CAR T and other immunotherapies are transforming the dreaded diagnosis into a manageable disease. How living drugs may become the final answer to this killer.
In 2008, just after she’d started kindergarten, Tori Lee was diagnosed with acute lymphoblastic leukemia (ALL), an aggressive form of blood cancer. Chemotherapy cures most children of the disease, but Tori wasn’t as lucky. A playful little girl who was doted on by her three older sisters, she “was treated with chemotherapy for about two years, and then she relapsed,” says her mother, Dana Lee. “We started a new protocol, with more intensive chemotherapy and radiation. She spent hundreds of days in the hospital.” And still the cancer held on.
With Tori growing weaker, her parents decided to take her to the Children’s Hospital of Philadelphia (CHOP) for several weeks of chemo in preparation for a bone marrow transplant, a complex and risky procedure. Just before the Lees were scheduled to leave for the hospital, her doctors told them that they would also collect Tori’s T cells as a backup plan: If Tori turned out to be too sick to have the transplant, she might be able to participate in an ongoing trial of a promising experimental treatment called CAR T, which takes a patient’s own immune cells and genetically reprograms them to kill cancer. CAR T had been used months earlier to cure another little girl, Emily Whitehead, with the same form of leukemia. “I reached out to the Whiteheads,” says Dana. “I was petrified to put my daughter, who’d been through multiple years of chemo, through the harsh reality of a bone marrow transplant.”
Still, deciding on CAR T therapy wasn’t easy. While Emily was doing great, several of the children who had followed her in the clinical trial at CHOP had died. Tori would be only the tenth to undergo the treatment. “We finally said, ‘All right, we want to try CAR T.’ We petitioned the study board to be included in the trial. We thought it gave her a better chance of survival” than the bone marrow transplant, says Dana.
In April 2013, doctors injected Tori with her own modified T cells. Six weeks later, her cancer was in remission. Four years on, Tori, now 14, remains cancer-free.
This past August, after 50 more patients in the trial went into remission, the FDA approved the treatment that had saved Emily and Tori. The process of genetically engineering CAR T cells, patented under the brand name Kymriah, is now available to other children and young adults under the age of 25 with ALL that hasn’t responded to standard treatment.
“Surgery, radiation, and chemotherapy cure a little over half of people who develop cancer. But that means almost 600,000 Americans die of the disease every year,” says Steven A. Rosenberg, MD, PhD, chief of the surgery branch at the National Cancer Institute (NCI) and one of the pioneers of the effort to use the immune system to fight cancer. “With the approval of CAR T, we’re taking a first step toward a completely new approach to curing cancers that have been incurable.”
Scientists have known since the 1890s that the immune system can destroy cancer cells. The trouble is that T cells—the immune cells that attack bacteria, viruses, and cancer cells—aren’t usually strong enough to wipe out malignancies completely.
In the 1980s, a team led by Dr. Rosenberg was the first to remove T cells from patients with cancer, multiply them in the lab, and then reinject them—in essence, turbocharging the patient’s own immune system to fight the disease. In an early study of this treatment, tumors in 11 of the 25 patients shrank by at least half, and one patient, with malignant melanoma, was cured. Still, in most cases, it wasn’t enough to eradicate the cancer.
But researchers continued to experiment and innovate. Immunologist Zelig Eshhar, a researcher at the Weizmann Institute of Science in Israel, thought he could use a recently developed gene therapy technique to make T cells into better cancer fighters. He engineered T cells to carry a chain of amino acids called chimeric antigen receptors (CARs). These CAR-carrying T cells—CAR Ts—seek out cells that may be cancerous. When the receptors on CAR T cells find cancer cells, the receptors latch on to them like a key fitting into a lock. That connection then acts like a trigger, telling the T cells to multiply like crazy and kill the cancer cells.
“CAR T therapy is something wholly new,” says David Porter, MD, an oncologist at the University of Pennsylvania. “It’s not a compound or a chemical. It’s made up of living cells. Once infused into a patient, a single CAR T cell can multiply into 10,000 cancer-fighting cells.”
While drugs, including those used in chemotherapy, are flushed from the body and typically have to be given repeatedly, CAR Ts “go on circulating through the bloodstream, in some cases for years,” Dr. Porter explains. During that time, they can track down and destroy more cancer cells that may arise. This may explain one of the most promising results of CAR T therapy: Of the 52 patients who responded to Kymriah, two thirds still showed no signs of cancer a full year after treatment.
In fact, the CAR T model worked so well that in October 2017, the FDA approved a second type, sold under the name Yescarta, for certain forms of non-Hodgkin lymphoma that, until now, have almost always proved fatal. Of the 101 adults with large B‑cell non‑Hodgkin lymphoma enrolled in the clinical trial of Yescarta, 72 responded, meaning their cancers diminished or disappeared. Over half had no detectable cancer after eight months.
One of the patients was a doctor himself. Diagnosed in 2014, Jeff Backer had developed visible masses of lymphoma cells under his arms and on his face, chest, and neck. A large mass on his back, the size of a fist, made it hard for him to lie down. In June 2016, he received the new CAR T therapy as part of the clinical trial. “Within a day or two, the lumps started getting softer, smaller, disappearing,” says Dr. Backer, who recently returned to his job as an emergency room physician in Orlando, Florida. “The response was unbelievable. It was as if a nuclear bomb had been dropped on the cancer.”
The process—and the cost
CAR T treatments are tailored for each individual cancer patient, with T cells isolated from the blood and then sent to a facility where new genes are inserted into them. The cells are then stimulated to grow into a legion of CAR Ts. The resulting cells are frozen, sent back to the patient, and then reinjected. The production process can take two to three weeks, and it’s jaw-droppingly expensive. The cost of Kymriah: $475,000 per treatment. Yescarta: $373,000.
Like all cancer treatments, CAR T has side effects. The immediate danger is a severe reaction, dubbed a cytokine storm, that begins with flu-like symptoms but can escalate into plummeting blood pressure, extreme confusion, hallucinations, tremors, and seizures. Today, researchers understand that the reaction is actually a sign the therapy is working. When CAR T cells go after cancer cells in large numbers, levels of immune chemicals called cytokines can rise dangerously. “In some patients with widespread disease, CAR T cells destroy up to seven pounds of malignant cells,” says Dr. Porter. The more extensive a patient’s cancer, the more likely a cytokine storm will follow the treatment.