T CELL & CANCER – THE WONDERS WE CREATED AND THE POTHOLES WE DUG

Immunotherapy and Willie Nelson

Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Gyorgyi

That’s what Jim Allison had to deal with when he learned how to use the immune system to attack and sometimes cure metastatic cancer. Allison was from a small town in Texas. His father was a country physician and his mother died of lymphoma when he was still a boy. Initially planning to follow in his father’s footsteps, he got interested in research as a high school student. In an interview he said that he was reluctant to become a physician because doctors have to be right almost all the time. Researchers, on the other hand, develop hypotheses and test them. If they aren’t wrong most of the time “they’re not on the edge.” He wrote poetry, liked to read, loved country music and later in his career played harmonica on the stage with Willie Nelson. At the University of Texas he studied biochemistry and earned a PhD. After his post doc year he got a job in a small lab that the University of Texas/M.D. Anderson Cancer Center was operating in Smithville… close to Austin.⁶

While in Texas he worked out the structure of the T cell antigen receptor and gained some notoriety. T cells, one of the white blood cells that float in our blood, are part of the immune system. They aren’t very good at recognizing abnormal proteins but they are efficient destroyers. When a dendritic or other watchdog cell spots a virus it processes the “stranger” and “presents” it to the antigen receptor on the T lymphocyte. Then the T lymphocyte deals with it. At one time early in Allison’s education he recalls a professor who doubted there was such a thing as a T cell. After his “receptor” accomplishment Allison took a year sabbatical and became a professor at the University of California, Berkeley.

He considered himself an immunologist and his lab tried to work out the relationship between the T cell and cancer. In animal studies T cells seemed to recognize and attack cancer cells. They latched on and released a poison, a protein called CD28 that should have destroyed the malignant cell. But the cancer somehow survived.

Another protein, CTLA-4, showed up after the CD28 was released. What was it doing there? A large pharmaceutical company had concluded it was another cell poison, and the company patented it as a poison.

Allison wasn’t so sure. So he developed an antibody to CTLA-4 and one of his fellows gave it to a mouse with cancer. A few days later the cancer was gone. The results surprised Allison. Blocking a cancer poison should not have contributed to the death of the tumor.

Allison asked his fellow to repeat the experiment. Since it was Christmas, he went on vacation. Allison manned the lab and watched the mouse as the tumors grew for a few days. Then they faded away. Allison immediately realized he might have something big, but he had to be sure. His group injected antibody that blocked CTLA-4 into the bodies of many different strains of mice. In the absence of CTLA-4 the poison produced by the T lymphocyte– the CD28– was able to destroy one tumor after another.

Allison realized his success meant our understanding of cancer and the immune system was wrong. “The biology was backwards”.

T lymphocytes, he hypothesized, recognized cancer cells, and they latched on. They injected a “poison” (CD-28) that should have killed the malignant cell. But cancer cells made an “antidote” (CTLA-4). It stopped the poison from working. His antibody blocked the antidote and it ALLOWED the poison to keep killing the bad cells.

Bristol Myers Squibb had patented CTLA-4. Their patent claimed CTLA-4 was the poison not the antidote. It was wrong—backwards. But the company had a patent and lawyers and money.

Allison was a valued scientist. His identification of the T cell antigen receptor was important. People in the field respected him. He was a full professor of Immunology at Cal Berkeley. Bright ambitious students studied with him.

But he wasn’t an M.D. His only interaction with sick people had occurred when he was a boy in a small Texas town. He had gone on house calls with his father, the town doctor.

Allison wanted to try his antibody on patients, but he didn’t think he could take the next step without Pharma’s help. He “spent almost two years going around and talking to a number of large and a few small biotech firms trying to interest them in his idea. There was a lot of skepticism. And the fact that Bristol Myers Squibb had a patent put people off. They claimed the intellectual property was ‘dirty.’

Eventually a small firm, Medarex, decided to give his antibody a shot. It was a big investment. Niels Lonborg a scientist at GenPharm, a company that was purchased by Medarex (in 1997), had mice that had made fully human antibodies. Lonborg created the antibody that later became the drug, Ipilimumab.

A trial of the drug on patients was arranged. As Allison explained in an interview, he “was totally committed” to the endeavor. He moved to New York, to be near Sloan Kettering Cancer Center “to make sure nobody hurt his baby– Nobody screwed up.” He moved to be a nuisance. The biology of Ipilimumab (the drugs generic name) was different than that of most cancer drugs. “Usually you treat patients. If the tumor grows in the face of treatment the drug is a failure.” But in the treated mice the cancer grew for a while, then withered. The tumor didn’t always regress but “there was overall survival.”

As shown in Breakthrough, a film that documented the subsequent struggle, his discovery came face to face with the people who ran big Pharma. Immunotherapy had failed in the past and to the conservative corporate money men Allison’s drug seemed like a long shot, not worth the risk. The doctor coordinating the trials, Rachel Humphrey believed in the product and was it’s chief advocate. When she faced the board she emphasized the drug’s effectiveness in one person. Men yelled at her and she took it.

A competitor, Pfizer, had an immunotherapy drug trial running at the same time. They halted their effort when the tumors in their patients they treated didn’t shrink 30 percent in 12 weeks. That was the FDA Standard.

With Allison’s drug the tumors kept enlarging but the patient’s felt well. Allison explained that’s how the drug works. The T cell gets into the tumor and starts killing cancer cells. It takes a long time before the tumor stops getting larger. As the trial progressed some of the people who were treated, twent home. When they were given a drug that hadn’t previously worked they got well. The recent drug got the credit for the improvement. Allison knew it wasn’t the recent medication, it was the T cells that continued to methodically kill the tumor.

Bristol Myers Squibb, his company eventually agreed to not use the number of people were alive at a year or two as an end point. They agreed to see if there was an improvement in total survival. After 3 years the patients who hadn’t received immunotherapy were all dead. Over 20 percent of the people who received Allison’s drug were alive and well three, four, and later 5 years later. The company couldn’t call it a cure. You never know. The cancer might come back. But they stayed well. The treatment sure acted like a cure.

Allison went to New York in 2004 but the drug wasn’t approved by the FDA until 2011. During the 7 years Allison lived in an apartment 3 blocks from the hospital. He gained weight. He knew the drug cured cancer and was frustrated by his need to keep explaining. At times he became angry. On one occasion he went into a tirade. He’d come so far and he was afraid they would conclude the drug failed. He was single minded and obsessed. His marriage fell apart. Malinda, the woman he met when he was a collage student, the coed who always felt he was the only person she ever loved—the most amazing human she ever saw– left.

In 1997 Medarex acquired GenPharm. In 2009 Bristol-Myers Squibb paid Medarex $2.4 billion and the companies merged.

Squibb charged $30,000 for an ipilimumab injection or $120,000 for a course of therapy. During Ipilimumab’s first year on the market, Squibb sold $706 million worth; they took in $462 million through the first half of 2013. And they thought they would sell $1.54 billion worth of the drug in 2018.

In 1992 a few Japanese scientists found another poison/antibody combination. The antidotes were called PD-L1 and PD-1. Drugs that block them were created by Pharma researchers, tested, approved by the FDA, and sell for about $150,000 a treatment.

In 2017 close to 1300 people with advanced melanoma were assessed 3 years post treatment. They lived in 21 countries. All had received a combination of two drugs nivolumab-plus-ipilimumab. 58% were alive and in 39% the disease had not progressed¹.

In another study: 5 years after the trial was started, Dr. James Larkin of the Royal Marsden in England and others assessed 300 plus people who had metastatic melanoma and who had been treated with two drugs that blocked the antidotes produced by melanoma cell. Marsden reflected that “Historically, 5-year survival rates among patients with metastatic melanoma were dismal.” The treatment had been hard on the bodies of the sufferers; only 58 percent seemed to have had a favorable response. But 52 percent of the 300+ were alive at five years. The median progression-free survival was 11.5 months. More than half the people treated, most of whom would have died without treatment, were still alive at 60 months.² Doctors evaluating new treatments for advanced cancer are reluctant to use the word cure. It’s always possible that the tumor will, at some point, start growing again.

In 2018 the PD-1 inhibor, nivolumab “showed a clinically meaningful survival benefit in some people who had advanced lung cancer.³

The clinical trials, hospital days, and advertising cost a lot of money and the companies that tweeked, developed and manufactured the drugs are working hard to recoup their outlay. In 2015 Dr Saltz of Sloan Kettering estimated the price tag for the two drugs used to treat melanoma was about $300.000 per person, and the copay, the “out-of-pocket charge was usually $60,000.⁴”

In 2018 Bristol-Myers Squibb sold $7.5 billion worth of Opdivo/nivolumab and Merck sold $7.1 billion worth of Keytruda/pembrolizumab

In 2018 Jim Allison was awarded the Nobel Prize

FROM A HISTORICAL POINT OF VIEW: In our ongoing battle with Cancer scientists have:

Proven smoking and asbestos are provocative;
Learned how to use chemotherapy more effectively;
Created means of prevention– like the HPV vaccine for cervical cancer;
Produced detection tools: colonoscopy, pap smears, mammograms, prostate and breast biopsies;
Developed monoclonal antibodies, small molecules, and hormone antagonizers that help control and destroy cancer cells;
Hypothesized that our immune system probably eradicates most newly created malignant cells;
And have started to learn how to use our T lymphocytes and our immune systems to control some malignancies.

https://www.cancer.gov/news-events/cancer-currents-blog/2017/yescarta-fda-lymphoma https://www.haaretz.com/science-and-health/.premium.MAGAZINE-the-scientist-who-paved-the-way-for-a-chimeric-cancer-therapy-1.5463978 https://www.nejm.org/doi/full/10.1056/NEJMp1711886