A "living drug" that could change the way we treat cancer | Carl June

Translator: Lulu Fitri Rahman Reviewer: Ade Indarta

So this is the first time I've told this story in public,

Ini pertama kalinya saya menceritakan ini di depan umum,

the personal aspects of it.

aspek personalnya.

Yogi Berra was a world-famous baseball player who said,

Yogi Berra adalah pemain bisbol terkenal yang berkata,

"If you come to a fork in the road, take it."

"Jika bertemu jalan bercabang, ambil keputusan."

Researchers had been, for more than a century,

Selama lebih dari satu abad, peneliti telah

studying the immune system as a way to fight cancer,

mempelajari sistem imun sebagai cara melawan kanker,

and cancer vaccines have, unfortunately, been disappointing.

dan vaksin kanker, sayangnya, mengecewakan.

They've only worked in cancers caused by viruses,

Vaksin hanya ampuh pada kanker yang disebabkan virus,

like cervical cancer or liver cancer.

seperti kanker serviks atau kanker hati.

So cancer researchers basically gave up on the idea

Jadi, sebenarnya peneliti tidak lagi mengandalkan konsep

of using the immune system to fight cancer.

penggunaan sistem imun untuk melawan kanker.

And the immune system, in any case, did not evolve to fight cancer;

Dan sistem imun, apa pun itu, tidak berkembang untuk melawan kanker,

it evolved to fight pathogens invading from the outside.

tapi untuk melawan patogen yang menyerang dari luar.

So its job is to kill bacteria and viruses.

Jadi, tugasnya membunuh bakteri dan virus.

And the reason the immune system has trouble with most cancers

Dan alasan sistem imun sulit memerangi sebagian besar kanker

is that it doesn't invade from the outside;

adalah karena kanker tidak menyerang dari luar,

it evolves from its own cells.

tapi berkembang dari selnya sendiri.

And so either the immune system does not recognize the cancer as a problem,

Jadi, sistem imun bisa jadi tidak mengenali kanker sebagai masalah,

or it attacks a cancer and also our normal cells,

atau justru menyerang sel kanker sekaligus sel normal kita,

leading to autoimmune diseases like colitis or multiple sclerosis.

menimbulkan penyakit autoimun seperti kolitis atau sklerosis multipel.

So how do you get around that?

Jadi, bagaimana cara mengatasinya?

Our answer turned out to be synthetic immune systems

Jawaban kami adalah sistem imun buatan

that are designed to recognize and kill cancer cells.

yang dirancang untuk mengenali dan membunuh sel kanker.

That's right -- I said a synthetic immune system.

Benar, saya bilang sistem imun buatan.

You do that with genetic engineering and synthetic biology.

Anda melakukannya dengan rekayasa genetika dan biologi sintetis.

We did it with the naturally occurring parts of the immune system,

Kami dengan komponen sistem imun yang terjadi secara alami,

called B cells and T cells.

yang disebut sel B dan sel T.

These were our building blocks.

Inilah komponen dasar kami.

T cells have evolved to kill cells infected with viruses,

Sel T berkembang untuk membunuh sel yang terinfeksi virus,

and B cells are the cells that make antibodies that are secreted

sedangkan sel B membentuk antibodi yang dikeluarkan

and then bind to kill bacteria.

untuk kemudian membunuh bakteri.

Well, what if you combined these two functions

Bagaimana jika kedua fungsi ini digabungkan

in a way that was designed to repurpose them to fight cancer?

dalam cara yang dirancang untuk melawan kanker?

We realized it would be possible to insert the genes for antibodies

Kami sadar bukan hal mustahil menyisipkan gen penghasil antibodi

from B cells into T cells.

dari sel B ke dalam sel T.

So how do you do that?

Bagaimana caranya?

Well, we used an HIV virus as a Trojan horse

Kami memanfaatkan virus HIV sebagai kuda troya

to get past the T cells' immune system.

untuk melewati sistem imun sel T.

The result is a chimera,

Hasilnya adalah chimera,

a fantastic fire-breathing creature from Greek mythology,

makhluk fantastis penyembur api dalam mitologi Yunani,

with a lion's head, a goat's body and a serpent's tail.

dengan kepala singa, tubuh kambing, dan ekor ular.

So we decided that the paradoxical thing that we had created

Jadi, kami memutuskan benda paradoksal ciptaan kami ini,

with our B-cell antibodies, our T cells carrier

dengan antibodi sel B, pengangkut sel T,

and the HIV Trojan horse

serta kuda troya HIV,

should be called "Chimeric Antigen Receptor T cells," or CAR T cells.

dinamai "sel T reseptor antigen chimeric", atau sel T CAR.

The virus also inserts genetic information

Virus itu juga menyisipkan informasi genetik

to activate the T cells and program them into their killing mode.

untuk mengaktifkan sel T dan memprogramnya sebagai pembunuh.

So when CAR T cells are injected into somebody with cancer,

Jadi, ketika sel T CAR disuntikkan ke pengidap kanker,

what happens when those CAR T cells see and bind to their tumor target?

apa yang terjadi begitu sel T CAR melihat target tumornya?

They act like supercharged killer T cells on steroids.

Ia bertindak seperti sel T pembunuh ganas terhadap steroid.

They start this crash-defense buildup system in the body

Sel T CAR memulai sistem penguatan pertahanan dalam tubuh

and literally divide and multiply by the millions,

dan secara harfiah terus membelah dan menggandakan diri,

where they then attack and kill the tumor.

lalu menyerang dan membunuh tumor.

All of this means that CAR T cells are the first living drug in medicine.

Ini artinya sel T CAR adalah obat hidup pertama di bidang kedokteran.

CAR T cells break the mold.

Sel T CAR membuka jalan baru.

Unlike normal drugs that you take --

Tidak seperti obat biasa yang Anda konsumsi,

they do their job and get metabolized, and then you have to take them again --

yang bekerja dan dimetabolisme, lalu harus diminum lagi,

CAR T cells stay alive and on the job for years.

Sel T CAR hidup dan terus bekerja selama bertahun-tahun.

We have had CAR T cells stay in the bodies of our cancer patients

Ada pasien kanker kami dengan sel T CAR yang menetap di tubuhnya

now for more than eight years.

hingga lebih dari delapan tahun.

And these designer cancer T cells, CAR T cells,

Dan sel T rancangan ini, sel T CAR,

have a calculated half-life of more than 17 years.

diperkirakan memiliki waktu paruh lebih dari 17 tahun.

So one infusion can do the job;

Jadi, dengan infus satu kali saja,

they stay on patrol for the rest of your life.

sel T CAR akan terus berpatroli seumur hidup.

This is the beginning of a new paradigm in medicine.

Inilah awal paradigma baru di bidang kedokteran.

Now, there was one major challenge to these T-cell infusions.

Sekarang, ada satu tantangan besar pada infus sel T ini.

The only source of T cells that will work in a patient

Satu-satunya sumber sel T yang akan bekerja di tubuh pasien

are your own T cells,

adalah sel Anda sendiri,

unless you happen to have an identical twin.

kecuali Anda memiliki kembar identik.

So for most of us, we're out of luck.

Sebagian besar dari kita kurang beruntung.

So what we did was to make CAR T cells.

Jadi, yang kami lakukan adalah membuat sel T CAR.

We had to learn to grow the patient's own T cells.

Kami belajar menumbuhkan sel T milik pasien sendiri.

And we developed a robust platform for this in the 1990s.

Dan kami mengembangkan platform yang kuat untuk ini pada 1990-an.

Then in 1997, we first tested CAR T cells in patients

Lalu pada 1997, untuk pertama kalinya kami menguji sel T CAR pada pasien

with advanced HIV-AIDS.

dengan HIV-AIDS stadium lanjut.

And we found that those CAR T cells survived in the patients

Kami menemukan sel T CAR bertahan di tubuh pasien

for more than a decade.

selama lebih dari sepuluh tahun.

And it improved their immune system and decreased their viruses,

Dan sistem imun mereka meningkat dan virus mereka menurun,

but it didn't cure them.

tapi mereka tidak sembuh.

So we went back to the laboratory, and over the next decade

Jadi kami kembali ke laboratorium, dan dekade berikutnya

made improvements to the CAR T cell design.

terus menyempurnakan rancangan sel T CAR.

And by 2010, we began treating leukemia patients.

Pada 2010, kami mulai mengobati pasien leukemia.

And our team treated three patients

Tim kami mengobati tiga pasien

with advanced chronic lymphocytic leukemia in 2012.

dengan leukemia limfosit kronis stadium lanjut pada 2012.

It's a form of incurable leukemia

Itu sejenis leukemia yang tidak bisa disembuhkan

that afflicts approximately 20,000 adults every year in the United States.

yang setiap tahun menyerang sekitar 20.000 orang dewasa di Amerika Serikat.

The first patient that we treated was a retired Marine sergeant

Pasien pertama kami seorang pensiunan sersan angkatan laut

and a prison corrections officer.

dan petugas lapas.

He had only weeks to live

Usianya tinggal hitungan minggu

and had, in fact, already paid for his funeral.

dan dia bahkan telah membayar biaya pemakamannya.

The cells were infused, and within days, he had high fevers.

Sel itu dimasukkan, dan dalam beberapa hari dia demam tinggi.

He developed multiple organ failures,

Dia mengalami kegagalan multi organ,

was transferred to the ICU and was comatose.

dipindahkan ke ICU, dan koma.

We thought he would die,

Kami mengira dia akan meninggal,

and, in fact, he was given last rites.

dan dia bahkan menerima sakramen terakhir.

But then, another fork in the road happened.

Tapi kemudian, jalan kembali bercabang.

So, around 28 days after the CAR T cell infusion,

Sekitar 28 hari setelah infus sel T CAR,

he woke up,

dia siuman,

and the physicians finally examined him,

dan dokter memeriksanya,

and the cancer was gone.

dan kankernya hilang.

The big masses that had been there had melted.

Massa besar yang tadinya ada telah hancur.

Bone marrow biopsies found no evidence of leukemia,

Biopsi sumsum tulang tak menemukan jejak leukemia,

and that year, in our first three patients we treated,

dan tahun itu, dari tiga pasien pertama yang kami obati,

two of three have had durable remissions now for eight years,

dua mencapai remisi selama delapan tahun sampai sekarang,

and one had a partial remission.

dan satu lagi remisi parsial.

The CAR T cells had attacked the leukemia in these patients

Sel T CAR menyerang leukemia di tubuh ketiga pasien ini

and had dissolved between 2.9 and 7.7 pounds of tumor in each patient.

dan menghancurkan antara 1,3 dan 3,5 kilogram tumor dalam setiap pasien.

Their bodies had become veritable bioreactors for these CAR T cells,

Tubuh mereka menjadi bioreaktor nyata untuk sel T CAR,

producing millions and millions of CAR T cells

yang menghasilkan jutaan sel T CAR

in the bone marrow, blood and tumor masses.

di sumsum tulang, darah, dan massa tumor.

And we discovered that these CAR T cells can punch far above their weight class,

Dan kami lihat sel T CAR sanggup bertarung di kelas yang lebih tinggi,

to use a boxing analogy.

menggunakan analogi tinju.

Just one CAR T cell can kill 1,000 tumor cells.

Satu sel T CAR saja dapat membunuh 1.000 sel tumor.

That's right -- it's a ratio of one to a thousand.

Benar, rasionya satu berbanding seribu.

The CAR T cell and its daughter progeny cells

Sel T CAR dan sel-sel keturunannya

can divide and divide and divide in the body

dapat membelah dan terus membelah dalam tubuh

until the last tumor cell is gone.

hingga sel tumor terakhir menghilang.

There's no precedent for this in cancer medicine.

Belum ada preseden untuk ini dalam pengobatan kanker.

The first two patients who had full remission

Kedua pasien pertama yang mencapai remisi penuh

remain today leukemia-free,

bebas leukemia hingga hari ini,

and we think they are cured.

dan kami pikir mereka sembuh.

These are people who had run out of options,

Mereka orang-orang yang tak lagi punya pilihan,

and by all traditional methods they had,

dan dengan semua metode tradisional yang dicoba,

they were like modern-day Lazarus cases.

mereka bagaikan Lazarus versi modern.

All I can say is: thank goodness for those forks in the road.

Saya hanya bisa bilang: syukurlah ada banyak jalan bercabang.

Our next step was to get permission to treat children with acute leukemia,

Langkah kami berikutnya adalah mendapat izin mengobati anak pasien leukemia akut,

the most common form of cancer in kids.

bentuk kanker paling umum pada anak.

The first patient we enrolled on the trial was Emily Whitehead,

Pasien pertama kami untuk uji coba ini adalah Emily Whitehead,

and at that time, she was six years old.

dan saat itu dia berumur 6 tahun.

She had gone through a series of chemotherapy

Dia telah menjalani serangkaian kemoterapi

and radiation treatments over several years,

dan pengobatan radiasi selama beberapa tahun,

and her leukemia had always come back.

tapi leukemia selalu datang lagi,

In fact, it had come back three times.

bahkan sampai tiga kali.

When we first saw her, Emily was very ill.

Ketika kami pertama kali melihatnya, Emily sakit parah.

Her official diagnosis was advanced, incurable leukemia.

Diagnosis awalnya leukemia stadium lanjut yang tidak bisa disembuhkan.

Cancer had invaded her bone marrow, her liver, her spleen.

Kanker menyerang sumsum tulang, hati, dan limpanya.

And when we infused her with the CAR T cells

Ketika kami menginfusnya dengan sel T CAR

in the spring of April 2012,

pada musim semi April 2012,

over the next few days, she did not get better.

selama beberapa hari berikutnya, dia tidak membaik.

She got worse, and in fact, much worse.

Kondisinya memburuk, dan bahkan jauh lebih buruk.

As our prison corrections officer had in 2010,

Seperti petugas lapas pasien kami pada 2010,

she, in 2012, was admitted to the ICU,

Emily, tahun 2012, dimasukkan ke ICU,

and this was the scariest fork in the whole road of this story.

dan ini cabang paling menakutkan dalam kisah ini.

By day three, she was comatose and on life support

Pada hari ketiga, Emily koma dan butuh alat penopang hidup

for kidney failure, lung failure and coma.

karena gagal jantung, paru-paru, dan koma.

Her fever was as high as 106 degrees Fahrenheit for three days.

Demamnya mencapai 41 derajat Celsius selama tiga hari.

And we didn't know what was causing those fevers.

Kami tidak tahu penyebab demam itu.

We did all the standard blood tests for infections,

Kami lakukan semua tes darah standar untuk infeksi,

and we could not find an infectious cause for her fever.

tapi tidak bisa menemukan infeksi yang menyebabkan demamnya.

But we did find something very unusual in her blood

Tapi kami menemukan kejanggalan dalam darahnya

that had never been seen before in medicine.

yang belum pernah ada di dunia pengobatan.

She had elevated levels of a protein called interleukin-6, or IL-6,

Dia mengalami peningkatan level protein bernama interleukin-6, atau IL-6,

in her blood.

dalam darahnya.

It was, in fact, more than a thousandfold above the normal levels.

Bahkan lebih dari seribu kali lipat di atas normal.

And here's where yet another fork in the road came in.

Di sinilah jalan bercabang kembali muncul.

By sheer coincidence,

Sungguh kebetulan,

one of my daughters has a form of pediatric arthritis.

salah satu putri saya mengidap artritis anak.

And as a result, I had been following as a cancer doc,

Akibatnya, sebagai dokter kanker, saya mengikuti perkembangan

experimental therapies for arthritis for my daughter,

terapi eksperimental untuk artritis bagi putri saya,

in case she would need them.

sekiranya dibutuhkan.

And it so happened that just months before Emily was admitted to the hospital,

Kebetulan, hanya beberapa bulan sebelum Emily masuk rumah sakit,

a new therapy had been approved by the FDA

sebuah terapi baru disetujui FDA

to treat elevated levels of interleukin-6.

untuk mengobati peningkatan level interleukin-6.

And it was approved for the arthritis that my daughter had.

Obat ini disetujui untuk artritis yang diidap anak saya.

It's called tocilizumab.

Namanya tocilizumab.

And, in fact, it had just been added to the pharmacy at Emily's hospital,

Bahkan obat ini baru saja ditambahkan di apotik rumah sakit Emily,

for arthritis.

untuk artritis.

So when we found Emily had these very high levels of IL-6,

Jadi, ketika kami menemukan level IL-6 Emily sangat tinggi,

I called her doctors in the ICU and said,

saya menghubungi dokternya di ICU dan berkata,

"Why don't you treat her with this arthritis drug?"

"Kenapa dia tidak diobati dengan obat artritis saja?"

They said I was a cowboy for suggesting that.

Mereka bilang saran saya nekat.

And since her fever and low blood pressure

Tapi karena demam dan tekanan darahnya yang rendah

had not responded to any other therapy,

tidak merespons terapi apa pun,

her doctor quickly asked permission to the institutional review board,

dokternya segera meminta izin dewan peninjau ulang institusional,

her parents,

orang tua Emily,

and everybody, of course, said yes.

dan semuanya, tentu saja, mengizinkan.

And they tried it,

Dan mereka mencobanya,

and the results were nothing short of striking.

dan hasilnya hampir mengesankan.

Within hours after treatment with tocilizumab,

Beberapa jam setelah diobati dengan tocilizumab,

Emily began to improve very rapidly.

Emily mulai menunjukkan peningkatan pesat.

Twenty-three days after her treatment,

Dua puluh tiga hari setelah pengobatan,

she was declared cancer-free.

dia dinyatakan bebas kanker.

And today, she's 12 years old and still in remission.

Dan sekarang, dia berusia 12 tahun dan masih dalam remisi.

(Applause)

(Tepuk tangan)

So we now call this violent reaction of the high fevers and coma,

Jadi, sekarang kami menyebut reaksi kuat demam tinggi dan koma ini,

following CAR T cells,

yang mengikuti sel T CAR,

cytokine release syndrome, or CRS.

sindrom pelepasan sitokin, atau CRS.

We've found that it occurs in nearly all patients who respond to the therapy.

Kami lihat ini terjadi pada hampir semua pasien yang merespons terapi tersebut.

But it does not happen in those patients who fail to respond.

Tapi tidak pada pasien yang gagal merespons.

So paradoxically,

Jadi uniknya,

our patients now hope for these high fevers after therapy,

pasien kami sekarang mengharapkan demam tinggi ini setelah terapi,

which feels like "the worst flu in their life,"

yang rasanya seperti "flu terparah seumur hidup,"

when they get CAR T-cell therapies.

saat menjalani terapi sel T-CAR.

They hope for this reaction

Mereka mengharap reaksi ini

because they know it's part of the twisting and turning path

karena tahu ini bagian dari titik balik

back to health.

untuk kembali sehat.

Unfortunately, not every patient recovers.

Sayangnya, tidak setiap pasien sembuh.

Patients who do not get CRS are often those who are not cured.

Pasien yang tidak mengalami CRS sering kali tidak sembuh.

So there's a strong link now between CRS

Jadi, ada kaitan kuat antara CRS

and the ability of the immune system to eradicate leukemia.

dan kemampuan sistem imun untuk membasmi leukemia.

That's why last summer,

Maka, musim panas lalu,

when the FDA approved CAR T cells for leukemia,

saat FDA menyetujui sel T CAR untuk leukemia,

they also co-approved the use of tocilizumab to block the IL-6 effects

mereka juga menyetujui penggunaan tocilizumab untuk memblokir efek IL-6

and the accompanying CRS in these patients.

dan CRS yang mengiringinya pada para pasien ini.

That was a very unusual event in medical history.

Ini kejadian yang sangat langka dalam sejarah kedokteran.

Emily's doctors have now completed further trials

Kini dokter Emily menyelesaikan uji coba lanjutan

and reported that 27 out of 30 patients, the first 30 we treated,

dan melaporkan 27 dari 30 pasien, 30 orang pertama yang kami rawat,

or 90 percent,

atau 90 persen,

had a complete remission

mencapai remisi lengkap

after CAR T cells, within a month.

setelah terapi sel T CAR, dalam sebulan.

A 90 percent complete remission rate in patients with advanced cancer

Angka remisi lengkap 90 persen pada pasien kanker stadium lanjut

is unheard of

belum pernah terdengar

in more than 50 years of cancer research.

selama lebih dari 50 tahun penelitian kanker.

In fact, companies often declare success in a cancer trial

Bahkan perusahaan kerap mengumumkan keberhasilan uji coba kanker

if 15 percent of the patients had a complete response rate.

jika 15 persen pasien memiliki angka respons lengkap.

A remarkable study appeared in the "New England Journal of Medicine" in 2013.

Sebuah studi luar biasa muncul di Jurnal Kedokteran New England pada 2013.

An international study has since confirmed those results.

Sebuah studi internasional juga mengonfirmasi hasil ini.

And that led to the approval by the FDA

Dan hasilnya, persetujuan FDA

for pediatric and young adult leukemia in August of 2017.

untuk leukemia anak dan remaja pada Agustus 2017.

So as a first-ever approval of a cell and gene therapy,

Jadi, sebagai terapi sel dan gen pertama yang disetujui,

CAR T-cell therapy has also been tested now

terapi sel T CAR kini juga diuji coba

in adults with refractory lymphoma.

terhadap orang dewasa dengan limfoma kambuhan.

This disease afflicts about 20,000 a year in the United States.

Penyakit ini menyerang sekitar 20.000 orang setahun di Amerika Serikat.

The results were equally impressive and have been durable to date.

Hasilnya juga mengesankan dan bertahan hingga hari ini.

And six months ago, the FDA approved the therapy of this advanced lymphoma

Dan enam bulan lalu, FDA menyetujui terapi limfoma stadium lanjut ini

with CAR T cells.

dengan sel T CAR.

So now there are many labs and physicians and scientists around the world

Jadi, sekarang banyak lab dan dokter dan ilmuwan di seluruh dunia

who have tested CAR T cells

yang menguji sel T CAR

across many different diseases,

untuk berbagai macam penyakit,

and understandably, we're all thrilled with the rapid pace of advancement.

dan jelas kami gembira dengan kemajuannya yang pesat.

We're so grateful to see patients who were formerly terminal

Kami sangat bersyukur para pasien yang tadinya tidak mungkin sembuh

return to healthy lives, as Emily has.

kini kembali sehat, seperti Emily.

We're thrilled to see long remissions that may, in fact, be a cure.

Kami gembira melihat remisi panjang yang bahkan mungkin sembuh.

At the same time, we're also concerned about the financial cost.

Di sisi lain, kami mengkhawatirkan masalah keuangan.

It can cost up to 150,000 dollars to make the CAR T cells for each patient.

Biayanya mencapai 150.000 dolar untuk pembuatan sel T CAR per pasien.

And when you add in the cost of treating CRS and other complications,

Dan jika ditambahkan biaya pengobatan CRS dan komplikasi lain,

the cost can reach one million dollars per patient.

biayanya bisa satu juta dolar per pasien.

We must remember that the cost of failure, though, is even worse.

Tapi kita harus ingat biaya kegagalannya jauh lebih besar.

The current noncurative therapies for cancer are also expensive

Terapi non-kuratif terkini untuk kanker juga mahal

and, in addition, the patient dies.

dan pasien tetap meninggal.

So, of course, we'd like to see research done now

Jadi, tentu saja kami menginginkan riset

to make this more efficient

yang menjadikan terapi ini lebih efisien

and increase affordability to all patients.

dan lebih terjangkau bagi semua pasien.

Fortunately, this is a new and evolving field,

Untungnya bidang ini baru dan terus berkembang,

and as with many other new therapies and services,

dan dengan banyaknya terapi dan layanan baru lain,

prices will come down as industry learns to do things more efficiently.

harga akan menurun karena industri belajar untuk lebih efisien.

When I think about all the forks in the road

Ketika saya memikirkan semua jalan bercabang

that have led to CAR T-cell therapy,

yang menghasilkan terapi sel T CAR,

there is one thing that strikes me as very important.

ada satu hal yang bagi saya amat penting.

We're reminded that discoveries of this magnitude don't happen overnight.

Kami diingatkan bahwa penemuan sebesar ini tidak terjadi dalam semalam.

CAR T-cell therapies came to us after a 30-year journey,

Terapi sel T CAR muncul setelah perjalanan 30 tahun,

along a road full of setbacks and surprises.

menyusuri jalan yang penuh rintangan dan kejutan.

In all this world of instant gratification

Di dunia yang menuntut kepuasan instan,

and 24/7, on-demand results,

serta hasil yang tersedia kapan saja,

scientists require persistence, vision and patience

ilmuwan membutuhkan keuletan, visi, dan kesabaran

to rise above all that.

untuk mengatasi semua itu.

They can see that the fork in the road is not always a dilemma or a detour;

Mereka bisa melihat jalan bercabang tak selalu menjadi dilema atau halangan.

sometimes, even though we may not know it at the time,

Terkadang, meski saat itu kita mungkin tidak tahu,

the fork is the way home.

cabang itulah jalan pulang.

Thank you very much.

Terima kasih banyak.

(Applause)

(Tepuk tangan)