Sci­ence & Tech  Health Is a cure for cancer in sight? Charles Grae­ber re­ports

Revo­lu­tion­ary work on the body’s im­mune sys­tem and a host of new drug tri­als mean that a cure for cancer may be in sight, writes Charles Grae­ber

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Last month, the No­bel prize in medicine was awarded for two break­through sci­en­tific dis­cov­er­ies her­alded as hav­ing “rev­o­lu­tionised cancer treat­ment”, and “fun­da­men­tally changed the way we view how cancer can be man­aged”. One of them went to a charis­matic, har­mon­ica-play­ing Texan named Jim Al­li­son for his break­through ad­vances in cancer im­munother­apy. His dis­cov­ery had re­sulted in trans­for­ma­tive out­comes for cancer pa­tients and a rad­i­cal new di­rec­tion for cancer re­search.

And yet many cancer pa­tients, and even some doc­tors, have hardly heard of cancer im­munother­apy or refuse to be­lieve it. Those who have strug­gle to make sense of the new menu of op­tions and sort rea­son­able hope from overblown hype.

“The emer­gence of cancer im­munother­apy has oc­curred so quickly, it’s hard for sci­en­tists, let alone physi­cians and pa­tients, to keep track of it all,” ex­plains Dr Daniel Chen, a Stanford on­col­o­gist and re­searcher who helped bring some of the new cancer break­throughs from lab to clinic. “The ti­dal wave of data is still teach­ing us fun­da­men­tal con­cepts about the in­ter­ac­tion of the hu­man im­mune sys­tem and hu­man cancer.” It’s also bring­ing us im­por­tant new ap­proaches to the treat­ment – and pos­si­bly the cure – of cancer. “So, this data needs to be dis­sem­i­nated as quickly as pos­si­ble.”

It’s es­ti­mated that nearly 40% of us will be di­ag­nosed with cancer in

our life­times and, un­til very re­cently, we’ve had three ba­sic op­tions for deal­ing with that news. We’ve had surgery for at least 3,000 years. We added ra­di­a­tion ther­apy in 1896. Then in 1946, chem­i­cal war­fare re­search led to the use of a mus­tard gas de­riv­a­tive to poi­son cancer cells and the ad­vent of chemo­ther­apy. More re­cently, we also started poi­son­ing cancer through drugs that at­tempt to starve tu­mours of nu­tri­ents or blood sup­ply.

Those tra­di­tional “cut, burn and poi­son” tech­niques are ef­fec­tive in about half of cases. It’s a laud­able med­i­cal ac­com­plish­ment that also leaves be­hind the other half of cancer pa­tients. Ac­cord­ing to the World Health Or­gan­i­sa­tion’s in­ter­na­tional agency for re­search on cancer, that trans­lates to 9,055,027 deaths world­wide in 2018 alone.

Our usual de­fence against dis­ease is our im­mune sys­tem. It does an ex­cel­lent job of sort­ing out what doesn’t be­long in the body and at­tack­ing it – ex­cept when it comes to cancer. For 100 years, the rea­sons be­hind that ap­par­ent fail­ure were a mys­tery. Jim Al­li­son’s break­through was the re­al­i­sa­tion that the im­mune sys­tem wasn’t ig­nor­ing cancer. In­stead, cancer was tak­ing ad­van­tage of tricks that shut down the im­mune sys­tem. But what if you could block those tricks and un­leash the im­mune sys­tem’s killer T-cells against the dis­ease?

The trick Al­li­son’s im­munol­ogy lab at the Univer­sity of Cal­i­for­nia, Berke­ley, found in­volved a pro­tein on the T-cell called CTLA-4. When stim­u­lated, CTLA-4 acted like a cir­cuit breaker on im­mune re­sponse. These brakes, which he called check­points, kept the cell killers from go­ing out of con­trol and trash­ing healthy body cells. Cancer took ad­van­tage of those brakes to sur­vive and thrive.

In 1994, the lab de­vel­oped an an­ti­body that blocked CTLA-4. “Roughly, it’s like tak­ing a brick and jam­ming it be­hind the T-cell brake pedal,” ex­plains Dr Max Krum­mel, an im­mu­nol­o­gist who had worked with Al­li­son on CTLA-4. When they in­jected it into can­cer­ous mice, the an­ti­body jammed be­hind CTLA-4’s brake pedal and pre­vented the T-cell at­tack from be­ing stopped. In­stead, the T-cells de­stroyed the tu­mours and cured the cancer.

What they had found would even­tu­ally win the No­bel. It would also fly in the face of what ev­ery prac­tis­ing on­col­o­gist had been taught about cancer and how to fight it. It took 15 years, says Krum­mel, be­fore they could fi­nally test whether what worked in mice would trans­late to peo­ple.

Block­ing the brakes on the im­mune sys­tem turned out to cause se­ri­ous tox­i­c­i­ties in some pa­tients. “We learned pretty quickly that im­munother­apy was not a free ride,” ex­plains Dr Jedd Wol­chok, a cancer im­munother­a­pist and one of the pri­mary in­ves­ti­ga­tors in the clin­i­cal tri­als for Al­li­son’s anti-CTLA-4 drug. “But we were also see­ing some re­mark­able things.” For some of the metastatic me­lanoma pa­tients in the study, even ter­mi­nal stage 4 pa­tients only days away from hospice, the drug ef­fec­tively cured their cancer.

“You never for­get that,” Wol­chok ex­plains. “And at the time, we re­ally had noth­ing that would work for metastatic me­lanoma.” In 2011, that anti-CTLA-4 drug would gain ap­proval as ip­il­i­mumab (trade name Yer­voy) for use treat­ing me­lanoma; it has since been ap­proved to treat kid­ney and col­orec­tal cancer. As a drug, it has saved many thou­sands of lives. But as a proof of con­cept, the suc­cess of ip­il­i­mumab proved that the im­mune sys­tem could, in fact, be weaponised against cancer. It also kicked off the search for newer, bet­ter im­mune check­points.

The first to be dis­cov­ered was called PD-1. Its dis­cov­erer, Dr Ta­suku Honjo of Ky­oto Univer­sity, shares this year’s No­bel in medicine. PD-1 is part of a sort of se­cret hand­shake that body cells give a T-cell, telling it: “I’m one of you, don’t at­tack.” Can­cers co-opted this se­cret hand­shake, trick­ing T-cells into be­liev­ing they were nor­mal, healthy body cells. But that hand­shake could be blocked, cre­at­ing a more pre­cise cancer-killing ma­chine with far fewer toxic side­ef­fects than block­ing CTLA-4.

In De­cem­ber 2015, the sec­ond gen­er­a­tion of check­point in­hibitors (called anti-PD-1 or anti-PD-L1, de­pend­ing on whether they’re block­ing the T-cell or tu­mour side of the hand­shake) was used to un­leash the im­mune sys­tem of Jimmy Carter and clear an ag­gres­sive cancer from his liver and brain. The news of the 91-year-old’s mirac­u­lous re­cov­ery sur­prised ev­ery­one, in­clud­ing the for­mer pres­i­dent him­self.

For many peo­ple, “that Jimmy Carter drug”, the anti-PD-1 drug pem­brolizumab, ap­proved last year and sold as Keytruda, was the first and only thing they’d heard about cancer im­munother­apy. Keytruda is cur­rently one of the most widely used of the new class of drugs, ap­proved for use against nine dif­fer­ent types of cancer in the US, and a smaller number in the UK, and that list is grow­ing rapidly, as is the number of acronyms for the dozens of new check­points be­ing tested. The im­mune sys­tem re­mains the deep ocean ecosys­tem of the hu­man body. We’ve barely be­gun to plumb its depths.

For re­searchers such as Chen and oth­ers, this is our peni­cillin mo­ment in the war on cancer. As a drug, peni­cillin cut in­fec­tion rates, cured some bac­te­rial dis­eases and saved mil­lions of lives. But as a sci­en­tific break­through, it re­de­fined the pos­si­ble and opened a fer­tile new fron­tier for gen­er­a­tions of re­searchers. Nearly 100 years after the dis­cov­ery of that one sim­ple drug, an­tibi­otics are an en­tire class of medicines with a global im­pact so pro­found that we take them for granted. In­vis­i­ble ter­rors that plagued and poi­soned mankind for mil­len­nia are now ca­su­ally van­quished at a high street chemist. “We’ve only just dis­cov­ered the check­point in­hibitors,” Chen says. “So it’s the break­through – we’ve just dis­cov­ered our peni­cillin.”

Seven years after the ap­proval of that first check­point in­hibitor, there are re­port­edly 940 “new” cancer im­munother­a­peu­tic drugs be­ing tested in the clinic by more than half-a-mil­lion cancer pa­tients in more than 3,000 clin­i­cal tri­als, with over 1,000 more in the pre­clin­i­cal phase.

Those num­bers are dwarfed by the number of tri­als test­ing im­munother­apy com­bi­na­tions or us­ing them in con­cert with chemo­ther­apy or ra­di­a­tion, which, Al­li­son notes, es­sen­tially turn the dead tu­mour into a cancer vac­cine. It’s hoped that, with check­point in­hibitors re­leas­ing the brakes, the im­mune sys­tem can ef­fec­tively fin­ish up what the chemo­ther­apy starts. There are so many on­go­ing tri­als it’s im­pos­si­ble to typ­ify their stages or re­sults, but sev­eral have been pos­i­tive. The Euro­pean So­ci­ety for Med­i­cal On­col­ogy re­cently an­nounced the first mod­est im­munother­apy suc­cess against triple neg­a­tive breast cancer, a hor­ri­bly ag­gres­sive dis­ease found pri­mar­ily in younger women, which has stub­bornly re­sisted pre­vi­ous treat­ment op­tions.

Nor are check­point in­hibitors the only im­munother­apy of cancer.

The im­mune sys­tem is the deep ocean of the hu­man body. We’ve barely be­gun to plumb its depths

There are cur­rently nu­mer­ous clin­i­cal tri­als in­volv­ing be­spoke vac­cines, cus­tomised to a pa­tient’s in­di­vid­ual cancer. An­other promis­ing tech­nique, known as adop­tive cell trans­fer, fer­tilises a clone army of ex­tracted T-cells, then rein­jects them into the pa­tient to chase down each cancer cell; an­other called chimeric T-cell ther­apy, or CAR-T, reengi­neers a pa­tient’s killer T-cell into a sort of robo­cop cancer killer, cre­at­ing a star­tlingly pow­er­ful liv­ing drug ca­pa­ble of adapt­ing to match cancer for a life­time. CAR-T has al­ready wiped out cer­tain forms of child­hood leukaemia. These are claims that sim­ple cancer drugs can’t make.

“The word cure can now be used in on­col­ogy,” says Dr Axel Hoos, an im­mu­nol­o­gist and for­mer global med­i­cal lead for the Bris­tolMy­ers Squibb im­mune-on­col­ogy pro­gramme. “It’s no longer fan­tasy or a cruel prom­ise that you can’t ful­fil. We don’t yet know who will be the lucky pa­tients who will be cured, but we have seen cures al­ready.”

Hype can be dan­ger­ous, just as false hope can be cruel. There’s a nat­u­ral ten­dency to in­vest too much hope in a new sci­ence, espe­cially one that prom­ises to turn the tables on a dis­ease that has, in some way, touched ev­ery­one’s life, and sober cau­tion is re­quired. Right now, there are only hand­ful of im­munother­a­pies avail­able. The ma­jor­ity of pa­tients re­spond par­tially or not at all and some even de­velop and ac­quire re­sis­tance to the dis­ease. But the mi­nor­ity of cancer pa­tients who have been shown to re­spond to these drugs ex­pe­ri­ence re­mis­sions mea­sured not in ex­tra weeks or months of life, but in life­times. “Such trans­for­ma­tive, durable re­sponses are the unique value propo­si­tion of the cancer im­munother­a­peu­tic ap­proach,” Chen says. But it’s im­por­tant to note that that po­ten­tial is dif­fer­ent from a guar­an­tee of any one out­come for any in­di­vid­ual pa­tient.

And as Wol­chok told me: “Im­munother­apy is not a free ride.” There is the tox­i­c­i­ties that oc­cur when a T-cell re­sponse in un­leashed. There is also the “eco­nomic tox­i­c­ity” of be­spoke cancer treat­ments that bring about durable re­mis­sion but cost up­wards of $1m. A third con­cern, espe­cially in ru­ral or un­der­served sec­tors, is ac­cess to both in­for­ma­tion and the drugs and drug tri­als them­selves. They’re out there but pa­tients and physi­cians need to be em­pow­ered to ask ques­tions and un­der­stand their choices. Sev­eral doc­tors tell me that the goal of treat­ment, if a cure isn’t pos­si­ble, is hold­ing on for the next break­through. If and when it comes, pa­tients and doc­tors need to be ready to un­der­stand it. “After all,” says Chen, “there’s noth­ing more use­less than ther­a­peu­tic break­throughs against cancer that peo­ple don’t know about.”

The Break­through: Im­munother­apy and the Race to Cure Cancer by Charles Grae­ber is out this week (Scribe, £16.99). To or­der a copy for £14.95 go to guardian­book­ or call 0330 333 6846

T-cells at­tach them­selves to a cancer cell.

Below: Jim Al­li­son, joint win­ner of the No­bel prize in medicine for his work on cancer and the im­mune sys­tem. Adolfo Chavez III/ MD An­der­son/EPA

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