科学の力でがんを克服する:CAR T細胞療法の物語


Carl June is the pioneer behind CAR T-cell therapy: a groundbreaking cancer treatment that supercharges part of a patient’s own immune system to attack and kill tumors. In a talk about a breakthrough, he shares how three decades of research culminated in a therapy that’s eradicated cases of leukemia once thought to be incurable — and explains how it could be used to fight other types of cancer.

カール・ジューンは、CAR T 細胞療法の先駆者です。CAR T 細胞療法は、患者自身の免疫系の一部を強化して腫瘍を攻撃して殺す画期的ながん治療法です。

画期的な進歩についての講演で、彼は 30 年にわたる研究が、かつては不治だと思われていた白血病を根絶する治療法にどのように結実したかを語り、他の種類のがんと闘うためにそれをどのように利用できるかを説明します。

A “living drug” that could change the way we treat cancer
スピーカー カール・ジューン
アップロード 2019/10/03

「がん治療法を変える可能性のある「生きた薬」(A “living drug” that could change the way we treat cancer)」の文字起こし

So this is the first time I’ve told this story in public, the personal aspects of it. Yogi Berra was a world-famous baseball player who said, “If you come to a fork in the road, take it.”

Researchers had been, for more than a century, studying the immune system as a way to fight cancer, and cancer vaccines have, unfortunately, been disappointing. They’ve only worked in cancers caused by viruses, like cervical cancer or liver cancer. So cancer researchers basically gave up on the idea of using the immune system to fight cancer.

And the immune system, in any case, did not evolve to fight cancer; it evolved to fight pathogens invading from the outside. So its job is to kill bacteria and viruses. And the reason the immune system has trouble with most cancers is that it doesn’t invade from the outside; it evolves from its own cells. And so either the immune system does not recognize the cancer as a problem, or it attacks a cancer and also our normal cells, leading to autoimmune diseases like colitis or multiple sclerosis.

So how do you get around that? Our answer turned out to be synthetic immune systems that are designed to recognize and kill cancer cells. That’s right — I said a synthetic immune system. You do that with genetic engineering and synthetic biology. We did it with the naturally occurring parts of the immune system, called B cells and T cells. These were our building blocks.

T cells have evolved to kill cells infected with viruses, and B cells are the cells that make antibodies that are secreted and then bind to kill bacteria. Well, what if you combined these two functions in a way that was designed to repurpose them to fight cancer? We realized it would be possible to insert the genes for antibodies from B cells into T cells. So how do you do that? Well, we used an HIV virus as a Trojan horse to get past the T cells’ immune system.

The result is a chimera, a fantastic fire-breathing creature from Greek mythology, with a lion’s head, a goat’s body and a serpent’s tail. So we decided that the paradoxical thing that we had created with our B-cell antibodies, our T cells carrier and the HIV Trojan horse should be called “Chimeric Antigen Receptor T cells,” or CAR T cells.

The virus also inserts genetic information to activate the T cells and program them into their killing mode. So when CAR T cells are injected into somebody with cancer, what happens when those CAR T cells see and bind to their tumor target? They act like supercharged killer T cells on steroids. They start this crash-defense buildup system in the body and literally divide and multiply by the millions, where they then attack and kill the tumor.

All of this means that CAR T cells are the first living drug in medicine. CAR T cells break the mold. Unlike normal drugs that you take — they do their job and get metabolized, and then you have to take them again — CAR T cells stay alive and on the job for years. We have had CAR T cells stay in the bodies of our cancer patients now for more than eight years. And these designer cancer T cells, CAR T cells, have a calculated half-life of more than 17 years. So one infusion can do the job; they stay on patrol for the rest of your life.

This is the beginning of a new paradigm in medicine. Now, there was one major challenge to these T-cell infusions. The only source of T cells that will work in a patient are your own T cells, unless you happen to have an identical twin. So for most of us, we’re out of luck.

So what we did was to make CAR T cells. We had to learn to grow the patient’s own T cells. And we developed a robust platform for this in the 1990s. Then in 1997, we first tested CAR T cells in patients with advanced HIV-AIDS. And we found that those CAR T cells survived in the patients for more than a decade. And it improved their immune system and decreased their viruses, but it didn’t cure them.

So we went back to the laboratory, and over the next decade made improvements to the CAR T cell design. And by 2010, we began treating leukemia patients. And our team treated three patients with advanced chronic lymphocytic leukemia in 2012. It’s a form of incurable leukemia that afflicts approximately 20,000 adults every year in the United States.

The first patient that we treated was a retired Marine sergeant and a prison corrections officer. He had only weeks to live and had, in fact, already paid for his funeral. The cells were infused, and within days, he had high fevers. He developed multiple organ failures, was transferred to the ICU and was comatose. We thought he would die, and, in fact, he was given last rites. But then, another fork in the road happened.

So, around 28 days after the CAR T cell infusion, he woke up, and the physicians finally examined him, and the cancer was gone. The big masses that had been there had melted. Bone marrow biopsies found no evidence of leukemia, and that year, in our first three patients we treated, two of three have had durable remissions now for eight years, and one had a partial remission. The CAR T cells had attacked the leukemia in these patients and had dissolved between 2.9 and 7.7 pounds of tumor in each patient. Their bodies had become veritable bioreactors for these CAR T cells, producing millions and millions of CAR T cells in the bone marrow, blood, and tumor masses.

And we discovered that these CAR T cells can punch far above their weight class, to use a boxing analogy. Just one CAR T cell can kill 1,000 tumor cells. That’s right — it’s a ratio of one to a thousand. The CAR T cell and its daughter progeny cells can divide and divide and divide in the body until the last tumor cell is gone. There’s no precedent for this in cancer medicine. The first two patients who had full remission remain today leukemia-free, and we think they are cured. These are people who had run out of options, and by all traditional methods they had, they were like modern-day Lazarus cases. All I can say is: thank goodness for those forks in the road.

Our next step was to get permission to treat children with acute leukemia, the most common form of cancer in kids. The first patient we enrolled on the trial was Emily Whitehead, and at that time, she was six years old. She had gone through a series of chemotherapy and radiation treatments over several years, and her leukemia had always come back. In fact, it had come back three times.

When we first saw her, Emily was very ill. Her official diagnosis was advanced, incurable leukemia. Cancer had invaded her bone marrow, her liver, her spleen. And when we infused her with the CAR T cells in the spring of April 2012, over the next few days, she did not get better. She got worse, and in fact, much worse. As our prison corrections officer had in 2010, she, in 2012, was admitted to the ICU, and this was the scariest fork in the whole road of this story.

By day three, she was comatose and on life support for kidney failure, lung failure, and coma. Her fever was as high as 106 degrees Fahrenheit for three days. And we didn’t know what was causing those fevers. We did all the standard blood tests for infections, and we could not find an infectious cause for her fever. But we did find something very unusual in her blood that had never been seen before in medicine. She had elevated levels of a protein called interleukin-6, or IL-6, in her blood. It was, in fact, more than a thousandfold above the normal levels.

And here’s where yet another fork in the road came in. By sheer coincidence, one of my daughters has a form of pediatric arthritis. And as a result, I had been following as a cancer doc, experimental therapies for arthritis for my daughter, in case she would need them. And it so happened that just months before Emily was admitted to the hospital, a new therapy had been approved by the FDA to treat elevated levels of interleukin-6. And it was approved for the arthritis that my daughter had. It’s called tocilizumab.

And, in fact, it had just been added to the pharmacy at Emily’s hospital, for arthritis. So when we found Emily had these very high levels of IL-6, I called her doctors in the ICU and said, “Why don’t you treat her with this arthritis drug?” They said I was a cowboy for suggesting that. And since her fever and low blood pressure had not responded to any other therapy, her doctor quickly asked permission to the institutional review board, her parents, and everybody, of course, said yes.

And they tried it, and the results were nothing short of striking. Within hours after treatment with tocilizumab, Emily began to improve very rapidly. Twenty-three days after her treatment, she was declared cancer-free. And today, she’s 12 years old and still in remission.

So we now call this violent reaction of the high fevers and coma, following CAR T cells, cytokine release syndrome, or CRS. We’ve found that it occurs in nearly all patients who respond to the therapy. But it does not happen in those patients who fail to respond. So paradoxically, our patients now hope for these high fevers after therapy, which feels like “the worst flu in their life,” when they get CAR T-cell therapies. They hope for this reaction because they know it’s part of the twisting and turning path back to health. Unfortunately, not every patient recovers. Patients who do not get CRS are often those who are not cured. So there’s a strong link now between CRS and the ability of the immune system to eradicate leukemia. That’s why last summer, when the FDA approved CAR T cells for leukemia, they also co-approved the use of tocilizumab to block the IL-6 effects and the accompanying CRS in these patients. That was a very unusual event in medical history.

Emily’s doctors have now completed further trials and reported that 27 out of 30 patients, the first 30 we treated, or 90 percent, had a complete remission after CAR T cells, within a month. A 90 percent complete remission rate in patients with advanced cancer is unheard of in more than 50 years of cancer research. In fact, companies often declare success in a cancer trial if 15 percent of the patients had a complete response rate. A remarkable study appeared in the “New England Journal of Medicine” in 2013. An international study has since confirmed those results. And that led to the approval by the FDA for pediatric and young adult leukemia in August of 2017.

So as a first-ever approval of a cell and gene therapy, CAR T-cell therapy has also been tested now in adults with refractory lymphoma. This disease afflicts about 20,000 a year in the United States. The results were equally impressive and have been durable to date. And six months ago, the FDA approved the therapy of this advanced lymphoma with CAR T cells. So now there are many labs and physicians and scientists around the world who have tested CAR T cells across many different diseases, and understandably, we’re all thrilled with the rapid pace of advancement. We’re so grateful to see patients who were formerly terminal return to healthy lives, as Emily has. We’re thrilled to see long remissions that may, in fact, be a cure.

At the same time, we’re also concerned about the financial cost. It can cost up to 150,000 dollars to make the CAR T cells for each patient. And when you add in the cost of treating CRS and other complications, the cost can reach one million dollars per patient. We must remember that the cost of failure, though, is even worse. The current noncurative therapies for cancer are also expensive and, in addition, the patient dies. So, of course, we’d like to see research done now to make this more efficient and increase affordability to all patients. Fortunately, this is a new and evolving field, and as with many other new therapies and services, prices will come down as industry learns to do things more efficiently.

When I think about all the forks in the road that have led to CAR T-cell therapy, there is one thing that strikes me as very important. We’re reminded that discoveries of this magnitude don’t happen overnight. CAR T-cell therapies came to us after a 30-year journey, along a road full of setbacks and surprises. In all this world of instant gratification and 24/7, on-demand results, scientists require persistence, vision, and patience to rise above all that. They can see that the fork in the road is not always a dilemma or a detour; sometimes, even though we may not know it at the time, the fork is the way home. Thank you very much.

「がん治療法を変える可能性のある「生きた薬」(A “living drug” that could change the way we treat cancer)」の和訳

これは、私がこの話を公に語るのは初めてです。Yogi Berraという世界的に有名な野球選手が言ったことがあります。「分岐点に来たら、それを選びなさい。」





その結果、キメラが生まれました。ギリシャ神話の中の素晴らしい火を吹く生物で、ライオンの頭、ヤギの体、そしてヘビの尾を持っています。それで、私たちのB細胞抗体、T細胞キャリア、そしてHIVトロイの木馬という矛盾したものは、「キメラ抗原受容体T細胞」、またはCAR T細胞と呼ばれるべきだと決定しました。

ウイルスはまた、T細胞を活性化し、彼らを殺すモードにプログラムするための遺伝情報を挿入します。そのため、CAR T細胞ががんを持つ人に注入されると、CAR T細胞は彼らの腫瘍の標的を見つけて結合すると、何が起こるでしょうか?それらはステロイドでパワーアップしたスーパーチャージされたキラーT細胞のように振る舞います。彼らは体内でこのクラッシュ防御の増強システムを開始し、文字通り数百万と分裂し増殖し、それから腫瘍を攻撃して殺します。

これにより、CAR T細胞は医学界で初めての生きた薬物となります。CAR T細胞は常識を打ち破ります。通常の薬とは異なり、摂取すると役目を果たして代謝され、それから再び摂取しなければなりませんが、CAR T細胞は数年間生きて役目を果たし続けます。私たちは、現在でも私たちのがん患者の体内にCAR T細胞が8年以上滞在しています。そして、これらのデザイナーがんT細胞、CAR T細胞は、計算された半減期が17年以上あります。1回の注入で仕事をすることができます。彼らはあなたの人生の残りの期間、巡回を続けます。


そこで私たちが行ったのは、CAR T細胞を作ることでした。私たちは患者自身のT細胞を増殖させる方法を学ぶ必要がありました。そして、1990年代にこれに関する堅牢なプラットフォームを開発しました。そして、1997年に初めて、CAR T細胞を進行性HIV/AIDSの患者に投与しました。そして、それらのCAR T細胞が患者の体内で10年以上生存することがわかりました。これにより、彼らの免疫系が改善され、ウイルスが減少しましたが、それでも彼らを治すことはありませんでした。

したがって、私たちは実験室に戻り、次の10年間でCAR T細胞の設計を改善しました。そして、2010年に、私たちは白血病患者の治療を始めました。そして、2012年に、私たちのチームは進行性の慢性リンパ性白血病を持つ患者3人を治療しました。これは、アメリカ合衆国で毎年約2万人の成人に発症する治癒不能な白血病の形態です。


そのため、CAR T細胞の投与後約28日後、彼は目を覚まし、医師たちがやっと彼を検査し、がんが消えていたことがわかりました。そこにあった大きな腫瘍が溶けてしまいました。骨髄生検では白血病の証拠は見つかりませんでした。そして、最初に治療した3人の患者のうち、2人は今や8年間持続する持続的な寛解を得ており、1人は一部の寛解を得ています。これらの患者のCAR T細胞は白血病を攻撃し、各患者の体内で2.9から7.7ポンドの腫瘍を溶かしました。彼らの体はこれらのCAR T細胞のための実質的なバイオリアクターとなり、骨髄、血液、および腫瘍塊で数百万、数百万のCAR T細胞を生産しました。

そして、これらのCAR T細胞は、ボクシングのたとえ話を使って、自分たちの重量級を遥かに超えるパンチを打つことができることがわかりました。たった1つのCAR T細胞が1,000個の腫瘍細胞を殺すことができるのです。その通り、1対1,000の比率です。CAR T細胞とその子孫の細胞は、最後の腫瘍細胞が消滅するまで体内で分裂し続けることができます。これはがん医学の中での先例はありません。完全な寛解を得た最初の2人の患者は今もなお白血病から解放されており、私たちは彼らが治癒されたと考えています。彼らは選択肢が尽きた人々であり、すべての伝統的な手段で、彼らは現代のラザロの例のようでした。私が言えることはただ一つ、その分岐点に感謝することです。


最初に彼女を見たとき、エミリーは非常に病気でした。彼女の公式の診断は進行した、治療不能の白血病でした。がんは彼女の骨髄、肝臓、脾臓に侵入していました。そして、2012年4月の春に彼女にCAR T細胞を投与した後、次の数日間、彼女は良くなりませんでした。むしろ、悪化し、実際にはずっと悪化しました。私たちが2010年に刑務所の刑務官であったように、彼女も2012年にICUに入院しました。そして、これがこの物語の中で最も恐ろしい分岐点でした。





ですから、CAR T細胞に続く高熱と昏睡状態といったこの激しい反応を、サイトカイン放出症候群、またはCRSと呼びます。我々は、この療法に反応するほとんどの患者で発生することを見つけました。しかし、反応しない患者では起こりません。ですから、逆説的に、私たちの患者は今、CAR T細胞療法を受けるときに、「人生で最悪のインフルエンザのように感じる」この高熱を望んでいます。彼らは、これが健康への曲がり角の一部であることを知っているからです。残念ながら、すべての患者が回復するわけではありません。CRSを発症しない患者は、しばしば治癒しない患者です。したがって、今やCRSと免疫系が白血病を根絶する能力との間には強い関連があります。これが、昨年FDAが白血病のためにCAR T細胞を承認する際、これらの患者のIL-6の影響とそれに伴うCRSをブロックするためのトシリズマブの使用も併せて承認した理由です。これは医学史上非常に異例の出来事でした。

エミリーの医師たちは、さらなる試験を完了し、最初に30人の患者、または90パーセントの患者がCAR T細胞治療後、1か月以内に完全寛解したと報告しました。進行がんの患者で90パーセントの完全寛解率は、50年以上のがん研究では聞いたことがありません。実際、企業は通常、がん治療の試験で患者の15パーセントが完全寛解率を示した場合に成功を宣言します。2013年に「ニューイングランドジャーナルオブメディシン」に驚くべき研究が掲載されました。その後、国際的な研究がこれらの結果を確認しました。そして、それが2017年8月にFDAによって小児および若年成人の白血病の承認につながりました。

細胞および遺伝子療法としての初の承認として、CAR T細胞療法は今や成人の難治性リンパ腫においても試されています。この疾患は米国で年間約20,000人に影響を与えています。結果は同様に印象的であり、これまでに持続しています。そして6か月前、FDAはこの進行性リンパ腫の療法をCAR T細胞で承認しました。ですから、世界中の多くの研究所や医師、科学者がCAR T細胞をさまざまな疾患で試験しており、その進歩の速さには理解できるものです。我々は、以前は末期であった患者が健康な生活に戻るのを見て、感謝しています。エミリーのように。我々は、事実上治癒である可能性のある長期寛解を見て、喜んでいます。

同時に、私たちは財政的な負担についても懸念しています。CAR T細胞を製造するための費用は、1人あたり最大15万ドルかかることがあります。さらに、CRSやその他の合併症の治療費を加えると、患者1人あたりの費用は100万ドルに達することもあります。しかし、失敗のコストを考えると、さらに悪いことです。現在のがんの非治癒療法も高額であり、さらに患者は死亡します。ですから、もちろん、これをより効率的にし、すべての患者が負担できるようにするために、今すぐ研究が行われることを望んでいます。幸いなことに、これは新しく進化している分野です。そして、他の多くの新しい療法やサービスと同様に、産業がより効率的に行う方法を学ぶにつれて、価格は下がっていくでしょう。

CAR T細胞療法を導いた道筋を考えると、非常に重要なことが一つあります。このような大きな発見は一夜にして起こるものではないということです。CAR T細胞療法は、挫折や驚きに満ちた30年間の道のりの後に私たちにもたらされました。この即時の満足と24時間365日、要求に応じた結果の世界で、科学者は忍耐力、ビジョン、そして忍耐力を持って、それらすべてを超える必要があります。彼らは、道の分かれ道が常にジレンマや迂回路ではないことを理解しています。時には、そのときはわからなくても、分かれ道が家への道なのです。ありがとうございました。