A T-cell is capable of eradicating a cancerous cell, but it’s not good at identifying the target. B lymphocytes are experts in identifying and marking targets, but they have no killer mechanism. What if the capabilities are combined?
Paraphrased words of Zelig Eshar, Weizmann Institute, Israel
The man who envisioned inserting a seeing-eye gene into T-cells, was raised in Rehovot, Israel, at a time when “the fragrance of orange blossoms and the sounds of crowing roosters” filled the air1.” He was earning a PhD in Boston, when he “decoded” the T cell receptor. That’s the molecule on the “skin” of T-lymphocytes that spots the remnants of viruses that are displayed on the surface of sentry cells. During his 20 years at the Weizmann institute in Israel, Eshar and his team developed and refined a special gene (a chimeric antigen receptor) that can be planted in the cytoplasm of a T cell. When it’s up and running it gives the T-cell the ability to both recognize and destroy targets.
In another part of the world a surgeon at the NIH, Steve Rosenberg, led a team that assembled a similar gene. Their CAR-T, however, specifically targeted cells that have the protein CD 19 on their outer membranes. They targeted 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 T.V. by Charlie Rose, and was featured in a Siddhartha Mukherjee’s cancer documentary.
When young, Rosenberg was present when his father, a Jewish immigrant from Poland, received one post card after another telling of relatives who had died in the death camps. The notes 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. They met when he was on call in the ER. 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 5 years, then 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. His sleep deprivation was brutal. He once fell asleep at a patient’s bed side and routinely dozed when he encountered a red light when driving home.
In 1968, as surgical resident he recalls admitting a man with a gall bladder attack who, 12 years earlier had undergone a cancer operation. The primary malignancy in the stomach was cut out but metastatic implants in the liver could not be resected. The man should have died but he didn’t. His immune system had apparently overcome the cancer. It happens rarely, but the event made an impression on Rosenberg
In 1974 Rosenberg started working at the National Cancer Institute and 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 colleague about a patient with lymphoma whose tumors shrank after they genetically engineered his T cells then poured them back into the person’s bloodstream.8 The patient later received more therapy, and has been free of cancer since. Rosenberg subsequently treated an occasional patient, and sent a copy of their gene in a plasmid to Addgene, the non-profit that makes genes available to interested researchers. By 2010 researchers could buy one of their plasmids for $75.
The following year 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. After an appropriate person, someone with a difficult to treat lymphoma, is identified, a large bore needle is inserted into a vein. It’s hooked to an apheresis machine and blood is drawn into a sophisticated instrument. The gadget’s 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 had already been inserted into a number of harmless viruses. The viruses are co-mingled with the T cells. They enter the “killers” and deposit the Car-T gene in its cytoplasm. The T cells are given time to reproduce, to increase in number. A month later, now modified, the T lymphocytes are returned to the treating facility. The patient is sometimes given intensive chemotherapy before the modified T-cells are dripped into his or her body. The person who received the modified T cells is watched carefully for up to 35 days because killing a large numbers of tumor cells can cause the body to release a large number of cytokines and they can make the patient very sick.
In the years after the process was developed a few desperate individuals without other options were treated. The approach was a new, expensive, and time consuming process. There were risks. Short term improvements might or might not mean a person’s life would be prolonged.
In 2009 a UCLA urologist and a businessman, Arie Bellgundrun, 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, as a young doctor he had briefly worked with Steve Rosenberg on cancer immunology. He eventually contacted his old boss, Dr. Rosenberg. 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 had tried to get interest from J and J and other companies but the approach was too new and different.
Bellgundrun was impressed.
“In 2012, Kite pharmaceuticals, partnered with Dr. Rosenberg and the NCI (National Cancer Institute) to further the research and development of multiple chimeric antigen receptor (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. When used in kids, in one study, CAR-T cells had eliminated malignant cells 83% 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 they 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 can now say they have 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 thereafter Medicare said they would pay for it.
The Scientist. The CAR T cell race. April 2015 https://www.the-scientist.com/bio-business/the-car-t-cell-race-35701
2. The Tranformed Cell by Steve Rosenberg. Putnam; 1992
3. https://ww w.addgene.org/107226/
https://www.nejm.org/doi/full/10.1056/NEJMoa1910607?query=featured_home https://www.goldmansachs.com/insights/talks-at-gs/arie-belldegrun.html
https://blogs.timesofisrael.com/sugar-coated-memories-of-rehovot/
https://www.the-scientist.com/bio-business/the-car-t-cell-race-35701
https://www.weizmann-usa.org/news-media/in-the-news/t-cell-therapies-for-cancer-from-outsider-to-pharmaceutical-darling https://boards.fool.com/macro-view-of-the-car-t-cell-sector-32661956.aspx?sort=wholeedit”car-t”
6. Furman, Jeffrey. “Climbing Atop the Shoulders of Giants: The Impact of Institutions o\nn Cumulative Research.” American Economic Review, 2013: 1933-1963.
http://dx.doi.org/10.1257/aer.101.5.1933 https://thewinnower.com/papers/2626-addgene-an-open-access-success-story
7. www.addgene.org.
8. Car t- https://pubmed.ncbi.nlm.nih.gov/20668228/