Motivating a malignant immune system
March 29, 2017
"I guessed something was not right," said Andrew Parker, 59, corporate manager of a tool and die company. Born in Bedford, England, and transplanted to Ann Arbor, Michigan, Parker frequently drove the 500 miles from his home to a client's shop in Tennessee. But this time, on the way home, his lower leg began to swell. Maybe it was "how I was sitting," he thought.
His doctor found something more ominous: three blood clots in the swollen leg. He gave Parker an anticoagulant and took a small sample of his blood for testing, just to be sure. The next day, March 16, 2016, he called Parker and told him to "come in right away."
The blood clots were the first symptom of an aggressive version of a deadly disease, acute lymphoblastic leukemia. " I had no other symptoms," Parker said. "I felt great, working out, playing golf."
Chemotherapy became his new workout. "You go in feeling good," Parker said. "You come out feeling terrible. It drains you."
The treatment brought little improvement. A second round of chemo had the same effect. In late April, his doctor decided it was time to send Parker to the Karmanos Cancer Institute (KCI), in Detroit.
The team at KCI offered blinotumumab, a monoclonal antibody designed for patients with Parker's disease. This approach, a form of immunotherapy, connects the immune system's T cells to a cell-surface marker found on leukemic B cells. Then the T cells kill the B cells. After one month of treatment, however, "there was no real change," Parker said. Two weeks later: no real progress.
The specialists were running out of options. So they referred Parker to Michael Bishop, MD, professor of medicine and director of the hematopoietic cellular therapy program at the University of Chicago Medicine.
"They told me Dr. Bishop had something new," Parker recalled. "I decided to do it. I had no choice."
Bishop, an authority on stem cell transplantation for blood cancers, suspected that Parker might be a good candidate for an emerging treatment known as CAR-T cell therapy that had produced some remarkable results for patients who did not benefit from standard therapies. But this was a painstaking, technically difficult and still experimental approach.
"Mr. Parker had a very aggressive disease," Bishop said. Neither chemotherapy nor immunotherapy could get him into remission. His marrow was packed, nearly 100 percent, with leukemic cells. He still had blood clots, which had to be cleared up before he could begin therapy. "This was the only treatment that offered any real hope for him."
By this time, Bishop has already administered CAR-T cell therapy to several patients. The first was Scott McIntyre, who had been battling diffuse large B cell lymphoma for years. He received his cells on May 18, 2016.
"It was like watching your first child being born," Bishop recalled. "Several million modified lymphocytes go in from this little package and then it's over. But once they go in, they find their target, they get turned on, they start dividing and attack."
McIntyre's course was relatively uncomplicated. He had some mild neurologic issues but he quickly responded to a short course of steroids and has done very well.
It wasn't quite so simple for Parker. It seemed at first that everything was ready to go. Bishop's team collected his lymphocytes and sent them to KITE Pharma, a California-based company that processed the cells. But the Food and Drug Administration, faced with this promising but experimental and potentially toxic approach, was being extra cautious. They wanted each patient treated in sequence.
"It was treat one patient, wait a week, treat one more, wait a week," said Bishop. Meanwhile, "Andy's sitting there in bed. His cells are ready to go. He needs to be treated soon, very soon, but he's number 3 in line." After a deluge of emails and phone calls, Bishop and the team from KITE were able to persuade the FDA to approve a compassionate exemption for Parker and on October 28, 2016, his cells finally were infused."
The FDA's caution was reasonable. CAR-T cell therapy is a complex process. Treatment begins with the removal of a few million of the patient's white blood cells, including T cells -- roving warriors of the immune system. These cells are then sorted and the T cells are reprogrammed.
The scientists used a virus to insert an antibody-like protein called a chimeric antigen receptor (CAR) into Parker's T cells. This receptor, which pokes through the cell surface, is designed to recognize and latch onto a protein called CD19 typically found only on leukemic cells and normal B cells. When they connect, the T cell kills the cancer cell.
"They took out my cells and put something in them," was Parker's explanation. "Whatever it is, it's good."
Treatment starts gently. The frozen cells are delivered to the patient's room and thawed out. After warming, the small bag of cells is attached to an intravenous drip. Then a few million highly focused, supercharged T cells flow into a vein in the patient's arm. This painless process lasts about five minutes.
Once the CAR-T cells enter the bloodstream, they multiply rapidly. They ignore cells with no visible CD19, but they find and destroy cells that exhibit CD19. If all goes according to plan, the CAR-T cells eradicate their targets, usually within a few weeks.
The first week after infusion was "great," Parker said. Then came two days in the ICU that were "like the flu, but seven times worse." The next day, however, he woke up feeling fine.
Within two weeks, his leukemic cells were hard to detect. After four weeks, he was in complete remission. A biopsy of his bone marrow showed no leukemic cells, no sign of cancer. One month after that, "same thing," Parker said. "Bone marrow biopsy. No cancer." He was back to work after two months and by three months, enjoying what Bishop called "a continuous complete remission."
"We're seeing about 80 to 90 percent complete remission rates for acute lymphoblastic leukemia," Bishop said. For diffuse large B-cell lymphoma, remission rates are lower, about 40 to 50 percent, which is still "pretty remarkable." These remissions tend to be durable.
This "may be the most exciting thing I've seen in my career," Bishop added. It takes transplantation "to a new degree, where we can see remarkable responses without, necessarily, the severity of the toxicities. And we don't even have to find a donor. This is just the infancy of this therapy."
The University of Chicago has been selected as one of the initial sites for new applications of CAR-T cells, based on new molecular targets, such as CD 20, CD22 and CD30, that may work for other cancers, including multiple myeloma and Hodgkin's disease. "Anything you can create an antibody for, you can create CAR-T cells for," Bishop said. "It may even apply to solid tumors."
"If you've got cancer," Parker adds, "go to the University of Chicago and get Dr. Bishop, and get this CAR-T cell. In five weeks, you'll beat it."
"The nurses were great," he added. "The food is terrible."
Parker has returned to work. He still takes antibiotics and an antifungal. He gets occasional indigestion, which he blames on the chemotherapy. He sometimes has cold fingers and toes, and he lost about 50 pounds during treatment, but since he weighed a little more than 250 before treatment, he's fine with that. He also plans to get married.
"My fiance, Mary Welliver, came to Chicago every weekend," he said. "She was there all the time, in Ann Arbor, at Karmanos and in Chicago. She kept me going, pushed me through this. We had the rings but since I was so sick, we never had the time. Now we do. We're going to do it this spring."
His doctor at Karmanos was "astounded by the results," Parker said.
So was Bishop. When they measured Parker's CD19 marker, prior to treatment, "it tested dim," Bishop said. "That would have predicted that it might not have worked."
Then, soon after Parker got his cells, "all of a sudden you see the results and you just go, wow. This is why we come to work every day."
"When you consider everything that this guy went through," Bishop added, "waiting, thinking he was going to get this potentially life-saving treatment, having it taken away, and then he finally got it. Just to see this," he said. "I almost cried."
CAR T-Cell Therapy
CAR T-cell therapy supercharges a patient's white blood cells to seek out and destroy cancer cells. Research at UChicago Medicine played a key role in the development of this exciting new immunotherapy.View videos and learn more
Michael R. Bishop, MD
Michael R. Bishop, MD, specializes in the diagnosis and treatment of lymphomas and leukemias. He is an expert in stem cell transplantation and cellular therapy, including CAR T-cell therapy, an advanced form of immunotherapy.Learn more about Dr. Bishop