You bet your life: Af­ter I was di­ag­nosed with a rare can­cer, I dis­cov­ered how a small band of physi­cian-sci­en­tists trig­gered a rev­o­lu­tion

Bioreg­num Opin­ion Col­umn by John Car­roll

It all start­ed to look se­ri­ous­ly bad when my legs be­gan to swell up, which I ini­tial­ly — stu­pid­ly — shrugged off. By the time it be­came ap­par­ent that my kid­neys had stopped work­ing, I grabbed an Uber af­ter ar­riv­ing at the air­port near where I live in Texas and head­ed straight to the ER of Val­ley Bap­tist Med­ical Cen­ter near the Mex­i­can bor­der.

For the first four days at Val­ley Bap­tist, I wit­nessed a health­care sys­tem at war with com­mon sense. My doc­tors would wan­der in and out in the morn­ing, of­fer­ing lit­tle de­tail and few an­swers in their brief pit stops. Some­times they didn’t come at all or just kept mov­ing if I was nod­ding off. I was sub­ject­ed to a poor­ly-han­dled pro­ce­dure to in­stall nephros­to­my tubes — which I was forced to loud­ly and pro­fane­ly de­mand from an in­ter­ven­tion­al ra­di­ol­o­gy team un­hap­py with my potas­si­um num­bers af­ter they tried wheel­ing me in and then back out of the in­ter­ven­tion­al ra­di­ol­o­gy are­na with­out ex­pla­na­tion. I don’t re­call even be­ing told about a colos­sal blood clot that threat­ened my life — but did get three rounds of dial­y­sis that may well have saved my life.

The ini­tial work­ing the­o­ry, as told to me by a PA in the ICU — Mike, the on­ly ac­tu­al source of in-depth in­for­ma­tion dur­ing my en­tire stay — was that lym­phoma had prob­a­bly swelled my lymph nodes and dammed up my kid­neys. I wish. On the fifth morn­ing, 48 hours af­ter a biop­sy, my on­col­o­gist in charge — who had ear­li­er told me in a bit of in­ten­tion­al ex­pec­ta­tion man­age­ment that it would take sev­en days to de­ter­mine what can­cer I had — rather tri­umphant­ly an­nounced that my pre­lim­i­nary biop­sy analy­sis con­clud­ed that I had neu­roen­docrine tu­mors with Merkel cell fea­tures.

All of the news, delivered with full-text to your inbox. For professionals discovering, developing, and marketing biopharmaceutical drugs.

SIGN UP

It was, he an­nounced, “stage 4.”

I know stage 4. Not good. But at this point I could say I’ve had bet­ter re­la­tion­ships with used car sales­men wear­ing joke ties. I hoped he was blun­der­ing on sparse in­for­ma­tion. And what was Merkel cell car­ci­no­ma, any­way?

The on­ly treat­ment, he added, with my wife stand­ing next to me, was chemo. No surgery, no ra­di­a­tion, and no ex­pla­na­tion. Just chemo.

I didn’t know it at the time, but he def­i­nite­ly screwed that up. If I had stayed at Val­ley Bap­tist and been treat­ed with chemo, I like­ly would have seen Merkel cell car­ci­no­ma rear back up with­in a few months, putting me on a sta­tis­ti­cal­ly short path to the grave.

As it turned out, there was a turn of good luck in­volved here as well. The pathol­o­gist han­dling the biop­sy had trained with the team at the Uni­ver­si­ty of Texas MD An­der­son Can­cer Cen­ter, and would iden­ti­fy as­pects of the can­cer cells that would con­vince my med­ical crew in Hous­ton ear­ly on that they were in­deed deal­ing with Merkel cell car­ci­no­ma.

As for Val­ley Bap­tist, I had al­ready de­ter­mined that I had to get the hell out of Dodge and make a run for a top-tier med­ical in­sti­tu­tion in the re­gion. My case man­ag­er said that if I want­ed to leave they would have to arrange a trans­fer. But I al­ready had the lay of the land from the small army of as­sis­tants and nurs­es who kept the hos­pi­tal on its rick­ety track. A nurse told my wife and I — sot­to voce — that as we were head­ed in­to the week­end, that could take days.

You should just go, she said qui­et­ly.

My wife drove the get­away car af­ter I signed the AMA (against med­ical ad­vice), and a friend in the in­dus­try helped text my way in­to MD An­der­son as we made the six-hour trip north.

“A com­plete waste of time”

Like a lot of peo­ple, I’ve heard about melanoma, skin can­cer trig­gered by ex­po­sure to the sun. I’m 67, I’ve spent a con­sid­er­able amount of time in the sun, and I knew I had risks. About sev­en months be­fore fate dropped a ton of can­cer bricks on my head, I had a full body ex­am done by a pro.

Na­da.

So I thought I had skin can­cer cov­ered.

Wrong again.

Merkel cells in the skin are there to as­sist with sen­sa­tion and touch.

“The den­si­ty of them is much high­er on the lips and the fin­ger­tips,” said Paul Nghiem, a lead­ing Merkel cell re­searcher at the Uni­ver­si­ty of Wash­ing­ton and the pres­ti­gious Fred Hutchin­son Can­cer Cen­ter in Seat­tle. “If you put your hand in your pock­et and you’re feel­ing the dif­fer­ence be­tween sand­pa­per and silk, those are Merkel cells telling you about tex­ture and touch.”

Nghiem, a der­ma­tol­o­gist by train­ing, end­ed up as Mr. Merkel Cell — one of the key fig­ures in this field with the longest, broad­est his­to­ry of treat­ing pa­tients — in a serendip­i­tous fash­ion. Back in the mid-1990s, his pro­fes­sor need­ed to pro­duce a chap­ter on Merkel cell car­ci­no­ma, and for the pro­fes­sor, Nghiem seemed the ob­vi­ous per­son to write it.

Nghiem didn’t much care for the as­sign­ment. But what start­ed out as a “com­plete waste of time” be­came the big fo­cus of his ca­reer, one that would con­tribute to a tidal shift in ther­a­py and of­fer a key role in ex­am­in­ing how this can­cer can be cured one day — or made liv­able — for most ad­vanced pa­tients.

Nghiem — an ef­fu­sive, en­thu­si­as­tic physi­cian-sci­en­tist — now doesn’t be­lieve Merkel cells be­come can­cer­ous. Rather, it seems to him that cells in the body are hi­jacked and ac­quire Merkel cell fea­tures as they turn can­cer­ous.

Merkel cell car­ci­no­ma can fol­low a melanoma-like process, ex­hib­it­ed on the skin by some­thing that may look like a nod­ule or raised bruise. A large ma­jor­i­ty of cas­es — pre­dom­i­nant­ly men above the age of 65 — are linked to the poly­omavirus, which in­hab­its a large swath of the pop­u­la­tion. Chat­ting about my case, Nghiem said I may have had some­thing vis­i­ble on the skin months be­fore the di­ag­no­sis, which could have gone un­no­ticed and then dis­ap­peared as it spread in­side the body.

He doesn’t know, of course. But he’s ob­served that peo­ple whose im­mune sys­tems have quelled can­cer on the skin be­fore it spread to lymph nodes tend to have a strong nat­ur­al re­sponse to fight­ing ad­vanced Merkel cell — giv­ing them a big boost when im­munother­a­py comes in­to play.

Wher­ev­er the can­cer­ous cells come from, once the cell di­vi­sion process be­gins, it tends to run amok in ad­vanced cas­es. As my doc­tor at MD An­der­son de­scribed it, where you see a sin­gle cell di­vi­sion in melanoma, you can run up the lethal score dozens of times faster with Merkel cell.

That makes it a quick and ef­fi­cient killer, a berserk­er cell, es­pe­cial­ly for the ad­vanced pa­tients who are not el­i­gi­ble for surgery. For those pa­tients, chemo was the orig­i­nal stan­dard of care. But chemo flat­tens the im­mune sys­tem, the ex­act op­po­site of what you want to do if you need to fight Merkel cell. Which is why most of the im­prove­ments on­col­o­gists saw in pa­tients treat­ed with chemo were bru­tal­ly tran­sient.

Ear­ly on in this process, my doc­tors con­clud­ed that Merkel cell car­ci­no­ma had spread to my lymph nodes, which in turn swelled and shut down my kid­neys. Blocked kid­neys were the first thing that came close enough to killing me — with my potas­si­um num­bers spik­ing in­to a dead­ly range. But Merkel cell isn’t just a sin­gu­lar rare can­cer, gen­er­at­ing some 3,000 new di­ag­noses a year. Be­cause my can­cer had ad­vanced in­to a seg­ment of my body that was choked with ar­ter­ies, veins, the path for kid­ney drainage and more among the swollen lymph nodes — a bi­o­log­i­cal traf­fic snarl — it was be­yond the reach of surgery. And it rep­re­sents one of about 1,000 new ad­vanced cas­es a year.

In oth­er words, I was one of just a slice of an al­ready tiny group.

That’s a far cry from one of the Big Can­cers like lung can­cer, where bio­phar­ma is throw­ing ma­jor cash. Ask any drug de­vel­op­er, large or small, what’s dri­ving their work, and they’ll tell you it’s all about pa­tients. But what they don’t say is that it’s typ­i­cal­ly a crit­i­cal mass of pa­tients. Pa­tients whose col­lec­tive cas­es can spin off bil­lions of dol­lars a year in rev­enue.

One thou­sand new cas­es a year in the US — where the mon­ey is in glob­al drug de­vel­op­ment — is not much of a mar­ket to tempt drug de­vel­op­ers.

And Merkel cell was nev­er a fa­vorite in the big can­cer sto­ry be­ing told to in­vestors over the last decade.

“You just go away”

Ip­il­i­mum­ab, the CT­LA-4 im­munother­a­py birthed by No­bel Prize win­ner Jim Al­li­son and sold as Yer­voy, be­came the pi­o­neer check­point in­hibitor in the field. Then came nivolum­ab (Op­di­vo) from Bris­tol My­ers Squibb and pem­brolizum­ab (Keytru­da), the King Kong of im­munother­a­py drugs that gen­er­at­ed $25 bil­lion of rev­enue for Mer­ck in 2023. Keytru­da made the big bucks by ze­ro­ing in on can­cer with a full pipeline of projects for one drug. It’s been mak­ing Mer­ck in­vestors hap­py campers ever since it was first ap­proved for ad­vanced melanoma in 2014.

Merkel cell car­ci­no­ma, it turns out, is one of the most im­muno­genic tu­mors in the book. Nghiem and oth­ers ad­vo­cat­ed ear­ly on that a drug that un­leashed the im­mune sys­tem would go a long way to treat­ing the can­cer. For them, Merkel cell was a clas­sic low-hang­ing fruit. The prob­lem was the har­vest was too small to whip up po­ten­tial in­dus­try back­ers.

Isaac Brownell

“It has the high­est re­sponse rate of any sol­id tu­mor to sin­gle-agent check­point,” Isaac Brownell flat­ly says. Brownell, a se­nior in­ves­ti­ga­tor and chief of the Cu­ta­neous De­vel­op­ment and Car­cino­gen­e­sis Sec­tion, Der­ma­tol­ogy Branch in­side the NIH, was di­rect­ly in­volved in the cut­ting-edge ear­ly re­search in­to im­munother­a­pies in MCC and has stayed fo­cused on it, screen­ing drugs for some­thing new. A lot of Merkel cell’s re­sponse to treat­ment has to do with the virus, he adds, which ex­press­es for­eign pro­tein — a clear tar­get the im­mune sys­tem was cre­at­ed to hunt down and de­stroy. In oth­er can­cers, tu­mors can get rid of pas­sen­ger mu­ta­tions and evade im­mune re­spons­es, mak­ing them a more dif­fi­cult tar­get. But what is for­eign and stays on the radar is a bea­con for im­munother­a­py.

So Nghiem and oth­ers went knock­ing on Bris­tol My­ers’ door to test a hy­poth­e­sis where they had high con­fi­dence of suc­cess.

The door stayed closed. They nev­er got a chance to test ip­il­i­mum­ab, said Nghiem, who al­so had a brief flir­ta­tion with Pfiz­er’s 4-1BB be­fore the big check­point in­hibitors came along.

But it didn’t get bet­ter with nivolum­ab, Bris­tol My­ers’ big PD-1 drug that stripped can­cer cells of the brakes ap­plied to the im­mune sys­tem. Elim­i­nat­ing can­cer’s abil­i­ty to thwart the im­mune sys­tem would sure­ly save lives, but Bris­tol My­ers made it clear they were go­ing to take a pass on Merkel cell.

“BMS said, ‘You just go away. We’re not in­ter­est­ed at all,’” Nghiem said.

Then, the re­searchers did some of their own strate­gic think­ing.

While Bris­tol My­ers and Mer­ck were hog­ging the spot­light with their PD-1s, Mer­ck KGaA came along with their PD-L1 called avelum­ab. I cov­ered this drug, and the com­pa­ny, close­ly at the time. And I wasn’t too kind. What I saw was a drug that would fail a string of im­por­tant stud­ies as the Ger­man out­fit fought against a 10-year track record of clin­i­cal fail­ures.

The first time my doc­tor at MD An­der­son, Mike Wong, brought up avelum­ab (sold as Baven­cio), I turned to my wife — an­oth­er long­time writer in bio­phar­ma — and asked her to re­mind me who made it.

“Mer­ck KGaA,” she said. EMD Serono in the US.

My re­ply: “Oh, shit.”

But what I saw as a pro­gram ripe for set­backs at one of the most ill-starred R&D groups in the in­dus­try looked like a his­toric op­por­tu­ni­ty for the small cir­cle of Merkel cell ex­perts in the world. And it was, in more ways than one.

“They were be­hind,” Nghiem re­calls about Mer­ck KGaA, which was part­nered with Pfiz­er at the time. “They were be­hind Bris­tol My­ers. They were be­hind [US] Mer­ck.” Merkel cell car­ci­no­ma looked to them like a short path to the mar­ket, where the in­dus­try part­ners — who would break up in 2023 — could gain an ini­tial ap­proval and then start to ex­pand the fran­chise with new in­di­ca­tions. That’s a clas­sic mar­ket strat­e­gy in the on­col­o­gy world.

Howard Kauf­man

Howard Kauf­man, then an in­ves­ti­ga­tor at the Rut­gers Can­cer In­sti­tute and a promi­nent mem­ber of the small cir­cle of Merkel cell afi­ciona­dos, used his role on the EMD Serono sci­en­tif­ic ad­vi­so­ry board to push for the study. It didn’t be­gin well.

“So the first thing they told me at EMD Serono was, of course, ‘There’s very few Merkel cell pa­tients,'” Kauf­man told me. “‘We’ll nev­er be able to do the study.’ I said: ‘No, you don’t un­der­stand. There’s very few pa­tients, and I know every doc­tor who takes care of them.'”

And the cher­ry on top: There were no com­pet­ing stud­ies. They had an open play­ing field to re­cruit pa­tients.

Kauf­man would go on to be the prin­ci­pal in­ves­ti­ga­tor in the maid­en tri­al of avelum­ab for MCC.

And there was more than one voice call­ing on Mer­ck KGaA to try its drug on Merkel cell. Brownell’s of­fice was just a hall­way away from not­ed NCI im­munother­a­py ex­pert James Gul­ley, who had done ear­ly-stage work on avelum­ab. Well aware of how far be­hind Mer­ck KGaA was with the drug, Brownell tout­ed Merkel cell as an ide­al tar­get for im­munother­a­py. And that helped spur the in­flu­en­tial Gul­ley to throw his weight be­hind the avelum­ab ap­proach, Brownell says.

The re­searchers ran avelum­ab through a small, sin­gle-arm Phase II study with da­ta on 88 pa­tients who had failed chemo and blew it out, kind of. The re­quire­ment on chemo, which would blunt ef­fi­ca­cy, was done at the in­sis­tence of the FDA, Kauf­man said. But reg­u­la­tors were al­so wait­ing for the da­ta.

One in three pa­tients re­spond­ed to the drug in the first co­hort, the FDA saw in that first clin­i­cal for­ay. About one in 10 had a com­plete re­sponse. For 86% who re­spond­ed, the re­sponse last­ed at least six months, drop­ping to 45% at 12 months. The re­searchers tracked du­ra­tion that last­ed from a few months to about two years.

No “sim­ple con­found­ing fac­tor”

From start to fin­ish, Kauf­man says, the tri­al took nine months, and the FDA came through with an ac­cel­er­at­ed OK just 2 weeks af­ter the fil­ing was ac­cept­ed, de­liv­ered in a sur­prise phone call while Kauf­man was at­tend­ing a satel­lite meet­ing for the So­ci­ety for Im­munother­a­py of Can­cer. He was caught com­plete­ly off guard by reg­u­la­tors’ speed.

I have to say, for a can­cer pa­tient, the da­ta they had in hand can be hard to muster a cheer for. Every­body wants bet­ter odds than that. But this was a field ac­cus­tomed to mis­er­able re­sults and re­searchers knew they had proven con­clu­sive­ly that they were on­to some­thing big.

There was no way you could mis­in­ter­pret the da­ta, said Nghiem, who helped lead the tri­al in Seat­tle. It more than sat­is­fied the FDA team around Richard Paz­dur that the ef­fi­ca­cy was clean. No “sim­ple con­found­ing fac­tor” could de­rail the con­clu­sion, he added. Avelum­ab worked, and the ac­cel­er­at­ed ap­proval came through in the spring of 2017, giv­ing Mer­ck KGaA its first re­al brag­ging rights to a sig­nif­i­cant R&D win in 10 years.

In 2018, the re­searchers con­clud­ed an­oth­er small study, this time for the US Mer­ck, which al­so in­clud­ed Nghiem, who said it “was very hard” to get the com­pa­ny on board. That study proved Keytru­da was a game-chang­er in front­line Merkel cell ther­a­py, with­out chemo. And re­searchers fol­lowed up with a con­fir­ma­to­ry batch of da­ta in front­line ther­a­py that sealed the reg­u­la­to­ry deal for Mer­ck KGaA.

The FDA cit­ed Keytru­da for a 56% over­all re­sponse rate, with a com­plete re­sponse of 24% on its ap­proval, ce­ment­ing the new front­line ap­proach as a new stan­dard of care.

Even with­out Bris­tol My­ers’ co­op­er­a­tion, nivolum­ab and ip­il­i­mum­ab are on the menu of pos­si­ble treat­ments for the sim­ple rea­son that im­munother­a­pies work for a bit bet­ter than half of pa­tients with ad­vanced Merkel cell car­ci­no­ma. And in some cas­es, it may prove to be a res­cue ap­proach for dy­ing pa­tients.

A third PD-1, reti­fan­limab (Zynyz) from In­cyte, would earn an ac­cel­er­at­ed FDA OK for MCC in 2023 — years af­ter the stan­dard of care had shift­ed de­ci­sive­ly. It’s rarely men­tioned by any of the physi­cians I spoke with.

Fast-for­ward sev­en years from that first OK and my on­col­o­gist at MD An­der­son would still rec­om­mend Baven­cio for my first swing at bat against this can­cer. There’s no sta­tis­ti­cal di­vide here. No one’s done any ran­dom­ized study of an im­munother­a­py for MCC, let alone a head-to-head.

And it’s not go­ing to hap­pen.

The re­searchers in the field are unan­i­mous that no one wants to foot the bill for more de­fin­i­tive work on a slice of a rare can­cer mar­ket. And be­sides, what pa­tients would vol­un­teer for any ran­dom­ized study with chemo when you have the clin­i­cal proof in hand? As for a head-to-head, there isn’t enough mon­ey at stake to com­pete for the mar­ket. And maybe not that much to dif­fer­en­ti­ate them­selves any­way.

Iron­i­cal­ly, the ab­sence of a ran­dom­ized study has kept im­munother­a­py side­lined to a sec­ond-line ther­a­py in Eu­rope. As a re­sult, Nghiem said, ex­pert prac­ti­tion­ers nudge the can­cer with chemo, but in low enough dos­es not to com­pli­cate their treat­ment, an­nounce chemo didn’t work and move on to im­munother­a­py.

It’s just an­oth­er ex­am­ple of gam­ing an in­ex­act sys­tem, where lead­ing prac­ti­tion­ers have learned how to avoid be­ing ham­strung by ei­ther re­cal­ci­trant phar­ma play­ers or mis­guid­ed reg­u­la­tors.

So why avelum­ab?

My MD An­der­son team likes the ac­tive Fc arm, com­pared to the in­ac­tive Fc arm in Keytru­da. That’s the down­ward spoke of an an­ti­body — un­der the Y-ax­is — that’s in use in the drug struc­ture. There can be some more com­pli­cat­ing fac­tors from this, but an ac­tive Fc arm can al­so de­liv­er ad­van­tages, like nat­ur­al killer cell re­cruit­ment.

It’s def­i­nite­ly a con­clu­sion reached by the seat of the prac­ti­tion­er’s pants. But prac­ti­cal ex­pe­ri­ence now fig­ures heav­i­ly in­to the state-of-the-art guess­work in­volved in treat­ing MCC. And at this point, the sec­ond wave of Merkel cell ther­a­py re­lies a lot on ob­ser­va­tion­al work and one-on-one ex­per­i­men­ta­tion.

“It was a fan­tas­tic 17-year run…”

Here’s an ex­am­ple of the way ex­pe­ri­ence is now in­flu­enc­ing treat­ment: Af­ter Kauf­man left the Rut­gers Can­cer In­sti­tute — de­ter­min­ing that he want­ed to de­vote his life to drug de­vel­op­ment and treat­ment af­ter be­ing of­fered a shot at the in­sti­tute’s top job — he wound up as CEO of a biotech start­up close­ly fo­cused on melanoma. He would like to ramp up some­thing in Merkel cell, but that’s proved elu­sive so far.

But one day a week he al­so treats pa­tients at Mass­a­chu­setts Gen­er­al Hos­pi­tal, where he’s set­ting up a non-melanoma skin can­cer cen­ter that in­cludes Merkel cell. He’s con­clud­ed that some pa­tients who aren’t re­spond­ing to im­munother­a­py can be pushed in­to the re­spon­der cir­cle with ra­di­a­tion.

That sort of hands-on ex­pe­ri­ence gets quick­ly cir­cu­lat­ed among the small band of Merkel cell spe­cial­ists. I’ve seen it in ac­tion first-hand in my own con­ver­sa­tions at MD An­der­son.

But the burst of in­vest­ment that fu­eled an on­go­ing wave of im­munother­a­py R&D in bio­phar­ma has yet to de­liv­er any new, ap­proved marked im­prove­ments in Merkel cell, de­spite the wide recog­ni­tion that it’s a great mod­el for im­muno­genic­i­ty and cell ther­a­py 2.0.

Part of that sev­en-year whiff in Merkel cell is at­trib­uted to the gen­er­al lack of en­thu­si­asm for tiny niche mar­kets. Af­ter the biotech boom went bust a cou­ple of years ago, small­er de­vel­op­ers al­so were less like­ly to de­vote re­sources to Merkel cell. And now the Merkel cell net­work sounds dis­tinct­ly spooked by the sud­den down­siz­ing that is go­ing on among the gi­ant play­ers as the re­treat of IPOs in biotech keeps the com­pe­ti­tion fo­cused on big tar­gets.

Case in point: The leg­endary Roche sub­sidiary Genen­tech re­cent­ly slashed its work in im­munother­a­py, bid­ding good­bye to Ira Mell­man, one of the best-known play­ers in the field who led the work on Tecen­triq.

“It was a fan­tas­tic 17-year run that al­lowed us to build pos­si­bly the biggest and best unit in in­dus­try or acad­e­mia de­vot­ed to the sci­ence of can­cer im­munol­o­gy and dis­cov­ery of im­munother­a­peu­tics,” Mell­man wrote on LinkedIn as he flagged his im­mi­nent de­par­ture.

And it’s over, as a down­sized unit is ab­sorbed in­to an­oth­er de­part­ment.

For Merkel cell in­sid­ers, it’s an ex­am­ple of a wide­spread re­treat that’s hav­ing a clear im­pact on their field.

“I think in­vestors are def­i­nite­ly mov­ing away from I/O,” Kauf­man said. “There’s no ques­tion about that…. There are a lot of oth­er com­pa­nies [be­sides Roche] that have been down­siz­ing their I/O ca­pa­bil­i­ties right now.”

Right around the time it gained ap­proval to use its new LAG-3 im­munother­a­py, re­latlimab, against melanoma, Bris­tol-My­ers cut a pro­gram for a suc­ces­sor to Yer­voy. It al­so didn’t go un­no­ticed in the Merkel cell cir­cle that Bris­tol My­ers’ ap­pli­ca­tion tied re­latlimab’s use to its al­ready OK’d Op­di­vo — pur­su­ing a mar­ket the phar­ma gi­ant be­lieves will hit $4 bil­lion by keep­ing it all in-house.

For these bat­tle-scarred re­searchers, the les­son is clear: The hunt for max­i­mum mar­ket cash con­tin­ues to di­rect their ef­forts.

Phil Green­berg

The big prob­lem with Merkel cell right now is that find­ing the dol­lars to do re­search is hard­er than ever. And ul­ti­mate­ly, an in­dus­try part­ner would be need­ed to take any new drug for­ward to a de­ci­sive tri­al, says Fred Hutch’s Phil Green­berg, one of the sci­en­tif­ic founders of Juno, which helped hatch the CAR-T rev­o­lu­tion and the move to en­gi­neered T cell ther­a­pies.

That’s a tough com­bi­na­tion to deal with, push­ing the bar high­er.

“The prob­lem now is that the lev­el at which there’s sup­port for these kinds of pro­grams in in­dus­try has re­al­ly got­ten small­er,” Green­berg tells me. “And so you need much more proof of prin­ci­ple be­fore you can en­gage es­sen­tial­ly some­body to help sup­port de­vel­op­ing it.

“The win isn’t big enough to jus­ti­fy the risk of the in­vest­ment. There was a time when peo­ple were will­ing to take that risk. It’s much less com­mon now.”

It hasn’t helped, he adds, that the NIH bud­get has, in re­al terms, been shrink­ing. “NIH grants are try­ing to de-risk the projects,” he said, and that doesn’t help ad­vance tru­ly in­no­v­a­tive, high-risk aca­d­e­m­ic projects.

And that steady re­treat in turn slows down their work, says Aude Cha­puis, Green­berg’s col­league at Fred Hutch.

“I think they’re all out of date”

“We’re nev­er go­ing to see a TV ad for the treat­ment of Merkel cell car­ci­no­ma, be­cause it is rare,” Har­vard’s Jim De­Caprio men­tioned in an in­ter­view on Merkel cell. But for De­Caprio, whose lab has long fo­cused on MCC, “there are cer­tain­ly op­por­tu­ni­ties to build on its re­al­ly spec­tac­u­lar re­sponse to check­point block­ade. To build on that op­por­tu­ni­ty.”

And the work is con­tin­u­ing, al­beit more slow­ly and with greater risk of wind­ing up in a dead end at an aca­d­e­m­ic in­sti­tute or be­ing added to an un­ap­proved tool­box that is grad­u­al­ly grow­ing in Merkel cell.

Green­berg and Cha­puis have been do­ing the kind of work in im­munother­a­py that has at­tract­ed biotechs and their le­gion of in­vestors. Their work on T cell re­cep­tor ther­a­pies went in­to cre­at­ing Affi­ni-T, which is ad­vanc­ing pro­grams for KRAS and p53. But when it came time to pri­or­i­tize the work af­ter care­ful­ly as­sess­ing what they need­ed to do with the mon­ey avail­able, Merkel cell went out the win­dow. Now Green­berg and Cha­puis are do­ing the ear­ly-stage re­search in Merkel cell.

That’s just the way it works, Affi­ni-T CMO Dirk Nagors­en tells me, in an in­dus­try that has un­der­gone more than two years of pri­or­i­ti­za­tion re­views.

Just about every­one in biotech will tell you that right now, it can be hard to raise fresh funds, with a big fo­cus on main­tain­ing a two- or three-year fi­nan­cial run­way and a be­liev­able timetable for hu­man da­ta. De­mand is hot for big re­sults in key mar­kets. As for Big Phar­ma, the em­pha­sis is on find­ing ther­a­pies that have been de-risked with hu­man da­ta, and Merkel cell re­mains on the fringes of their com­mer­cial radar.

John Con­nol­ly

John Con­nol­ly, the chief sci­en­tif­ic of­fi­cer at the Park­er In­sti­tute for Can­cer Im­munother­a­py (PI­CI), as­signs the cur­rent chill to a tem­po­rary phase — which will re­heat as im­por­tant new im­munother­a­pies are ap­proved.

“Agree with you on the rare dis­eases eval­u­a­tion,” he re­spond­ed to one of my emails. “I’m not sure about the broad based re­treat from I/O. Can­cer is still a huge pay­day, even for Big Phar­ma, and dis­cov­er­ies come in waves. A cou­ple of wins will have them back in droves. Keep an eye on PI­CI.”

PI­CI — found­ed by Face­book bil­lion­aire Sean Park­er — has been sup­port­ing work at Fred Hutch that aims to make it to the leader of the cell ther­a­py 2.0 move­ment, in­clud­ing the ef­forts to di­rect­ly en­gage sol­id tu­mors. For the re­searchers, Merkel cell car­ci­no­ma is still an ide­al tar­get to es­tab­lish proof of prin­ci­ple.

Aude Cha­puis

“It’s pret­ty much near­ly a 100% of these Merkels will ex­press CD200,” says Cha­puis, cit­ing re­search that in­cludes Brownell. “So it can be a very use­ful binder for the switch re­cep­tor that Phil had … and with that we have re­done a con­struct.”

Us­ing some state re­search mon­ey de­rived from the Big To­bac­co set­tle­ment, they’re now lin­ing up a small tri­al to test their new-and-im­proved TCR tech on.

Ni­na Bhard­waj, the di­rec­tor of im­munother­a­py at the Tisch Can­cer In­sti­tute at Mount Sinai, has been do­ing her own work on per­son­al­ized can­cer vac­cines, us­ing neoanti­gens to mount a re­newed at­tack right against the can­cer cells.

There are a va­ri­ety of ex­per­i­men­tal pro­grams like this go­ing on. Kauf­man end­ed up as CEO of a Till­man Gern­gross start­up called Ankyra, which is us­ing an alu­minum hy­drox­ide scaf­fold­ing tech to hold IL-12 in a des­ig­nat­ed space, hope­ful­ly con­cen­trat­ing its pow­er­ful ef­fect in one place, while avoid­ing the sys­temic tox­i­c­i­ty that has re­peat­ed­ly thwart­ed IL-12 ther­a­pies. For now, Merkel cell is not in the pipeline, but his CMO brings it up rou­tine­ly as a promis­ing tar­get.

As for Brownell, the spec­trum of work that he’s been do­ing from dis­cov­ery through ear­ly clin­i­cal in­cludes a pro­gram screen­ing drugs to see whether he can find some­thing that would prove an as­sist for Merkel cell. That work led him to au­ro­ra ki­nase B, which has worked well in virus-pos­i­tive mouse mod­els. And that, in turn, led him to a com­pa­ny that was test­ing the ap­proach in an­oth­er neu­roen­docrine tu­mor, but ran in­to a road­block with tox­i­c­i­ty. Now he’s wait­ing to see if the com­pa­ny can work out the tox is­sues, but it’s an up­hill fight.

“As you’re aware,” Brownell says, “when things don’t pan out quick­ly and get re­turn on in­vest­ment, com­pa­nies quick­ly lose in­ter­est in de­vel­op­ing stuff.”

On­colyt­ics — in­fect­ing can­cer cells with a virus that de­stroys them — has al­so come up on the MCC radar. There’s on­ly one on­colyt­ic ther­a­py on the mar­ket: T-VEC from Am­gen. On­colyt­ics are promis­ing, but tox­i­c­i­ty has reined in the mar­ket for T-VEC. Still, a num­ber of biotechs are work­ing on com­bos us­ing on­colyt­ic virus­es, in­clud­ing CG On­col­o­gy, which has promis­ing blad­der can­cer da­ta from a small study. That’s now in a se­ries of late-stage stud­ies, but noth­ing in Merkel cell car­ci­no­ma.

That dis­cov­ery part of the sto­ry is still very much de­vel­op­ing, and I’ll keep you post­ed on what comes out of it.

Con­nol­ly is op­ti­mistic that a com­bi­na­tion ap­proach pos­si­bly us­ing a can­cer vac­cine can come in­to play here. And we’ve been ex­plor­ing some of the ex­per­i­men­tal fron­tier in Merkel cell to see if an IND for one per­son might be the right move at a lat­er date.

I’m will­ing. If you want to find com­mit­ment, talk to pa­tients.

But the old rules of the R&D game need to change if you ex­pect to see new ther­a­pies com­ing along, Kauf­man said. Es­pe­cial­ly in this con­strained en­vi­ron­ment.

“I think we have to change the el­i­gi­bil­i­ty cri­te­ria for the stud­ies,” Kauf­man said. “I think we have to change the end­points. And I think we have to change the study de­signs, be­cause I think they’re all out of date.”

RE­CIST may work for chemo, he adds, but it’s wrong for im­munother­a­py. And he point­ed to ip­il­i­mum­ab’s ear­ly near-demise as an ex­am­ple of that.

“I’m wor­ried that we’re throw­ing away drugs that may ac­tu­al­ly be work­ing, be­cause we’re us­ing out­dat­ed end­points,” Kauf­man said.

Ul­ti­mate­ly, he says, it may just get down to the biotechs in the field, as the FDA sig­nals its will­ing­ness to re­view new stan­dards and pa­tients who are fail­ing ap­proved drugs die off. But Big Phar­ma re­mains “too ner­vous about chang­ing them.”

“I didn’t or­der that”

I’ve cov­ered hun­dreds if not thou­sands of clin­i­cal tri­als in­volv­ing on­col­o­gy ther­a­pies. But I’ve nev­er cov­ered a can­cer drug as a pa­tient un­til now.

Along the way, I found out a lot more about what the term “fight­ing can­cer” ac­tu­al­ly means; what it re­quires of all of us as we are laid up, sub­ject­ed to painful reme­dies and poked and prod­ded and checked for vi­tals with re­lent­less com­pas­sion.

I al­so learned a lot about the re­al world of drug re­search, where in­ves­ti­ga­tors some­times form net­works of in­sur­gent col­lab­o­ra­tors, shar­ing what they learn and adapt­ing stan­dards of care while ex­plor­ing bet­ter ways of keep­ing pa­tients alive. It in­volves a lot of ed­u­cat­ed guess­work, and get­ting in­tro­duced to that in­for­mal net­work should be job num­ber one of any Merkel cell can­cer pa­tient.

Right now, Merkel cell and oth­er mar­gin­al pro­grams are what get dropped from pipelines. You can de­nounce it, cuss it and even, maybe, gen­er­ate some pop­u­lar heat around it. But you’re not go­ing to change it. Math rules, and these peo­ple are very, very bright.

Not long ago, I was talk­ing to Har­vard’s Tim Springer. One of his star­tups had found a great can­di­date for preeclamp­sia, but it was a tough sell to in­vestors or the in­dus­try be­cause the mar­ket was so small. I can re­late to that now like nev­er be­fore. This di­vide be­tween com­mer­cial and pa­tient in­ter­est presents a re­al dilem­ma — if you’re on the pa­tient and in­ves­ti­ga­tor side of things.

With­out the pas­sion­ate par­tic­i­pa­tion of a small group of ex­perts in Merkel cell, the im­munother­a­py rev­o­lu­tion may well have ar­rived way late — ne­glect­ed by com­pa­nies that were ei­ther too daunt­ed by the prospect of mount­ing a study in a rare can­cer or sim­ply un­in­ter­est­ed in pur­su­ing it.

You can count any de­lays in lives lost too ear­ly. Their per­sis­tence paid off in lives saved or sig­nif­i­cant­ly pro­longed. And that de­serves to be rec­og­nized as they strug­gle to im­prove on ther­a­pies for a mar­gin­al dis­ease like Merkel cell car­ci­no­ma.

The sys­tem it­self is geared to keep pa­tients anony­mous. That’s the law. But I start­ed sound­ing off about my con­di­tion from day one on so­cial me­dia. I had a chance of boot­ing up my own in­for­mal sci­en­tif­ic ad­vi­so­ry net­work of some of the most renowned ex­perts of a small field. And I was de­ter­mined to take it.

It was my edge, when I was short of edges.

The key ques­tion, though, is whether there’s a broad­er ben­e­fit to try­ing to spot­light an is­sue like this.

A cou­ple of things: One, there’s a huge seg­ment of health­care in Amer­i­ca that — re­gard­less of dis­ease — is just need­less­ly killing peo­ple. Doc­tors who care more about their pre­cious ego than the pa­tient. War­ring de­part­ments. Just bad de­ci­sion-mak­ing. No idea what team­work means for pa­tients fac­ing a Ru­bik’s Cube of threats. Ut­ter­ly in­ca­pable of com­mu­ni­cat­ing clear­ly and hon­est­ly with pa­tients. Work­ing in in­sti­tu­tions which have put a high pri­or­i­ty on prof­its.

In these in­sti­tu­tions, in­for­ma­tion can be used to man­age pa­tients’ ex­pec­ta­tions rather than ed­u­cate them on the dis­ease and their chances. Peo­ple need to be warned about that and learn how to avoid the val­ley of death and un­need­ed pain. You don’t need to be man­aged in­to an ear­ly grave.

At one point when I was ar­gu­ing at Val­ley Bap­tist about my ur­gent need for nephros­to­my tubes, I men­tioned some­thing my physi­cian’s as­sis­tant had said. “He’s got no sway down here,” came the turf-mas­ter re­ply in in­ter­ven­tion­al ra­di­ol­o­gy. An­oth­er time my nephrol­o­gist erupt­ed an­gri­ly when he saw that I’d had a per­ma­nent catheter in­stalled in my neck in case I need­ed an­oth­er emer­gency dial­y­sis. “Who or­dered that? I didn’t or­der that,” he said as he humphed away, nev­er to be seen again.

Pa­tients can dis­ap­pear in these wide cracks that ap­pear in med­ical care. If you see it, run. MD An­der­son is 180 de­grees from that. You get an ex­pla­na­tion every time you’re talk­ing to the lead doc­tor. Then they check to make sure it’s sunk in. Then they fol­low up with a sur­vey to see if it stuck.

Two, and this is par­tic­u­lar­ly true in can­cer care, you need to be ag­gres­sive about get­ting care and learn what is hap­pen­ing to you. I end­ed up with some great guides on this jour­ney, and I owe them every­thing.

Three, I could have used a quick in­tro spe­cif­ic to Merkel cell car­ci­no­ma when I got the di­ag­no­sis. There isn’t one, so I de­cid­ed to write it my­self.

And fi­nal­ly, there’s a hell of a tale here about a small group of re­searchers who man­aged to work around a bio­phar­ma in­dus­try that is large­ly in­dif­fer­ent to Merkel cell car­ci­no­ma in spe­cif­ic and rare dis­eases in gen­er­al. And these in­ves­ti­ga­tors are still fight­ing the bat­tle to achieve bet­ter out­comes for pa­tients — even as the in­dus­try mounts a staged re­treat from im­munother­a­py and aca­d­e­mics find it tougher than ever to raise funds for the work.

I’m not out of the woods yet. And it’s un­like­ly I ever will be, this side of my demise. I don’t know when I’m go­ing to die. I can on­ly be sure that the date may be draw­ing clos­er, per­haps much clos­er, than I had count­ed on.

So it goes.

Now there’s a choice of drugs and a lot of stuff that’s off the books. I have a Plan A, a Plan B un­der re­view and maybe a Plan C in there as well. And it’s ear­ly days. I’m al­so ex­plor­ing a Hail Mary. I’m not go­ing to ask for one more day on earth, un­less I can do some­thing with it.

If I’m go­ing to die, I’m not go­ing to be ig­no­rant about the rea­sons why. I know the odds and I’ll ul­ti­mate­ly make my own de­ci­sions, with ad­vice. My choic­es get nar­row­er, but I haven’t run out — yet.