THE DISCOVERY THAT T CELLS DESTROY CANCER CELLS

 

An immunologist Lloyd Old is credited as the first modern researcher whose research life was devoted to trying to “understand how the immune system could—at times-- reject tumors.” In the 1970s he created vaccines to antigens on tumors, but the "clinical outcomes they produced were insufficient" and his failures caused some to become "skeptical about the therapeutic potential of tumor immunology.”

https://www.science.org/doi/10.1126/science.1217940 

Decades later a Texan named Jim Allison was studying the relationship between T-lymphocytes and cancer, and he made a discovery that revolutionized our thinking.  Allison's father was a country physician and his mother developed lymphoma and died when he was a boy.   He initially planned to follow in his father’s footsteps but as a high school student he got interested in research.  In a later interview, he claimed 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, and loved country music.  Later in his career he 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.

While in Texas, he worked out the structure of the T cell antigen (the protein complex on the outside of the cell that "recognizes fragments of antigens."  T cells are one of the white blood cells that float in our blood and 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.” Then it “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.

His group learned that after the CD 28 was released, another protein, CTLA-4, showed up. What was it doing there? A large pharmaceutical company had concluded it was another cell poison and that company patented it as a poison.

Allison wasn’t so sure they were right, and he developed an antibody that blocked CTLA-4. 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 poison should not have contributed to the death of the tumor. Allison asked his fellow to repeat the experiment. Since it was Christmas, the fellow went on vacation and Allison manned the lab. He watched the mouse as the tumors grew for a few days, then faded away.

Allison immediately realized he might have something big, but he had to be sure. His group injected antibodies 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 CD 28—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” (CD28) 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. 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. Bright, ambitious students studied with him. He was a full professor of immunology at Cal Berkeley. But he wasn’t an MD. His only interaction with sick people had occurred when, as 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 the following close to two years going around and talking to a number of large and a few small biotech firms. He tried to interest someone in his idea. There was a lot of skepticism. 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. Niels Lonborg, a scientist at GenPharm, a company that was purchased by Medarex (in 1997), had mice that made fully human antibodies. Lonborg created the antibody to CTLA-4. It later became the drug ipilimumab.

Bristol Myers Squibb agreed to try the drug on patients. 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 drug’s 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 it withered. The tumor didn’t always regress, but “there was overall survival.”

As shown in Breakthrough, a film that documented Allison’s subsequent struggle, his discovery ran headlong into big Pharma naysayers. Immunotherapy had failed in the past. To the conservative corporate money men, Allison’s drug seemed like a long shot that was not worth the risk. The doctor coordinating the trials, Rachel Humphrey, believed in the product. She was its chief advocate. When she faced the Pharma company board, she emphasized the fact that the drug had been effective in one person. That alone made it worth pursuing. Board members yelled at her and she took it.

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

With Allison’s drug, the tumors kept enlarging but the patients felt well. Allison explained that’s how the drug works. The T cell gets into the tumor and starts killing cancer cells, but it takes a long time before the tumor stops getting larger. As the drug trial progressed, some people who were treated went home and their doctor gave them a drug that had not previously worked. This time the old drug seemed to work. The person got well, and the old drug got the credit for the improvement. Allison knew they weren’t responding to a drug that had failed and was being reintroduced. The people were better because the T cells had continued to methodically kill the tumor.

Bristol Myers Squibb, his company, eventually agreed the end point of their study would not be the number of people who were alive at one year or two years. They would instead see if there was an improvement in total survival.

At the end of three years, people who hadn’t received immunotherapy were all dead. Three, four, and five years after they were treated over 20 percent of the people who received Allison’s drug were alive and well. The company couldn’t call it a cure. The tumor might someday start to grow. You never know. But the people who responded stayed well and 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 intervening seven years, Allison lived in an apartment three blocks from the hospital. He gained weight and was frustrated by his need to keep explaining why the tumor was still present. At times he became angry. On one occasion, he went into a tirade. He’d come so far and he was afraid the company would conclude the drug failed. When he became single minded and obsessed, it affected his relationship with his wife. Malinda, the woman he met when he was a college 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. 

In the 1990s Tasuku Honjo, a prominent Japanese researcher discovered PD-1, a protein that keeps T-lymphocytes from attacking cancerous cells.  A researcher at Medarex developed the antibody that blocked PD-1 and allowed T cells to destroy certain types of cancer. In time additional drugs that block PD-1 and PD L-1 were fashioned, tested, and shown to prevent the growth of some malignancies. 

In 2017 close to 1,300 people in 21 countries who had advanced melanoma, were assessed 3 years post treatment.  All had received a combination of two drugs nivolumab (a PD-1 inhibitor)-plus-ipilimumab (a drug that targets CTLA-4).  Fifty-eight percent were alive and in 39 percent the disease had not progressed. 

In another study, Dr. James Larkin of the Royal Marsden in England and others assessed 300-plus people who had metastatic melanoma. They had been treated with two drugs that blocked the antidotes produced by melanoma cell. “Historically, 5-year survival rates among patients with metastatic melanoma were dismal,” and the new treatment was hard on the bodies of the sufferers. Only 58 percent of the people treated seemed to have had a favorable response. But 52 percent of the 300-plus, most of who would have died without treatment were still alive at five years.

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

Bristol-Myers Squibb listed the price of a course of treatment with ipilimumab (CTLA-4 Yervoy) at $150,000, and the price of a course of treatment with nivolumab (PD-1 Opdivo) at $150,000.  The drugs brought in revenues of $7.5 billion in 2018.

The Merck PD-1 blocker pembrolizumab--Keytruda fetched $7.1 billion that year.

In 2018 Jim Allison shared the Nobel Prize with Tasuku Honjo, the investigator who discovered PD-1.  When he received the award Honjo wore a traditional Japanese hakama and haori jacket, and he donated his half of the prize money to young researchers at Kyoto University.  

While Allison and Honjo were devising a drug that allowed T cells to fight cancer, researchers at the Weizmann institute in Israel and at the NIH developed a two headed biological device that could be planted in T cells and give the cells the ability to recognize and destroy. 

T lymphocytes are capable of destroying cancerous cells, but they have trouble recognizing them. B lymphocytes are experts in identifying invaders and marking them with antibodies, but they have no killer mechanism.  

Zelig Eshar  spent decades developing a seeing eye gene that he could insert into T cells.  Raised in Rehovot, Israel, professor Eshar earned a PhD in Boston. While there, he “decoded” the T cell receptor. It’s the molecule on the outer surface of the T-lymphocytes that spots remnants of viruses that are displayed on the outside of sentry cells. During his 20 years at the Weizmann Institute in Israel, Eshar and his team developed and refined a gene that they planted in the cytoplasm of a T cell. It gave the cell the ability both to recognize and destroy worrisome proteins.

In another part of the world, a surgeon at the NIH, Steve Rosenberg, led a team that assembled a similar gene. Their CAR-T (chimeric antigen receptor) specifically targeted cells that have the protein CD 19 on their outer membranes. CD 19 is only found on the surface of B lymphocytes.

A compulsive researcher, Rosenberg once wrote that he enjoyed “working through the night in the lab, drinking thick pasty coffee that had been on the burner for hours, walking out into the sunrise, and watching the city come to life.” During his 40 NIH years, “there were probably only 40 days when I wasn’t in the hospital, checking on research or seeing patients.” Over the years, he wrote a book about his efforts, was interviewed on TV by Charlie Rose, and was featured in Siddhartha Mukherjee’s cancer documentary.

When he was young, Rosenberg was present when his father, a Jewish immigrant from Poland, received one postcard after another telling of relatives who had died in the death camps. The notifications evoked a depth of silence, and Rosenberg tasted pain. His desire to stop everyone’s ache was not the sole reason he wanted to become a doctor, but it played a major role.

Steve was married to Alice, an emergency room nurse who disliked doctors’ egos and was determined she would not marry one. The two met when he was on call in the emergency room. It was a slow night—not much business, and she called him over and led him outside to gaze at the moon-filled sky. They dated for five years before he told her, “We can’t see each other anymore. Otherwise it will be too difficult to break it off.” She answered, “It’s already too late.” After they married and had children, he was a surgical resident and worked many nights. He once fell asleep at a patient’s bedside and he routinely dozed when he stopped for a red light when driving home. His sleep deprivation was brutal.

In 1968, as surgical resident, he recalls admitting a man with a gallbladder attack who had undergone a cancer operation 12 years earlier. The primary malignancy was in the stomach. When it was cut out, there were metastatic implants in the liver that could not be resected. The man should have died, but he didn’t. His immune system apparently overcame the cancer. It happens rarely, but the event made an impression on the young doctor.

In 1974, Rosenberg started working at the National Cancer Institute. He began his search for a way to help the body’s immune defenses fight cancer.

In 2010, he and his colleague James Kochenderfer told their medical colleagues about a patient with lymphoma whose tumors shrank after they altered his T cells. They added a gene that allowed his T lymphocytes to recognize CD 19. That’s an antigen that is only found on the surface of the healthy and malignant B cells. After the gene was added, they allowed the changed T cells to multiply. Then they poured them back into the person’s bloodstream.  The patient became and remained cancer free. Rosenberg subsequently treated an occasional patient using the same approach. He also sent a copy of the gene in a plasmid to Addgene.

Addgene is a nonprofit that’s based in Cambridge, Massachusetts. Since it was founded in 2004, the company has collected over 80,000 gene-containing plasmids from over 4,000 research labs around the world. When researchers have isolated a gene, performed research, and written a paper, they often want to move on. If they want to make their gene available to others, they can package the gene in a plasmid and send it to Addgene. The company preserves and catalogs the important chains of DNA and they announce their presence on their website. In 2010, researchers could buy one of the plasmids that contains a gene for $75.

In 2011 Dr. June, at the University of Pennsylvania, wrote about two of three patients with chronic lymphocytic leukemia who were similarly treated and went into complete remission. At the time, he didn’t think the infusion was ready for general use. As Dr. June explained, “Some of these responses don’t last—there’s resistance. We still have to run rigorous randomized studies to determine if the therapies are effective, and whether they are cost-effective, and whether they can be delivered at scale.”

CAR-T infusion often takes a month to prepare. It’s a therapy some doctors consider when they are dealing with someone with a difficult-to-treat lymphoma. Once the patient is identified and consents, a large-bore needle is inserted into a vein. It is hooked to an apheresis machine. Blood is drawn into the sophisticated instrument. A centrifuge spins the blood, picks out the T cells, and returns the rest of the blood to the patient. The collection is then “prepared, frozen, and sent to the facility where CAR-T genes have been inserted into a number of harmless viruses.” The viruses are allowed to infect the T cells. They deposit the gene into its cytoplasm, and the T cells are given time to reproduce and increase in number. Before they are infused into the person with lymphoma, the patient is sometimes given intensive chemotherapy. After the altered T cells are infused, the patient is watched carefully for up to 35 days. The death of a large numbers of tumor cells can cause the body to release cytokines and they can make the patient very sick.

In the years after the process was developed, a few individuals who had no other option were successfully treated. The approach was new, expensive, and time consuming. There were risks. The short-term improvements may or may not have meant the person’s life would be prolonged.

In 2009, a UCLA urologist and businessman, Arie Belldegrun, founded Kite Pharmaceuticals in Santa Monica. He searched the academic market to see who, if anyone, knew how to use the immune system to fight cancer. Years before, when he was a young doctor, he had briefly worked with Steve Rosenberg on cancer immunology. He eventually contacted his old boss. Dr. Rosenberg showed him the X-rays of several patients he had successfully treated with CAR-T. It’s a onetime treatment. When gene therapy works, the cancer is gone in three to four weeks. Rosenberg wanted to commercialize the process and tried to interest Johnson & Johnson and a few other companies in the project. The companies all thought the approach was too new and different.

Belldegrun was impressed. “In 2012, Kite Pharma partnered with Dr. Rosenberg and the NCI (National Cancer Institute) to further the research. They are attempting to develop multiple chimeric antigen receptors (CAR) and T cell receptor (TCR) based products.”

In 2018, the FDA gave two companies permission to sell a new, unproven type of immunotherapy that treats lymphoma. In one study, CAR-T cells were used in kids. They eliminated malignant cells 83 percent of the time for at least three months.

To get FDA approval, Kite had to prove their approach was effective. Since it’s unethical to run a study where some qualified patients are not treated—where there are “controls”—the FDA is allowing the company to use historical controls to prove their approach is effective. By the end of February 2020, 108 people had been followed long enough. Kite was finally able to say they had proven the approach prolongs the life of at least some people.

Kite, Novartis, and other companies are starting to offer CAR-T treatment. Kite charges $375,000 for processing a person’s lymphocytes. In 2017, Gilead purchased Kite for $11.9 billion. Three years later, Medicare said they would pay for the process..

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063988/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063988

In 2023 a number of centers reported the results of CAR T treatments developed by two pharmaceutical companies. 

In July Novartis reported the results of their CAR T treatment for ‘early relapsed or refractory large B-cell lymphoma.”

They gave CAR T--axi-cel to (180 patients) and aggressive chemotherapy with and without autologous bone marrow transplant to (179 patients).

4 years later 82 people in the CAR T group and 95 people who received standard treatment were dead.  14.7% of the people who had CAR T treatment were alive and progression free and 3.7 percent of people who received standard chemotherapy (often with autologous bone marrow transplant) were similarly alive and progression free.  https://www.nejm.org/doi/full/10.1056/NEJMoa2301665

In July 2023 Janssen pharmaceutical reported the treatment of 419 people with refractory myeloma with CAR T or standard aggressive treatment.  Almost 80 percent of the people who received CAR T and 49 percent of people who received standard therapy were alive and progression free at the one year mark.  https://www.nejm.org/doi/full/10.1056/NEJMoa2303379

In 2023 Robert Chiesa, an Italian MD working at Great Ormund Street hospital in the U.K., reported the creation of a universal, off-the-shelf chimeric antigen receptor (CAR) T cells to treat kids with childhood lymphoblastic lymphoma.  .

https://www.nejm.org/doi/full/10.1056/NEJMoa2300709

His group used a lentivirus to carry the CAR into the T cell.  The CAR targeted CD7 (CAR7).  It is a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL).  

They used  CRISPR to inactivate two genes and avoid lymphodepleting serotherapy and they evaded graft - versus - host disease by editing the gene for the β chain of the T-cell receptor.