My name is Dr. Keri Reynolds.

我是凱里-雷諾茲博士。

I'm the Clinical Director of Inpatient Oncology at the Massachusetts General Hospital, and I direct the Severe Immunotherapy Complications Service and Program at the Massachusetts General Hospital Cancer Center.

我是麻省總醫院腫瘤住院部的臨床主任，同時也是麻省總醫院癌症中心嚴重免疫療法併發症服務和項目的負責人。

Today, I will cover cancer immune checkpoint inhibitors, drug overview, and mechanism of action.

今天，我將介紹癌症免疫檢查點抑制劑、藥物概述和作用機制。

Immune checkpoint inhibitors have truly revolutionized the treatment of cancer.

免疫檢查點抑制劑確實徹底改變了癌症的治療。

The key takeaways for today's video are, describe the mechanism of action of immune checkpoint inhibitors, review the impact of immune checkpoint inhibitors on metastatic patient survival rates, and recognize the applications for immune checkpoint inhibitors for early lines of therapy.

今天視頻的主要內容包括：描述免疫檢查點抑制劑的作用機制；回顧免疫檢查點抑制劑對轉移性患者生存率的影響；認識免疫檢查點抑制劑在早期治療中的應用。

So taking a step back, Immunology 101.

退一步講，免疫學 101。

Many times a day, an antigen, the small blue round circle at the top, is presented on an antigen-presenting cell by way of an MHC molecule, a major histocompatibility complex molecule.

每天，抗原（即頂部的藍色小圓圈）會通過 MHC 分子（一種主要組織相容性複合體分子）多次出現在抗原呈遞細胞上。

It's presented to the TCR, the T-cell receptor, on that bluish-purplish cell, the T-cell.

它呈現給藍紫色細胞（T 細胞）上的 TCR（T 細胞受體）。

And that is signal one.

這就是信號一。

But in order to get immune activation, there has to be a co-stimulatory, a second signal.

但要激活免疫，必須有輔助刺激信號，即第二個信號。

That is shown in the red CD80 or CD86, binds with CD28.

紅色的 CD80 或 CD86 與 CD28 結合。

And then the T-cell can be off to the races.

然後，T 細胞就可以開始比賽了。

It can proliferate, secrete cytokines, and start to migrate to tissue in order to recognize that antigen.

它可以增殖、分泌細胞因子，並開始向組織遷移，以識別抗原。

But soon, because we don't want overwhelming activation, soon, there has to be a break or checkpoints on the system to be able to control that immune activation.

但很快，因為我們不希望出現壓倒性的激活，很快，系統上就必須有一個斷點或檢查點來控制免疫激活。

And the checkpoints, you can see CTLA-4, it comes to the cell surface.

檢查點，你可以看到 CTLA-4，它出現在細胞表面。

And then CTLA-4 can out-compete that co-stimulatory signal to get negative regulation as a checkpoint.

然後，CTLA-4 可以超越共刺激信號，作為檢查點獲得負調控。

Similarly, that T-cell traffics out to the periphery, but soon, it expresses PD-1, programmed cell death one.

同樣，T 細胞會向外周擴散，但很快就會表達 PD-1，即程序性細胞死亡 1。

In addition, the tissue has ligands.

此外，組織中還有配體。

Both of these checkpoints are negative regulators to decrease immune activation.

這兩個檢查點都是減少免疫激活的負性調節器。

Cancer has a way of co-opting the immune system and evading it.

癌症有辦法與免疫系統合作，躲避它。

And so in order to have adaptive immune system activation to recognize cancers, drugs have been developed against PD-L1, the ligand, and against PD-1 on the T-cell, and against CTLA-4.

是以，為了激活適應性免疫系統來識別癌症，人們開發了針對配體 PD-L1、T 細胞上的 PD-1 和 CTLA-4 的藥物。

And if we take a step back and look at all of the FDA-approved immune checkpoint inhibitors, there are now nine.

如果我們回過頭來看看 FDA 準許的所有免疫檢查點抑制劑，現在有九種。

And what has this done for the field of oncology?

這對腫瘤學領域有什麼影響？

It is a true breakthrough therapy.

這是一種真正的突破性療法。

You will not be able to read every box on this slide, but it's just to show you the FDA approvals over the last decade.

你不可能讀完這張幻燈片上的每一個方框，但這只是為了向你展示過去十年中食品及藥物管理局的準許情況。

It started in 2011 with ipilimumab for metastatic melanoma.

它於 2011 年開始使用伊匹單抗治療轉移性黑色素瘤。

In addition, PD-1 in 2014 for metastatic melanoma.

此外，PD-1 於 2014 年用於治療轉移性黑色素瘤。

At the time in 2011, before we had these drugs, the average overall survival for metastatic melanoma was about a year.

2011 年，在我們擁有這些藥物之前，轉移性黑色素瘤的平均總生存期約為一年。

And we had the carbazine chemotherapy that worked about 5% to 20% for a response rate, depending on the literature you read.

卡巴嗪化療的反應率約為5%到20%，具體取決於你閱讀的文獻。

And it only worked for a few months.

而且只用了幾個月。

Now we have patients over 30% up to over 50% living out years and years with melanoma because of checkpoint.

現在，我們有超過 30% 甚至超過 50% 的黑色素瘤患者因為使用了檢查點而活了很多年。

It's a true breakthrough therapy.

這是一種真正的突破性療法。

And since that time, now there are over 83 FDA-approved indications, as you can see here, in over 17 types of cancer.

從那時起，現在已有超過 83 種 FDA 準許的適應症，如圖所示，涉及超過 17 種癌症類型。

Importantly, the boxes, the light blue just show single agent immune checkpoint inhibitor approvals, but the dark blue show combinations.

重要的是，淺藍色方框中顯示的只是單藥免疫檢查點抑制劑的準許情況，而深藍色方框中顯示的是聯合用藥情況。

So we are starting to combine an immune checkpoint inhibitor and an immune checkpoint inhibitor, or immune checkpoint inhibitor and chemo, or immune checkpoint inhibitor and targeted therapy.

是以，我們開始將免疫檢查點抑制劑和免疫檢查點抑制劑，或免疫檢查點抑制劑和化療，或免疫檢查點抑制劑和靶向治療結合起來。

So combinations are truly the way forward.

是以，組合才是真正的出路。

In addition, we're starting to see it in earlier lines of therapy, meaning it's no longer just in metastatic disease.

此外，我們開始在早期治療中使用這種療法，這意味著它不再僅僅用於轉移性疾病。

But in over 17 cancer types, it is approved.

但在超過 17 種癌症類型中，它都獲得了準許。

And it's approved earlier in melanoma in lung.

而且它在肺部黑色素瘤的治療中更早獲得準許。

In 2021, it's earlier in esophageal, triple negative breast cancer, bladder, and renal cell.

2021 年，食管癌、三陰性乳腺癌、膀胱癌和腎細胞癌的發病率較高。

So new checkpoints are coming down the pipeline.

是以，新的檢查站將陸續建成。

In fact, there are over 2,000 clinical trials in development with checkpoints.

事實上，目前有 2,000 多項臨床試驗正在使用檢查點進行開發。

So this was a document from 2020 that showed that we are estimated to treat over 230,000 patients with checkpoint on standard of care therapy in 2020.

是以，這是一份2020年的文件，其中顯示，預計到2020年，我們將治療超過23萬名接受標準護理療法的檢查點患者。

There have been multiple approvals, so that number is higher.

有多項準許，所以這個數字更高。

And about 10% to 30% have immune-related adverse events, serious immune-related adverse events.

約 10%至 30%的人出現免疫相關不良事件，即嚴重的免疫相關不良事件。

So that is anywhere from 23,000 to 69,000 individuals with serious immune-related adverse events.

是以，有 2.3 萬到 6.9 萬人發生了嚴重的免疫相關不良事件。

Please see our next video for immune-related adverse events.

請參閱我們的下一個視頻，瞭解與免疫相關的不良事件。

But as a summary, we know that immune checkpoint inhibitors are now standard of care, that a subset of patients experience these durable long-term responses.

但綜上所述，我們知道免疫檢查點抑制劑是目前的治療標準，一部分患者會出現這些持久的長期反應。

So this is a good news story.

是以，這是一個好消息。

The success of single-agent checkpoint has led to combination approvals.

單藥檢查點的成功導致了聯合用藥的準許。

And we're moving those therapies to earlier lines of therapy called the adjuvant space.

我們正在將這些療法轉移到更早的輔助治療領域。

Thank you so much for watching.

感謝您的收看。

I hope you found this video educational.

希望這段視頻對您有所啟發。

And I'll see you in the next video.

我們下期視頻再見。