們相信這種預測未來需求的策略將產生顯著的成果。每個項目都有可能徹底改變 CAR T 療法在治療疾病中的應用並塑造醫療實踐的未來。

Now, I would like to handle the call over to Zach to discuss the status of ALPHA3 trial and provide a deeper dive into the latest data from our ALLO-316 program.

現在，我想與 Zach 通話，討論 ALPHA3 試驗的狀態，並深入了解我們的 ALLO-316 計劃的最新數據。

Thank you, David. This quarter, Allogene has made substantial progress moving us closer to potentially redefining treatment options in both oncology and autoimmune diseases through our innovative AlloCAR T platform. Looking ahead to 2025, we're energized by the advancements in our pivotal cema-cel trial, the upcoming IND submission for ALLO-329 and the promising data for ALLO-316 in advanced renal cell carcinoma, recognized by the FDA as a potential breakthrough.

謝謝你，大衛。本季度，Allogene 透過創新的 AlloCAR T 平台取得了重大進展，使我們更接近重新定義腫瘤和自體免疫疾病的治療方案。展望 2025 年，我們的關鍵性 cema-cel 試驗的進展、即將提交的 ALLO-329 IND 以及 ALLO-316 在晚期腎細胞癌治療中的良好數據（被 FDA 認定為潛在突破）都為我們帶來了活力。

While we won't have an update on the ALPHA3 first line consolidation trial for cema-cell until mid-2025 when we finalize our go forward lymphodepletion regimen, I want to recognize our exceptional clinical team. They are navigating a highly complex landscape to bring trial sites online amid intense competition and I'm incredibly proud of their accomplishments to date.

儘管直到 2025 年中期我們最終確定淋巴細胞清除方案時，我們才會對 Cema-cell 的 ALPHA3 一線鞏固試驗進行更新，但我還是要對我們出色的臨床團隊表示讚賞。他們在極其複雜的環境中奮力前行，在激烈的競爭中將試驗站點上線，我對他們迄今為止所取得的成就感到無比自豪。

Since its launch in June, the trial has successfully activated 27 of the planned 50 sites, with approximately 60% of those at community centers. Although the proportion will shift as more academic sites are activated, this early emphasis on community-based centers is essential to assuring broad accessibility. If any CAR T therapy can make meaningful inroads into community settings, we believe, it will be an allogeneic product like ours. Beyond the LD selection in mid-2025, we continue to anticipate primary event-free survival data by the end of 2026 with potential for a biologics license application submission in 2027.

自 6 月啟動以來，該試點計畫已成功啟動計畫中的 50 個站點中的 27 個，其中約 60% 位於社區中心。雖然隨著更多學術場所的啟動，這一比例會發生變化，但早期對社區中心的重視對於確保廣泛的可及性至關重要。我們相信，如果任何 CAR-T 療法能夠在社區環境中取得有意義的進展，它將是像我們的一樣的異體產品。除了 2025 年中期的 LD 選擇之外，我們還將繼續預計在 2026 年底獲得無主要事件生存期數據，並有可能在 2027 年提交生物製劑許可申請。

I'd like to now turn your attention to ALLO-316 and the data we released this morning. We are excited to share ground-breaking Phase 1 data on ALLO-316, our first AlloCAR T product candidate for the treatment of advanced renal cell carcinoma or RCC. This data showcases the encouraging responses found in heavily-pretreated patients and underscores the potential for ALLO-316 to become a pivotal off-the-shelf CAR T therapy for solid tumors.

現在我想請大家關註一下 ALLO-316 和我們今天早上發布的數據。我們很高興與大家分享 ALLO-316 的突破性 1 期數據，ALLO-316 是我們首個用於治療晚期腎細胞癌或 RCC 的 AlloCAR T 候選產品。這些數據顯示了在接受過大量治療的患者中發現的令人鼓舞的反應，並強調了 ALLO-316 成為治療實體腫瘤的關鍵現成 CAR T 療法的潛力。

Let's dive into the details. I'll first start with response rates. A single infusion of ALLO-316 demonstrated an impressive 50% best overall response rate and a 33% confirmed response rate in patients with metastatic kidney cancer, with high CD70 target expression, defined as a Tumor Proportion Score, or TPS, above 50%. Importantly, the majority of patients with advanced or metastatic RCC have CD70 TPS scores at or above this level.

讓我們深入了解細節。我先從回覆率開始。對於轉移性腎癌患者，單次輸注 ALLO-316 顯示出令人印象深刻的 50% 最佳總體反應率和 33% 的確認反應率，這些患者的 CD70 標靶表達率較高（定義為腫瘤比例評分 (TPS) 高於 50%）。重要的是，大多數晚期或轉移性 RCC 患者的 CD70 TPS 評分等於或高於該水平。

Given the number of previous therapies these patients have been on, most of which were in combination, I can't overstate how meaningful this data is, a single infusion that generates responses in patients with advanced disease and also yields what we would call a treatment break. This is part of the reason we believe our investigators are eager to enroll patients in this trial.

考慮到這些患者之前接受過的治療的數量，其中大多數是聯合治療，我不能過分強調這些數據的意義，一次輸注就可以使晚期疾病患者產生反應，同時也產生我們所謂的治療中斷。我們相信，這也是我們的研究人員渴望招募病患參與這項試驗的原因之一。

Just as exciting as the response rates we've seen in TRAVERSE is the dose cohorts where we are seeing them. The rates I just mentioned, 50% overall and 33% confirmed responses, occurred in our selected Phase 1b expansion dose cohort. This dose cohort featured a standard fludarabine and cyclophosphamide-based lymphodepletion regimen. We believe the unprecedented antitumor activity of this allogeneic CAR in a solid tumor setting is attributable in part to our proprietary CD70 Dagger Technology.

我們在 TRAVERSE 中看到的反應率同樣令人興奮的是我們所看到的劑量組。我剛才提到的發生率為整體 50% 和確認反應率為 33%，這些發生在我們選定的 1b 期擴展劑量組中。此劑量組採用標準的氟達拉濱和環磷酰胺為基礎的淋巴細胞清除方案。我們相信，這種同種異體 CAR 在實體腫瘤環境中前所未有的抗腫瘤活性部分歸功於我們專有的 CD70 Dagger 技術。

With this technology and our deepening understanding of its intrinsic ability to selectively deplete activated CD70 positive alloreactive host T cells, we have seen robust expansion and sustained activity of ALLO-316 even with standard Flu Cy lymphodepleting chemotherapy regimens. This highlights the potential of the CD70 CAR as a next generation allogeneic platform capable of producing meaningful clinical responses in solid tumors and, in the case of ALLO-329, which incorporates the Dagger Technology, in autoimmune disorders as well.

利用這項技術以及我們對其選擇性消耗活化的 CD70 陽性同種反應性宿主 T 細胞的內在能力的深入了解，我們已經看到 ALLO-316 即使在標準 Flu Cy 淋巴細胞消耗化療方案下也能強勁擴增和持續活性。這凸顯了 CD70 CAR 作為下一代同種異體平台的潛力，該平台能夠在實體腫瘤中產生有意義的臨床反應，而對於採用 Dagger 技術的 ALLO-329 而言，其也能在自體免疫疾病中產生有意義的臨床反應。

Lastly, and something that has been much discussed, with the addition of another 20 patients enrolled, since the last data update, we have gained significant experience handling the potent activity of ALLO-316 and have established a safety profile that could enable continued progress in a challenging field like CAR T therapy for solid tumors.

最後，這也是被廣泛討論的一點，自上次數據更新以來，隨著另外 20 名患者的加入，我們在處理 ALLO-316 的強效活性方面獲得了豐富的經驗，並建立了安全性概況，這可以使我們在像實體腫瘤的 CAR-T 療法這樣具有挑戰性的領域繼續取得進展。

Through our newly implemented diagnostic and management algorithm, we have been able to effectively recognize and treat immune effector cell associated HLH like syndrome known as IECHS. Much like what was done in the early days of CAR T development as the industry wrestled with CRS and neurotoxicity, developing and proactively utilizing tools to mitigate risk, creates a pathway to maximizing potential efficacy and improving patient outcomes.

透過我們新實施的診斷和管理演算法，我們能夠有效地識別和治療免疫效應細胞相關 HLH 樣症候群（即 IECHS）。就像 CAR-T 開發早期業界努力解決 CRS 和神經毒性問題時所做的那樣，開發並積極利用工具來降低風險，為最大限度提高潛在療效和改善患者預後開闢了一條途徑。

The strength of our data has led to RMAT designation for ALLO-316, signifying the FDA's acknowledgment of ALLO-316 as a potential treatment for advanced RCC. While we don't typically comment on FDA interactions, the speed with which this designation was received reflects the promising impact ALLO-316 may have for patients with advanced or metastatic RCC.

我們數據的可靠性使得 ALLO-316 獲得 RMAT 認定，顯示 FDA 承認 ALLO-316 是一種治療晚期腎細胞癌的潛在方法。雖然我們通常不會對 FDA 的相互作用發表評論，但獲得該頭銜的速度反映了 ALLO-316 對晚期或轉移性 RCC 患者可能產生的良好影響。

The data will be featured in an oral presentation at the International Kidney Cancer Symposium, or IHCS, on November 8th, followed by a poster presentation at the Society For Immunotherapy of Cancer, or SITC's, annual meeting on November 9th. Both presentations will be accessible on our website.

這些數據將於 11 月 8 日在國際腎癌研討會 (IHCS) 上進行口頭報告，隨後於 11 月 9 日在癌症免疫治療學會 (SITC) 的年會上進行海報展示。這兩個簡報都可以在我們的網站上查看。

We continue to actively evaluate ALLO-316's safety and efficacy in the Phase 1b expansion cohort. This will help define the optimal dose for Phase 2 trials setting the stage for development for our CAR T technology in solid tumors. We are deeply encouraged by these results and the opportunity to offer hope to patients in need of new options for managing their disease. Today's data is a testament to the potential of ALLO-316 and ultimately, Allogene's commitment to advancing the field of CAR T cell therapy. We look forward to providing further updates, as we move into the next stages of development across all of our programs.

我們將繼續積極評估 ALLO-316 在 1b 期擴展隊列中的安全性和有效性。這將有助於確定第 2 階段試驗的最佳劑量，為我們的 CAR T 技術在實體腫瘤中的發展奠定基礎。這些結果讓我們深受鼓舞，我們有機會為需要新方法治療疾病的患者帶來希望。今天的數據證明了 ALLO-316 的潛力，並最終證明了 Allogene 對推動 CAR-T 細胞治療領域發展的承諾。隨著我們所有專案進入開發的下一階段，我們期待提供進一步的更新。

I'll now turn this call over to Geoff.

現在我將這通電話轉給傑夫。

Thank you, Zach. As I noted last quarter, Allogene is in an enviable position. We control the only clinically validated allogeneic CD19 CAR T product in a pivotal trial, positioned to transform how and where CAR Ts are used in heme malignancies.

謝謝你，扎克。正如我上個季度所指出的，Allogene 處於令人羨慕的地位。我們在關鍵試驗中控制了唯一經過臨床驗證的異體 CD19 CAR T 產品，旨在改變 CAR T 在血液惡性腫瘤中的使用方式和位置。

We control the only allogeneic CAR T that has shown real potential in solid tumors, and we control the only CD19/CD70 dual CAR that has been specifically designed to treat autoimmune disease. To continue with David's hockey analogy, these three shots on goal all have the potential to be transformative.

我們控制著唯一一種在實體腫瘤中顯示出真正潛力的同種異體 CAR T，我們控制著唯一一種專門設計用於治療自體免疫疾病的 CD19/CD70 雙 CAR。繼續大衛的曲棍球類比，這三次射門都有可能帶來改變。

Let me now turn to our financial highlights. Our cash balance as of the end of third quarter 2024 was $403.4 million in cash, cash equivalents, and investments, and our cash runway continues to extend into the second half of 2026. Q3 2024 research and development expenses were $44.7 million which includes $5.6 million in expenses associated with non-cash, stock-based compensation.

現在我來介紹一下我們的財務亮點。截至 2024 年第三季末，我們的現金餘額為 4.034 億美元（包括現金、現金等價物和投資），我們的現金跑道將繼續延伸到 2026 年下半年。2024 年第三季研發費用為 4,470 萬美元，其中包括 560 萬美元的非現金股票薪酬相關費用。

General and administrative expenses in Q3 were $16.3 million, which includes $7.8 million of non-cash, stock-based compensation expense. For Q3 2024, our net loss was $66.3 million or $0. 32 per share, including non-cash, stock-based compensation expense of $13.4 million and $10.7 million in non-cash impairment of long-lived asset expense.

第三季的一般和行政費用為 1,630 萬美元，其中包括 780 萬美元的非現金股票薪資費用。2024 年第三季度，我們的淨虧損為 6,630 萬美元，即 0 美元。每股收益 32 美元，其中包括 1,340 萬美元的非現金股票薪酬費用和 1,070 萬美元的非現金長期資產減損費用。

For 2024, we continue to expect a cash burn of approximately $200 million. We continue to expect full year 2024 GAAP operating expenses to be approximately $300 million, which includes estimated non-cash, stock-based compensation expense of approximately $60 million. This guidance excludes any impact from potential business development activities.

到 2024 年，我們預計現金消耗仍將達到約 2 億美元。我們繼續預計 2024 年全年 GAAP 營運費用約為 3 億美元，其中包括估計約 6,000 萬美元的非現金股票薪酬費用。本指引不包括任何潛在業務發展活動的影響。

We'll now open the call for questions.

我們現在開始回答問題。

(Operator Instructions) Tyler Van Buren, TD Cowen.

（操作員指示）Tyler Van Buren，TD Cowen。

Hi, guys. Good afternoon and congratulations on all the progress. I have a couple for you. The first one is just on the RCC data, the 30% confirmed response rate in these late line patients is, of course, pretty impressive. So can you give us insight into when you might be done with the expansion cohort and be able to start a pivotal for potential approval? And then the second is just regarding the read throughs of the 316 data to your 329 autoimmune program.

嗨，大家好。下午好，祝賀您的所有進展。我有一對給你。第一個是關於 RCC 的數據，這些晚期患者中 30% 的確認反應率當然是相當令人印象深刻的。那麼，您能否向我們透露何時可以完成擴展隊列並能夠開始獲得潛在批准的關鍵步驟？然後第二個只是關於將 316 個數據讀取到 329 個自體免疫程式中。

I agree that these data with just FC is impressive as we think about reducing or removing lymphodepletion. But can you discuss your confidence and safety in autoimmune specifically and why the 316 data might not be the best read through?

我同意，當我們考慮減少或消除淋巴細胞耗竭時，這些僅使用 FC 的數據就令人印象深刻。但是您能具體討論一下您對自身免疫的信心和安全性嗎？

Tyler, this is David Chang. The first one in terms of the status of ongoing TRAVERSE study, let me turn it over to Zach to answer the questions that you had.

泰勒，這是大衛張。第一個問題是關於正在進行的 TRAVERSE 研究的狀態，讓我把它交給 Zach 來回答你的問題。

Thanks, David, and thanks, Tyler. Great questions. The first one, how many patients do we expect to enroll into this expansion cohort? So we're aiming for approximately 20. We think that that will give us the sort of adequate number of patients to really ascertain response rate as well as durability, which of course we'll have to wait for that some of that information, to come in into next year. So we expect to be able to give a program update next year.

謝謝，大衛，謝謝，泰勒。很好的問題。第一個問題，我們預期這個擴展隊列將招募多少患者？因此我們的目標是大約 20。我們認為，這將為我們提供足夠數量的患者，以真正確定反應率和耐久性，當然，我們必須等到明年才能獲得這些資訊。因此我們希望明年能夠提供計劃更新。

As for the second question on 329, so we continue to be quite encouraged by the Dagger effect in the 316 program and we have some additional data in the poster that will kind of illustrate that even further. As with additional patients having been treated, we have more and more confidence that this is real. And in fact, we have selected a Phase 1b expansion lymphodepletion regimen that does not include ALLO-647. So we've already been able to demonstrate efficacy, with a reduced -- substantially reduced lymphodepletion regimen. So we have pretty high confidence actually that that will carry forward into the 329 program.

至於 329 的第二個問題，我們繼續對 316 計劃中的 Dagger 效應感到十分鼓舞，並且我們在海報中還有一些額外的數據可以進一步說明這一點。隨著更多患者得到治療，我們越來越相信這是真實的。事實上，我們選擇了不含 ALLO-647 的 1b 期擴展淋巴細胞清除方案。因此，我們已經能夠證明，透過減少——大幅減少淋巴細胞清除方案，其療效是顯著的。因此我們實際上非常有信心這將延續到 329 計劃中。

We don't intend to use 647 in the autoimmune setting. We'll be dealing with chemotherapy alone and while we haven't disclosed exactly the plan to really pressure test the ability to reduce or eliminate lymphodepletion that is definitely one of the key objectives of the early phase of that study.

我們不打算在自體免疫環境中使用 647。我們將單獨進行化療，雖然我們還沒有透露具體的計劃，但真正對減少或消除淋巴細胞耗竭的能力進行壓力測試，這絕對是該研究早期階段的主要目標之一。

And then finally, just to comment quickly on the safety piece. So we know that patients with advanced malignancies are fundamentally different from an inflammatory milieu from patients with autoimmune disease. Secondly, it's pretty obvious from the existing data that the duration of CAR T persistence and functional activity, namely the duration of, say, B cell aplasia as a biomarker of CAR T cell activity, we know that that is substantially lower in the autoimmune setting than it is in somebody who's got a very, very bulky tumors as many of the patients in the 316 program did.

最後，我只想快速評論一下安全部分。因此我們知道晚期惡性腫瘤患者的發炎環境與自體免疫疾病患者的發炎環境有著根本的不同。其次，從現有數據可以明顯看出，CAR-T 持久性和功能活動的持續時間，也就是作為 CAR-T 細胞活性生物標誌物的 B 細胞發育不全的持續時間，我們知道在自身免疫環境中，這一持續時間比患有非常非常大的腫瘤的人（如 316 計劃中的許多患者）要低得多。

Overall, we think that the intensity of the therapy that will be required in an autoimmune patient will be comparatively lower. That said, we have built a lot of experience dealing with the toxicity associated with ALLO-316 through management of infections, the details around IECHS. We have a really good handle on how to diagnose and manage these. We think that: Number one, lower intensity therapy in AIV. Number two, we will be absolutely ready for any talks that does crop up.

整體而言，我們認為自體免疫患者所需治療的強度相對較低。也就是說，我們在透過感染管理以及 IECHS 相關細節處理 ALLO-316 相關毒性方面積累了豐富的經驗。我們非常了解如何診斷和管理這些問題。我們認為：第一，AIV的治療強度要低。第二，我們將為任何即將舉行的會談做好絕對準備。

Tyler, let me just add. I mean, I think over the years we have learned that the patient population and indications and the tumor burden, so the target burden greatly influences safety as well as efficacy. So yes, we know, a lot from our experience in 316 and also through the course of developing 316, we learned to manage the adverse event a lot better.

泰勒，讓我補充一下。我的意思是，我認為多年來我們已經了解了患者族群和適應症以及腫瘤負擔，因此目標負擔極大地影響了安全性和療效。所以是的，我們從 316 的經驗以及開發 316 的過程中了解到很多，我們學會了更好地管理不良事件。

And to your specific question about the read through into the autoimmune program, my view is that this is something that we have to clinically test. I don't think there is a much read through that you can make, because of the indication target burden are so different between advanced kidney cancer versus autoimmune disease.

對於您關於解讀自體免疫程序的具體問題，我的觀點是，這是我們必須進行臨床測試的事情。我認為您不需要做太多閱讀，因為晚期腎癌和自體免疫疾病的適應症目標負擔有很大不同。

Brian Cheng, JPMorgan.

摩根大通的 Brian Cheng。

Hi. Thanks for taking our question. This is Sean on for Brian. Could you give us a better sense of the Grade 5 events that you reported in the data today? Were there any confounding effects that led to those cases? And on the IECHS case, could you walk through how the management algorithm is implemented? How easy will it be for doctors to monitor potential IECHS events?

你好。感謝您回答我們的問題。這是肖恩 (Sean) 取代布萊恩 (Brian)。您能否讓我們更了解您在今天的數據中報告的 5 級事件？是否存在一些混雜效應導致了這些情況的發生？關於 IECHS 案例，您能介紹一下管理演算法是如何實作的嗎？對醫生來說，監測潛在的 IECHS 事件是否容易？

Yes. Sean, thanks for those great questions. I mean, we disclose all the adverse event findings from the 316 and especially in oncology in patients with advanced metastatic disease. In my experience, there is never a simple adverse event. It's very much confounded by the underlying disease and also a lot of times in Phase 1 the doses that we use as well as different lymphodepletion that we have tested. So I can simply say that every case of the adverse events that we see in the 316, especially the Grade 5 events that you mentioned, are very confounded.

是的。肖恩，謝謝你提出這些很棒的問題。我的意思是，我們揭露了 316 的所有不良事件發現，特別是晚期轉移性疾病患者的腫瘤學發現。根據我的經驗，從來不會發生簡單的不良事件。它與潛在疾病有很大關係，而且在第一階段，我們使用的劑量很多時候以及我們測試過的不同淋巴細胞清除術也讓人困惑。因此，我可以簡單地說，我們在 316 中看到的每一例不良事件，特別是您提到的 5 級事件，都非常令人困惑。

I'll ask Zach to answer the second question.

我會讓札克回答第二個問題。

Yes. Thanks, Sean, and David. As far as management of IECHS, the algorithm that we've developed and is detailed in the upcoming SITC materials is pretty clear. It's very analogous in fact to the algorithms that were developed in the early days for CRS and ICANS. So there's sort of a two-step process. You monitor signs and symptoms and lab values carefully and there is, if you are convinced that there is an inflammatory process ongoing based on the diagnostic criteria, which are very, very clear, then you institute first-line therapy, and then you escalate quickly if you don't see a very rapid response to that first line therapy.

是的。謝謝，肖恩和大衛。就 IECHS 的管理而言，我們開發的演算法（在即將發布的 SITC 資料中詳細說明）非常清晰。事實上，它與早期為 CRS 和 ICANS 開發的演算法非常類似。所以這是一個兩步驟過程。您要仔細監測體徵、症狀和實驗室值，如果根據非常非常明確的診斷標準，您確信存在正在進行的發炎過程，那麼您就要進行一線治療，如果您沒有看到對一線治療的快速反應，那麼您就要迅速升級治療。

This is a tried-and-true methodology for managing CAR T related talks and this one is just a slightly different flavor given that it's IECHS. It should be pretty clear and pretty easy to implement. And in fact, it has been easy to implement in the study, when we needed it.

這是管理 CAR T 相關談判的久經考驗的方法，鑑於它是 IECHS，因此略有不同。它應該非常清晰並且非常容易實現。事實上，當我們需要它時，它很容易在研究中實現。

And Sean, I would also add, this entity, IECHS, now that it's more widely-recognized and based on the publications over the last couple of years, there's a much better understanding. And in fact, as people better understand this entity, it is being recognized as spectrum of cytokine release syndrome, but time course is a little bit different. And I think all these nuanced understanding is making the management of this hyper inflammatory events a lot easier.

肖恩，我還要補充一點，IECHS 這個實體現在已經得到了更廣泛的認可，並且根據過去幾年的出版物，人們對此有了更好的理解。事實上，隨著人們對該實體的了解不斷加深，它被認為是細胞激素釋放症候群的譜系，但時間過程略有不同。我認為所有這些細緻的理解使得這種過度發炎事件的管理變得容易得多。

Michael Yee, Jefferies

傑富瑞（Jefferies）

Hey, guys. Thanks for the updates. We had two questions. One was on your first line lymphoma study. I know it's early, but maybe just comment a little bit about what you're seeing out there in terms of the screening rate for MRD positivity? How are things in terms of execution going? And how are you thinking about the pace of enrollment, as you are getting that underway?

嘿，大家好。感謝您的更新。我們有兩個問題。其中一項是關於第一線淋巴瘤的研究。我知道現在還為時過早，但您能否就您所看到的 MRD 陽性篩檢率發表一點評論？執行方面進展如何？在你們進行這項工作時，您認為招生速度如何？

And then the second question is about autoimmune. Obviously, that has been a big focus point for a lot of different companies and actually we're seeing a lot of dynamics around CAR T versus T cell engagers and how battle around that. Maybe just comment about how you see CAR T there versus T cell engagers and talk a little bit about your perspective there, given what we're seeing out there. Thank you.

第二個問題是關於自體免疫。顯然，這一直是許多不同公司關注的重點，實際上我們看到了圍繞 CAR-T 與 T 細胞接合劑的許多動態以及如何圍繞這一問題的競爭。也許只是評論一下您如何看待 CAR T 與 T 細胞接合劑，並根據我們所看到的情況談談您的觀點。謝謝。

Mike, nice to hear from you. Always fantastic questions. I'm going to reverse the order. I'm going to talk about the AID and different modality that's going into, and I'll ask Zach to get back to the frontline study. I think what we all have to recognize is that through the experience of autologous CAR T over the last two to three years, people are sort of looking at the autoimmune disease as well as other diseases that are caused by overreactive B cells or antibody productions. We can think, how to manage these diseases in a totally different way.

麥克，很高興收到你的來信。總是提出奇妙的問題。我要撤銷這個命令。我將談論 AID 和正在進行的不同模式，然後我會請扎克回到前線研究。我認為我們都必須認識到，透過過去兩三年自體 CAR-T 的經驗，人們正在關注自體免疫疾病以及由過度反應的 B 細胞或抗體產生引起的其他疾病。我們可以思考如何用完全不同的方法來治療這些疾病。

B cell depletion, which is really underlying mechanism behind what are using T cell engagement or CAR T. I mean, that is being target and people are realizing that this can bring a substantial so called drug-free and disease-free interval to patients. When I think about autoimmune indications, I mean, there is so many different diseases and so many opportunities with respect to the modality, the way we view about different modalities and there are more than one modalities that can coexist. And even within one particular modality, I think there can be multiple successful stories. And if you look at the history of autoimmune drug development, that's exactly the case.

B 細胞耗竭，這實際上是使用 T 細胞參與或 CAR T 背後的潛在機制。當我考慮自體免疫指徵時，我的意思是，有這麼多不同的疾病和如此多的機會，就模式而言，我們看待不同模式的方式，以及可以共存的多種模式。我認為，即使在某一特定模式中，也可能有多個成功案例。如果你回顧自體免疫藥物開發的歷史，你會發現情況確實如此。

So I just want to emphasize the opportunities, the great opportunities that there is. Obviously, even in that context, our team thinks about, how is different modalities different and everything comes with a different twist. But for the allogeneic CAR T, I mean, one is this is off-the-shelf, the convenience and all those things factor in. And also, CAR T usually is being viewed as a once-and-done, one-time treatment. I think these are very attractive proposition to the physicians, who are managing the autoimmune disorders.

所以我只想強調存在的機遇，巨大的機會。顯然，即使在這樣的背景下，我們的團隊也會思考，不同的模式有何不同，以及一切都有何不同。但對於同種異體 CAR-T，我的意思是，一是它是現成的，方便，所有這些因素都考慮在內。此外，CAR-T通常被視為一次性治療。我認為對於治療自體免疫疾病的醫生來說，這些都是非常有吸引力的主張。

Lastly, the focus of our ALLO-329 development program is really to address one of the sort of perceived challenges of CAR T, which is the lymphodepleting chemotherapy. The way that the 329 is designed is to really address this head on with a built-in Dagger Technology that's coming from the CD70 portion of our dual CAR T. And like anything else, we are really accelerating this program and some of the key questions that you are asking. As the data matures, data emerges, I think we will know a lot better. But we feel very excited about ALLO-329 and potential benefits that it can bring to the patients with autoimmune disorders.

最後，我們的 ALLO-329 開發計劃的重點實際上是解決 CAR T 的已知挑戰，即淋巴細胞清除化療。329 的設計方式是透過內建的 Dagger 技術真正正面解決這個問題，該技術來自我們的雙 CAR T 的 CD70 部分。隨著數據的成熟和數據的湧現，我認為我們將會了解更多。但我們對 ALLO-329 以及它能為自體免疫疾病患者帶來的潛在益處感到非常興奮。

Zach, on the first question?

札克，​​關於第一個問題？

Yes. Thanks, Mike, for the question. So what I can say is that the enthusiasm and the engagement from our clinical trial sites has really been through the roof. I am, on a daily basis, extremely excited by the pace at which we're able to onboard sites, the activity of the sites that have been onboarded. I would say in these early days of the trial, there are -- things are sort of unfolding in a standard way, and especially as the as we pointed out in the prepared remarks and in the press release, the earliest sites to activate here have been predominantly community sites and some of them, in fact, some of the more active sites don't have CAR T experience.

是的。謝謝邁克提出這個問題。因此我可以說的是，我們的臨床試驗站點的熱情和參與度確實已經達到了頂峰。每天，我都對我們入駐網站的速度以及已入駐網站的活動感到非常興奮。我想說，在試驗的早期階段，事情正在以標準的方式展開，特別是正如我們在準備好的評論和新聞稿中指出的那樣，最早啟動的站點主要是社區站點，事實上，其中一些比較活躍的站點沒有 CAR-T 經驗。

So they're requiring a little extra handholding, but there is absolutely no shortage of engagement and enthusiasm and even the patients that are screening MRD negative, they're deriving a nice benefit, right, because they're getting access to something a little bit more prognostic than what is out there already. So very, very, very encouraging launch to the trial.

因此，他們需要一些額外的指導，但絕對不缺乏參與和熱情，甚至那些 MRD 篩檢結果為陰性的患者也從中獲益良多，因為他們能夠獲得比現有方法更有預後的資訊。因此，這次試驗的啟動非常非常令人鼓舞。

I would say that I mean, the study is progressing as planned. There are certain things that we are finding out. I mean, compared to pre-COVID days, site activation is a lot more -- requires a lot more hands on approach to get all the documents taken care of and also get the site ready. That's where I really recognize our clinical operations team to be so reactive and handling that very effective. I'm very proud of what they have done with the site activation, which is, as Zach had said, going very smoothly.

我想說的是，研究正在按計劃進行。我們正在發現一些事情。我的意思是，與新冠疫情之前相比，場地啟動要困難得多——需要採取更多的實際行動來處理所有文件並做好場地準備。這就是我真正認識到我們的臨床營運團隊反應迅速且處理得非常有效的地方。我對他們為網站激活所做的工作感到非常自豪，正如扎克所說，網站激活進展非常順利。

Salveen Richter, Goldman Sachs.

高盛的薩爾文·里希特（Salveen Richter）。

Hey, guys. This is Mark on for Salveen. Congrats on the quarter and thank you for taking our question. I have two quick ones on ALLO-316 and the data that was released today. It seems that for the FC lymphodepletion without the CD52, that group performed a little bit better than the CFA group that did have the CD52. I realize the ends are small here, but can you speculate as to why there's that difference?

嘿，大家好。我是 Salveen 的馬克。恭喜本季取得的成績，並感謝您回答我們的問題。我對 ALLO-316 和今天發布的數據有兩點簡短的看法。似乎對於沒有 CD52 的 FC 淋巴細胞清除，該組的表現比具有 CD52 的 CFA 組要好一點。我知道這裡的差異很小，但你能推測為什麼會有這種差異嗎？

And also, can you discuss what you are looking for in the Phase 1b expansion cohort data that's planned for 2025? Like what threshold of data would give you confidence on the forward regulatory path?

另外，您能討論一下您在計劃於 2025 年進行的 1b 階段擴展隊列數據中尋找什麼嗎？例如，什麼樣的資料閾值可以讓您對未來的監管路徑充滿信心？

Mark, great to hear from you. I mean, let me just quickly respond to the first question. It's a small number. We are seeing responders both with FCA and FC. But the fact that we are seeing the responses in FC is probably the most interesting finding from our SITC, the poster presentation. As an allogeneic CAR T program, we foresee that this program moving forward with a standard, full site-based lymphodepletion without need for any kind of enhancement in the lymphodepletion. And that's really coming from the underlying Dagger biology that's intrinsic from the CD70. The differences that you're seeing, I think, with the small numbers, I would not read too much into that.

馬克，很高興收到你的來信。我的意思是，讓我快速回答第一個問題。這是一個很小的數字。我們看到了 FCA 和 FC 的回應者。但事實上，我們在 FC 中看到的回應可能是我們從 SITC（海報展示）中發現的最有趣的東西。作為同種異體 CAR T 項目，我們預見該項目將以標準的、全部位淋巴細胞清除術為基礎向前發展，而不需要在淋巴細胞清除術中進行任何形式的增強。這實際上源自於 CD70 固有的底層 Dagger 生物學。我認為，對於您所看到的較小數字的差異，我不會進行過多的解讀。

Zach, do you want to take the second question?

札克，​​你想回答第二個問題嗎？

Yes. I think, as I mentioned a moment ago, we're shooting for 20 patients at this Phase 1b regimen, and then sort of awaiting for that durability. So I think if you just look numerically where we sit right now from a confirmed response rate, I think are numerically better than the third-line options that are currently approved in this context.

是的。我想，正如我剛才提到的，我們計劃在這個 1b 期方案中招募 20 名患者，然後等待其持久性。因此，我認為，如果僅從數字上看我們目前所處的確認回應率，我認為在數字上比目前在這種情況下批准的第三線選項要好。

So we're pretty happy with that. Of course, it's always nice to see even more responses. But the question I think is that we'll just need to wait a little bit longer on is the durability. We've got a couple of nice ongoing remissions out several months in the patients treated with the Phase 1b regimen. I think stay tuned for that program update next year.

我們對此非常滿意。當然，看到更多的回應總是令人高興的。但我認為的問題是，我們只需要等待一段時間才能確定其耐用性。幾個月來，接受 1b 期方案治療的患者取得了良好的持續緩解效果。我認為請繼續關註明年的該計劃更新。

Jack Allen, Baird.

傑克艾倫、貝爾德。

Hi. Thanks so much for taking the questions and congratulations to the team on the progress. I guess the first question, I had was, I didn't see a mention of the ALPHA2 study in the CLL cohort in your release, so maybe I missed it on the call. But is that still planned and ongoing, and how should we think about the go forward path there?

你好。非常感謝您回答這些問題，並祝賀團隊的進步。我想我第一個疑問是，我沒有在您的新聞稿中看到對 CLL 隊列中的 ALPHA2 研究的提及，所以也許我在電話中錯過了它。但這是否仍在計劃中並正在進行中？

And then, Zach, I think you just touched on it quite a bit on the 316 program and the bar for durability. I was hoping you could just elaborate how you think about the existing standard-of-care and what you're looking to see for durability from 316 in RCC? Thanks so much.

然後，扎克，我想你剛剛相當詳細地談到了 316 計劃和耐用性標準。我希望您能詳細說明您對現有護理標準的看法，以及您希望 316 在 RCC 中的耐用性如何？非常感謝。

Hi, Jack. I'll take the first question and I'll have Zach answer the second one. The CLL study is ongoing and we are currently in the process of prioritizing different programs. When I look at the overall pipeline, without a question, the ALPHA3 study in the frontline consolidation is our top priority. And as we have sort of advanced the 329, we are realizing that this could potentially be very important program for Allogene and perhaps even for the entire field.

你好，傑克。我來回答第一個問題，然後請札克回答第二個問題。CLL 研究正在進行中，我們目前正在對不同的項目進行優先排序。當我審視整個管道時，毫無疑問，一線整合中的 ALPHA3 研究是我們的首要任務。隨著 329 的不斷推進，我們意識到這對 Allogene 乃至整個領域來說都可能是一個非常重要的項目。

So we are spending a lot of time to accelerate as much as we can with the 329 program. Certainly, the solid tumor program, it's also giving us sort of pause about what to do. In all this context, yes, the CLL study is ongoing, but it will be part of prioritization, and we will be providing a program update in next year.

因此，我們花了大量時間盡可能加速 329 計畫。當然，實體瘤計畫也讓我們對下一步該做什麼感到猶豫不決。在所有這些背景下，是的，CLL 研究仍在進行中，但它將成為優先事項的一部分，我們將在明年提供計劃更新。

And then, Jack, just to kind of elaborate a little bit more on efficacy, I'll broaden it a bit to sort of speak generally. So first, I want to point out again that FDA has recognized this program with the RMAT designation as a potential breakthrough for patients in relapsed refractory post TKI, post checkpoint blocker. So if you look at that subset of patients that are in the third line, I think outcomes there both from a response rate as well as a PFS are fairly modest.

然後，傑克，為了更詳細地闡述功效，我將稍微擴大一點，以便一般性地講。首先，我想再次指出，FDA 已認可這項具有 RMAT 資格的項目，認為它對於 TKI 治療後復發難治性患者、檢查點阻斷劑治療後復發難治性患者來說是一個潛在的突破。因此，如果您看一下第三線的患者子集，我認為從反應率和 PFS 來看，結果都是相當適中的。

And the other thing I'll point out there is that that's continuous therapy. So what we have to offer here is potentially an equivalent or improved response rate and then a period of treatment-free remission. And I think that's always been one of the key attributes and attractive points of CAR T therapy generally speaking and it's no different in this context.

我要指出的另一件事是，這是持續治療。因此，我們在這裡提供的是潛在等效或改進的反應率，然後是一段無需治療的緩解期。我認為這一直是 CAR-T 療法的關鍵屬性和吸引力之一，在這種情況下也不例外。

So I think we have to take all of that together in mind and nobody would be happier than I, except for potentially the patients themselves, if we were able to put these patients into very, very durable remissions. That's of course what we're hoping to do. But we have to wait and see how that shakes out and where -- how it lines up to the existing therapies, as I said, with the PFS on the order of a handful of months.

因此，我認為我們必須把所有這些因素考慮在內，如果我們能夠讓這些患者的病情獲得非常非常持久的緩解，那麼除了患者自己之外，沒有人會比我更高興。這當然是我們希望做的。但我們必須拭目以待，看看結果如何，以及它與現有療法的對比情況，正如我所說，PFS 大約為幾個月的時間。

So the bar is quite low here and we hear that continuously from our investigators, who are constantly looking to put patients on this trial. So we have a lot of support from the investigator community here to continue pushing forward and they're seeing real benefits to their patients.

所以這裡的門檻很低，我們不斷從研究人員那裡聽說這一點，他們一直在尋找讓患者參與這項試驗的方法。因此，我們得到了研究人員社群的大力支持，得以繼續推進，他們也看到了病人真正的益處。

Biren Amin, Piper Sandler.

比倫阿明、派珀桑德勒。

Thank you for taking my questions. Zach, for ALLO-316, what kind of a durability do you need to see to give you confidence to go meet with FDA on a pivotal design at the end of 2025? And then, I guess on ALLO-329 with the IND planned imminently, what type of indications are you expecting to pursue in the Phase 1? Thanks.

感謝您回答我的問題。扎克，對於 ALLO-316，您需要看到什麼樣的耐久性才能讓您有信心在 2025 年底就關鍵設計與 FDA 會面？然後，我猜，對於即將計劃進行的 ALLO-329 IND，您希望在第一階段尋求哪種類型的適應症？謝謝。

Zach?

扎克？

Yes. Thanks, David. Thanks, Biren. Good question. On 316, I'll paraphrase what I've said so far, which is, I think the bar is low here. We've got two of these patients who are in the confirmed responses in that -- in the first group and treated at the Phase 1b regimen who are in ongoing nice deep partial remissions at four and six months. They're continuing to deepen over time. We'll have to see how those in the subsequently treated patients develop. The fact that we have this RMAT designation, which is just nothing more than a few days old now, it does give us access to kind of more frequent and in-depth conversations with FDA.

是的。謝謝，大衛。謝謝，Biren。好問題。關於 316，我將重複我迄今為止所說的內容，也就是說，我認為這裡的門檻很低。我們在第一組中找到了兩名確認有反應的患者，他們接受了 1b 期方案治療，並在四個月和六個月時持續處於良好的深度部分緩解狀態。隨著時間的推移，它們不斷加深。我們將必須觀察隨後接受治療的患者的情況如何發展。事實上，我們獲得 RMAT 指定才幾天，它確實使我們能夠與 FDA 進行更頻繁、更深入的對話。

So I think they're, by virtue of having granted this designation, they're enthusiastic about the potential for this therapy. And I think we're just going to have to wait for that durability data to come in and then go and have that conversation when the time comes.

因此我認為，憑藉授予這一稱號，他們對這種療法的潛力充滿熱情。我認為我們只需要等待耐用性數據的到來，然後在適當的時候進行討論。

As far as the second question on indications for 329, the preponderance of the data that's out there right now is in rheumatologic conditions, first and foremost is lupus. We have said all along this year that we're going to be starting our focus there in rheumatology. We haven't yet said exactly, which indications we're going to pursue and in what order. But suffice it to say, we are watching the data develop in the field. We're very excited about rheumatology. We're watching to see how others are expanding beyond that, but we're going to be taking a path that really follows that proof-of-concept data.

至於 329 適應症的第二個問題，目前掌握的大量數據是關於風濕病的，首先是狼瘡。我們今年一直說，我們將開始將重點放在風濕病學領域。我們尚未明確說明我們將要追蹤哪些跡象，以及按照什麼順序追蹤。但可以說，我們正在觀察該領域的數據發展。我們對風濕病學非常感興趣。我們正在觀察其他人是如何擴展這一領域的，但我們將採取一條真正遵循概念驗證數據的道路。

John Newman, Canaccord Genuity.

約翰紐曼，Canaccord Genuity。

Hi, guys. Great progress. Thank you for taking my question. David, I wondered if you could talk about the importance of breaking, pathological B cell and T cell response in autoimmune disease. We've heard a lot, and we've seen a lot of focus on B cell depletion levels, which seems very important. We've seen a lot of focus on the phenotype of the B cells when they recover, but not very many people have talked about how the T cells are involved. So I'm just curious as to how you think about that with your product?

嗨，大家好。很大的進步。感謝您回答我的問題。大衛，我想知道您是否可以談談破壞病理性 B 細胞和 T 細胞反應在自體免疫疾病中的重要性。我們聽到了很多，我們看到很多人關注 B 細胞耗竭水平，這似乎非常重要。我們看到很多人關注 B 細胞恢復時的表現型，但很少人談論 T 細胞是如何參與其中的。所以我只是好奇您是如何看待您的產品的？

John, great question. That probably goes beyond even my scientific understanding. But if you go to the immunology literature, the interaction between different lymphocytes leading to the B cell development and B cell differentiation into the antibody producing cells. I mean, that is complex. And still, one of the main contributor of that B cell, the maturation is the T cells as well as some other cells. By the way, these other sort of lymphocytes that are involved in enhancing the B cell response, they also express CD70.

約翰，這個問題問得好。這可能甚至超出了我的科學理解範圍。但如果你查閱免疫學文獻，你會發現不同淋巴球之間的相互作用會導致 B 細胞發育，而 B 細胞分化為抗體產生細胞。我的意思是，這很複雜。而且，B 細胞成熟的主要貢獻者之一是 T 細胞以及一些其他細胞。順便說一下，參與增強 B 細胞反應的其他類型的淋巴細胞也表達 CD70。

So from our perspective, yes, when the B cells get depleted, all the indications are the returning B cells have a naive phenotype. They will have to undergo some kind of maturation and to become pathogenic again. And I think by going after both B cell and the activated T cell early on, they can potentially address the underlying pathology more fully rather than just going after a single B cell component. That's hypothesis.

因此從我們的角度來看，是的，當 B 細胞耗盡時，所有跡像都表明返回的 B 細胞具有幼稚表型。它們必須經歷某種成熟過程才能再次變得具有致病性。我認為，透過儘早追蹤 B 細胞和活化的 T 細胞，他們可以更全面地解決潛在的病理，而不是只追蹤單一 B 細胞成分。這只是假設。

Another thing that's very important to us is, in addition to what CD70 can bring in that equation is that CD70 has the Dagger in a biologies, which allows us to use ALLO-329 with a minimum lymphodepletion. I mean, we have already shown in the 316 program, even as an allogeneic, when there is a Dagger Technology incorporated into it, you don't need any enhancement. I think this is something that we can extrapolate into the autoimmune indications and that underlies our plan to reduce or eliminate the lymphodepletion during the initial investigation of ALLO-329 in patients with autoimmune disorders.

對我們來說非常重要的另一件事是，除了 CD70 可以帶來什麼之外，CD70 在生物學中具有匕首，這使我們能夠以最低限度的淋巴細胞耗竭使用 ALLO-329。我的意思是，我們已經在 316 計劃中展示過，即使作為同種異體，當其中融入了 Dagger 技術時，你不需要任何增強。我認為這是我們可以推斷出自體免疫指徵的東西，也是我們在對自體免疫疾病患者進行 ALLO-329 初步研究期間減少或消除淋巴細胞耗竭的計劃的基礎。

Luca Issi, RBC Capital

伊西（Luca Issi），加拿大皇家銀行資本

Great. Thanks so much for taking my question and congrats on the progress. Maybe Zach or David, on RCC, do you have any tumor aspirates or renal biopsies here? Wondering if you have any evidence suggesting that the cells are actually able to infiltrate the tumor microenvironment here, which I think is something that has been kind of the main historical issue here for CAR T for solid tumors. So any color there much appreciated. And then maybe just to clarify, is it fair to assume that all the responses so far are PRs and not CRs?

偉大的。非常感謝您回答我的問題，並祝賀您的進展。也許是 Zach 或 David，關於 RCC，你們這裡有腫瘤抽吸物或腎臟切片嗎？想知道您是否有任何證據表明這些細胞實際上能夠滲透到這裡的腫瘤微環境，我認為這是 CAR-T 治療實體腫瘤的主要歷史問題。因此，任何顏色都倍受讚賞。然後也許只是為了澄清一下，是否可以公平地假設到目前為止所有的回應都是 PR 而不是 CR？

Zach, you want to take that question?

札克，​​你想回答這個問題嗎？

Sure. Luca, as always great questions. The first one, the answer is, yes. We have actually quite a number of tumor aspirates and biopsies that we have collected within the first couple of weeks after infusion. And, we do have a figure in the poster that really lays that out. In fact, there's a dozen, contemporaneous biopsies and peripheral blood samples.

當然。盧卡，一如既往地提出了很棒的問題。第一個問題，答案是肯定的。實際上，我們在輸注後的最初幾週內收集了相當多的腫瘤抽吸物和活檢樣本。而且，海報中確實有一個人物真實地展現了這一點。事實上，有十幾個同時進行的活檢和周邊血液樣本。

In that figure, it's quite convincing actually that the ability of ALLO-316 to get into the tumor bed itself is quite robust, and we see essentially in almost all of those 12 biopsies equivalent CAR trans gene in the tumor aspirate is in the peripheral blood drawn at the same time. So we find that to be extremely encouraging in terms of getting to where the cells need to be the source the site of pathology.

從該圖中可以非常令人信服地看出，ALLO-316 進入腫瘤床的能力非常強大，並且我們幾乎在全部 12 個活檢樣本中都看到，腫瘤抽吸物中的等效 CAR 轉基因與同時抽取的外周血中的一樣。因此，我們發現，這對於找到細胞所需的病理來源位置非常令人鼓舞。

Regarding your second question about PRs and CRs, we did have one complete metabolic remission in a patient who had an antecedent confirmed PR. So it was a PR that deepened to a complete remission. Unfortunately, that patient contracted COVID and expired from that infection. So sort of an extremely unfortunate situation to die from an infection, when you're in remission, but that patient was in a complete remission in addition to the other ongoing and deepening PRs.

關於您提出的第二個問題，即 PR 和 CR，我們確實在先前已證實 PR 的患者中實現了完全代謝緩解。因此，這是一次深化到完全緩解的 PR。不幸的是，該患者感染了 COVID 並因此去世。因此，當您的病情處於緩解期時，死於感染是一種極其不幸的情況，但該患者除了其他正在進行和加深的 PR 之外，還處於完全緩解期。

Samantha Semenkow, Citi.

Samantha Semenkow 的花旗銀行。

Hi, good afternoon. Thanks for taking the question. I just wanted to follow-up on some of the prior questions on the safety data for ALLO-316 and completely understanding that the underlying disease burden is a confounder here. But is there any rationale that targeting CD70 in the context of the Dagger Technology could also be contributing to the grade five events and just overall safety profile? And what are your thoughts on, how that could translate into your autoimmune program, particularly in the context of how you're thinking about choosing a dose for that program? Thank you.

嗨，下午好。感謝您回答這個問題。我只是想跟進關於 ALLO-316 安全數據的一些先前的問題，並完全理解潛在的疾病負擔是這裡的混雜因素。但是，是否有理由認為，在 Dagger 技術背景下針對 CD70 也可能導致五級事件和整體安全狀況？您如何看待這一點，如何將其轉化為您的自身免疫計劃，特別是在您考慮為該計劃選擇劑量的情況下？謝謝。

Hi, Samantha. Let me take the question. We are looking, like, in any drug development, all the safety findings very carefully. But especially in the 316 study, I do believe the poster will go online like pretty soon. So it will be more detailed. I mean, these are very heavily pretreated patients, really running out of options. And usually in that kind of situation. They are pretty sick patients. And so, yes, these events did occur, but trying to read through that to what may happen in autoimmune patients with autoimmune disorder, I don't think there is much that we can read through.

你好，薩曼莎。請讓我來回答這個問題。就像任何藥物開發一樣，我們會非常仔細地觀察所有的安全性發現。但特別是在 316 研究中，我確實相信海報很快就會上網。所以會更加詳細。我的意思是，這些患者之前接受過大量治療，他們真的沒有選擇了。通常都是在這種情況下。他們都是病情相當嚴重的病人。是的，這些事件確實發生了，但嘗試透過這些事件來了解自體免疫疾病患者中可能發生的情況，我認為我們能了解的內容並不多。

And the second question is, does this have to do with the Dagger Technology? Dagger Technology, what it does is really enhance the pharmacodynamic effect of CAR T. So yes, to some extent, but at the end, this is really how you develop the ABCs of drug development. We are dealing with active drugs, which is always a good place to start. And then we have to find the right cell dose and for the CAR T, right lymphodepletion, that balances out efficacy and the safety. So like anything else, as I said before, these are the things that will be part of the Phase 1 study, as we advance the ALLO-329 program.

第二個問題是，這跟 Dagger 技術有關係嗎？Dagger 技術，它所做的就是真正增強 CAR-T 的藥效學效果。我們正在處理活性藥物，這始終是一個很好的起點。然後，我們必須找到正確的細胞劑量和適合 CAR-T 的正確淋巴細胞清除方法，以平衡療效和安全性。正如我之前所說，隨著 ALLO-329 計劃的推進，這些都將成為第一階段研究的一部分。

Matthew Biegler, Oppenheimer.

馬修·比格勒，奧本海默。

Great. Thanks. Hi, everyone. Just one from us. Can you talk about patient retention efforts in ALPHA3? Because the question we often get is why a patient randomized to watch and wait would choose to stay in the trial versus maybe some form of like off label consolidation treatment. I don't even know if that exists, but can you just kind of comment on that theory that we're hearing? Thanks.

偉大的。謝謝。大家好。我們只有一個。您能談談 ALPHA3 的患者保留工作嗎？因為我們經常被問到的問題是，為什麼隨機觀察等待的患者會選擇繼續參與試驗，而不是某種形式的非說明書鞏固治療。我什至不知道這是否存在，但你能對我們聽到的這個理論發表評論嗎？謝謝。

Hi, Matt. Yes, it's David. Let me take that question, give Zach a little bit of break. The standard-of-care in large B cell lymphoma after they complete the treatment is watch and wait. And watch and wait meaning that they undergo periodic radiographic scans to see what's happening to the disease. And it occurs at a different interval after the completion of the AlloCAR T treatment. In terms of that particular question about patient retention, I mean, the patients who are enrolled in our study, they'll be getting the best standard-of-care that is available to them.

你好，馬特。是的，是大衛。讓我來回答這個問題，讓札克休息一下。大B細胞淋巴瘤完成治療後的標準治療方法是觀察並等待。觀察並等待意味著他們要定期接受放射掃描以了解病情的發展。並且它發生在AlloCAR T治療完成後的不同間隔內。關於患者保留的具體問題，我的意思是，參加我們研究的患者將獲得他們所能獲得的最佳標準護理。

In our discussions with the investigator, they feel that that is very sufficient for them to carry out the conversation with the patient and retain the patients on the study. Obviously, in this setting, when patient progresses, they can go on to any of the available treatment. But when the patient progresses, I mean, they already had the primary event. The primary endpoint of the ALPHA3 study is the event-free survival. So when somebody starts the next treatment, I mean, that is an event in the event-free survival analysis.

在我們與研究人員的討論中，他們認為這足以讓他們與患者進行對話並讓患者繼續參與研究。顯然，在這種情況下，當患者病情進展時，他們可以繼續接受任何可用的治療。但是當病人的病情進展時，我的意思是，他們已經發生了原發事件。ALPHA3 研究的主要終點是無事件存活期。因此，當某人開始下一項治療時，我的意思是，這是無事件存活分析中的一個事件。

Sami Corwin, William Blair.

薩米·科溫、威廉·布萊爾。

Hi, thanks for taking our question. This is Brooke on for Sami. So we are wondering, going off on APLHA3 again. How has physician interest been with the ALPHA3 trial, and what feedback have you received on what aspects of potential use of cema-cel in the first line is most valuable? Like, is it community use, affordability, time to treat or something else?

您好，感謝您回答我們的問題。這是布魯克 (Brooke) 代替薩米 (Sami)。所以我們想知道是否能再次啟動 APLHA3。醫生對 ALPHA3 試驗的興趣如何？例如，是社區使用、可負擔性、治療時間還是其他？

Great question. Zach, you want to take that?

好問題。札克，​​你想拿走那個嗎？

Sure. Thanks, Brook. Overall, the enthusiasm is extremely high. Honestly, having been part of the team at Kite that really led to the approval of Yescarta. I mean, I lived and breathed, third line LBCL for several years. I can say that the level of enthusiasm for ALPHA3, has been as high, if not higher than those early days in, of the ZUMA-1 trial. So I think physicians broadly recognize that, if ALPHA3 is successful, that this will usher in a new era of LBCL management and kind of fundamentally change the paradigm.

當然。謝謝，布魯克。整體來說，熱情非常高漲。老實說，作為 Kite 團隊的一員，我真正促成了 Yescarta 的批准。我的意思是，我已經在 LBCL 三線患者中生活和呼吸了好幾年。我可以說，人們對 ALPHA3 的熱情程度與 ZUMA-1 試驗初期一樣高，甚至更高。因此我認為醫生們普遍認識到，如果 ALPHA3 成功，這將開啟 LBCL 管理的新時代，並從根本上改變範式。

As far as why they think that, which is the second part of your question, I think it's all those features that you mentioned. I think, first is, being able to implement, a new and novel and highly accurate prognostic tool in this MRD test, being able to respond immediately to the result, that is something that is, paradigm shifting unto itself. And to be able to do that with an off-the-shelf therapy that, literally within days of receiving the MRD positive result, you can initiate lymphodepletion and then deliver a potentially curative dose of CAR T cells and to do that in community settings that have been on the sidelines of the CAR T revolution from the beginning.

至於他們為什麼會這麼想，也就是你問題的第二部分，我認為是你提到的所有這些特點。我認為，首先，能夠在這種 MRD 測試中實施一種全新且高度準確的預後工具，能夠立即對結果做出反應，這是一種範式轉移。並且能夠透過現成的療法做到這一點，在收到 MRD 陽性結果後的幾天內，就可以啟動淋巴細胞清除，然後提供潛在治癒劑量的 CAR T 細胞，並且在從一開始就處於 CAR T 革命邊緣的社區環境中進行。

So we see enthusiasm coming from sites, community sites that don't have a lot of CAR T experience or any CAR T experience because it's giving them access to this. We see enthusiasm from academic sites, because they see how this could fundamentally alter the future of frontline LBCL management. So it's really kind of a grab bag of really exciting topics, that we're hearing lots of positive feedback from.

因此，我們看到那些沒有太多 CAR-T 經驗或任何 CAR-T 經驗的網站和社區網站的熱情，因為它讓他們獲得這些經驗。我們看到學術界的熱情，因為他們看到這將從根本上改變第一線 LBCL 管理的未來。因此，這確實是一個充滿真正令人興奮的話題的大雜燴，我們聽到了很多正面的回饋。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

Hi, thank you for taking my question and congrats on the progress this quarter. I had a safety question about ALLO-316. It looks like you had multiple DLTs at the dose Level 2 that you're using in the expansion cohort, including one of the, Grade 5AEs. Can you just speak to how you see the acceptability of this safety profile, if it's more or less unchanged once you have data in the full 20 patients you're targeting for the cohort? Thank you.

你好，感謝您回答我的問題，並對本季度的進展表示祝賀。我對 ALLO-316 的安全問題有疑問。看起來您在擴展隊列中使用的劑量水平 2 有多個 DLT，其中包括其中一個 5 級 AE。您能否談談您如何看待這個安全性概況的可接受性，一旦您獲得針對該群體的全部 20 名患者的數據，它是否或多或少不會發生變化？謝謝。

Zach, you want to take that question?

札克，​​你想回答這個問題嗎？

Sure. I'll point out that the DLTs were in -- it was the same cell dose, it was 80 million, but it was in patients who had received FCA conditioning. So the inclusion of ALLO-647. Those we have reached the DLT limit in that cohort. So we did not advance dosing any further in the FCA arms beyond dose Level 2.

當然。我要指出的是，DLT 的細胞劑量相同，均為 8,000 萬，但對像是接受 FCA 調理的患者。因此納入了 ALLO-647。我們已經達到了該群體的 DLT 限制。因此，我們沒有在 FCA 組中進一步提高劑量水平（超過 2 級）。

So because the overall treatment intensity is lower in the FC-only arm, the elimination of one of the three-part lymphodepletion, we did not encounter DLTs in that cohort and the efficacy seem to be the best in the subsets that we were evaluating in a dose exploration phase. So that's why that was selected.

因此，由於僅 FC 組的整體治療強度較低，消除了三部分淋巴細胞清除中的一項，我們在該隊列中沒有遇到 DLT，並且在劑量探索階段我們評估的子集中，療效似乎是最好的。這就是選擇它的原因。

Yes. We never take any kind of safety findings slightly, but the two DLTs, there have been two DLTs as our press release indicated. One was a DLT that we had previously disclosed back in 2023 when we presented at AACR. And that was patient who had previous exposure to checkpoint inhibitor before going on to another study in autoimmune hepatitis. Again, it's somewhat confounded DLT, but it is a DLT from the protocol perspective. The second one is the one that is described as a cardiogenic shock in this data communication.

是的。我們從不輕視任何安全發現，但正如我們的新聞稿所指出的那樣，已經有兩次 DLT。其中一個是我們在 2023 年 AACR 上展示時披露過的 DLT。該患者在參加另一項自體免疫性肝炎研究之前曾接觸過檢查點抑制劑。再次強調，它是有點令人困惑的 DLT，但從協議角度來看它是一種 DLT。第二個就是在這次數據通訊中被描述為心因性休克的那個。

Laura Prendergast, Raymond James.

勞拉·普倫德加斯特、雷蒙德·詹姆斯。

Hi, guys. Congrats on the progress. I was generally just curious, the rate of enrollment in these autoimmune indication studies for cell therapy has been pretty slow. As you think about 326 entering Phase 1, how are you guys planning on maneuvering these headwinds?

嗨，大家好。祝賀你取得進展。我只是很好奇，這些針對細胞療法的自體免疫適應症研究的招募率一直很慢。當您想到 326 進入第一階段時，您打算如何應對這些不利因素？

Laura, I mean, great question. I mean, that's a topic that we are following pretty closely as other companies present about the enrollment status. But the general sense I get is like, six, nine months ago, every enrollment seem to be pretty slow, but definitely the enrollment into the autoimmune studies are picking up. And this is very typical.

蘿拉，我的意思是，這個問題問得好。我的意思是，這是我們正在密切關注的話題，因為其他公司也介紹了招生情況。但我的整體感覺是，六、九個月前，每次招生似乎都很慢，但自體免疫研究的招生人數肯定在增加。這是非常典型的。

I mean, you're dealing with the investigators who have not had any CAR T experience in the beginning. I mean, we certainly learned that when we were involved in CD19 CAR T during the development. But once they get somewhat familiar with the CAR T, things will speed up. And I think that's exactly what we are seeing.

我的意思是，你一開始就與沒有任何 CAR T 經驗的研究人員打交道。我的意思是，我們在參與 CD19 CAR T 開發的過程中肯定了解了這一點。但一旦他們熟悉了 CAR T，事情就會加快。我認為這正是我們所看到的。

In our case, not only we are going into an area where physicians are getting some familiarity with the CAR T, but we are also going in with the allogeneic CAR T, which really takes away a lot of logistic complexity of administering the CAR T. So we are very hopeful that as we move into the autoimmune, we will be able to execute studies smoothly.

在我們的案例中，我們不僅進入了醫生對 CAR-T 比較熟悉的領域，而且我們還進入了同種異體 CAR-T，這確實消除了 CAR-T 管理的許多後勤複雜性。 因此，我們非常希望，隨著我們進入自身免疫領域，我們將能夠順利開展研究。

Thank you. That concludes our question-and-answer session. I'd like to turn the conference back over to management for any additional comments.

謝謝。我們的問答環節到此結束。我想將會議交還給管理層，以便他們發表其他評論。

Yes. I just want to end by saying that our commitment remains clear, to bring transformative off-the-shelf therapies to patients with difficult-to-treat cancer or autoimmune diseases. With each new milestones, we move closer to realizing the potential of our CAR T products in ways that could reshape treatment landscape across oncology and autoimmune diseases. And with that, thank you very much for joining us on this journey. And operator, you may now disconnect.

是的。最後，我只想說，我們的承諾始終明確，為患有難以治療的癌症或自體免疫疾病的患者提供變革性的現成療法。隨著每一個新里程碑的實現，我們都離實現 CAR T 產品的潛力更近一步，重塑腫瘤學和自體免疫疾病的治療前景。最後，非常感謝您與我們一起踏上這趟旅程。接線員，您現在可以斷開連接了。

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

感謝大家參加今天的會議。該計劃確實結束了。您現在可以斷開連線。