Bill Brennan sits at a patio table at the Wind Crest retirement development in Highlands Ranch. It is appropriately breezy. A walking stick he doesn’t particularly need leans against his chair. He greets pretty much all who pass by name: “Hi Andy. Hi Jill.” He just remembers names, and so people rememberhis, ever expanding his circle of friends. It’s a gift, he says.
Brennan, 81, was, as of April 30, dying of a blood cancer called B-cell non-Hodgkin lymphoma. He had gone through two courses of chemotherapy; they had failed. Now a tumor the size of a ping-pong ball swelled under the skin near his right ear, another smaller one grew by his left ear, and many larger masses lurked his torso. His neck was badly swollen. The cancer was running rampant. Then on May 1, he received two injections.
Those injections contained his own cells – sort of. Four weeks earlier, under the supervision of UCHealth blood cancer specialist Dr. Enkhtsetseg Purev, Brennan had watched an apheresis machine suck blood from one arm, separate out white blood cells, and feed the rest back into his other arm. Purev sent the cells to Juno Therapeutics, which was sponsoring a clinical trial of an immunotherapy for B-cell non-Hodgkin lymphoma patients who had failed two rounds of chemotherapy: patients like Brennan.
In a Juno Therapeutics laboratory, technicians genetically engineered each patient’s T-cells (a type of white blood cell) such that they would recognize a particular protein, CD19, on cancerous B-cells that otherwise hide from the immune system. The engineered products are called CAR-T cells, CAR being shorthand for “chimeric antigen receptor.” Then, for a couple of weeks, the modified CAR-T cells were left to multiply millions of times over.
CAR-T cell immunotherapy takes flight
CAR-T cell immunotherapy is as exciting as anything happening in cancer care. Having spent decades in research labs, CAR-T emerged as a U.S. Food and Drug Administration approved therapy in August 2017, in the form of a leukemia drug called Kymriah. A second drug, Yescarta, won approval for non-Hodgkin lymphoma two months later. Both are for patients for whom traditional chemotherapy has stopped working. Both cure perhaps one-third of patients entirely, with the majority surviving more than a year without the cancer’s advance (cancers sometimes mutate to not express CD19 or other CAR-T cell therapy targets). UCHealth University of Colorado Hospital (UCH) is the only medical center in the region administering either of these FDA-approved therapies.
Brennan could have gone that route. But the Juno Therapeutics trial provided an avenue that avoided the high costs of the therapy itself ($400,000 to $500,000, roughly) and those of the extensive ancillary care required to ensure CAR-T cell therapies’ safe use. Purev, an MD-PhD faculty member at the University of Colorado School of Medicine, is leading the branch of the Juno trial happening at UCH. Brennan would become the trial’s oldest patient.
Brennan retains the eroded remnants of an accent crystallized in the Bay Ridge neighborhood of Brooklyn. He’s still tall, too, and his stature, combined with athletic gifts at an echelon as lofty as that of his facility with names, landed him a basketball scholarship at the University of Dayton, where he played until breaking his leg and finishing out his undergraduate years as the team’s manager. He met his wife, Rochelle, while an MBA student at Indiana University in Bloomington. They married in 1961; he went into financial services; they had three kids who eventually provided seven grandchildren. Ten years ago, he was diagnosed with low-grade lymphoma. That ultimately led to Brennan’s spleen being removed. Two years ago, the low-grade lymphoma became virulent.
UCHealth hematologist Dr. Stuart Lind, Brennan’s longtime doctor, referred him to UCHealth blood cancer specialist Dr. Brad Haverkos. In May 2017, Haverkos started Brennan on a combination of chemotherapy drugs called R-EPOCH. In its wake, scans showed Brennan to be clear of cancer. In February 2018, he was doing physical therapy at the UCHealth Lone Tree Medical Center when he remarked to a physical therapist that he thought he had pulled a groin muscle. She was concerned: that’s an area with many lymph nodes, and it was swollen. Haverkos confirmed that the cancer was back. Absent some extraordinary intervention, Brennan would be gone in a matter of months.
The right place
An extraordinary intervention happened to be available, Haverkos knew. The University of Colorado School of Medicine, where UCH doctors are faculty, is investing heavily in becoming a global immunotherapy leader. They’ve brought in leaders in the field such as Purev and Dr. Terry Fry, a CAR-T cell therapy pioneer previously at the National Institutes of Health. The institution is investing $20 million in the Human Immunology & Immunotherapy Initiative, or HI3, to assemble and focus talent, foster collaboration across the many disciplines involved in this new approach to patient care, and provide a shared infrastructure to speed the pace of innovation and its transition from lab to clinic. The university’s Gates Biomanufacturing Facility is among the few in the country capable of producing CAR-T cell batches for clinical trials. In short, Brennan had come to the right place.
Brennan initialed page after page of a document outlining the risks associated with CAR-T cell therapy, which range from feverishness to death. For three days at the end of April, he went on a mild chemotherapy to quell his immune system’s reaction to the pending injections. On May 1, he watched as vials of his own genetically engineered cells disappeared into his bloodstream.
Immune modulation, as it is called, is a balancing act. You want to supercharge the immune system, but you also want to keep that system from ravaging the body, which diseases from asthma to lupus to rheumatoid arthritis show can happen. The breadth of expertise required to assess and maintain immunological balance despite the introduction of billions of engineered, cancer-killing T-cells is why CAR-T cell therapy will long remain the domain of major academic medical centers such as UCH.
On the wall of Brennan’s 11th floor room at UCH hung a sheet of copier paper listing possible side-effects of CAR-T cell therapy. Some – fever, low blood pressure and blood oxygen, rigors, headache, muscle pain – fell under the heading “cytokine release symptoms,” the results of an immune system reacting with a massive inflammatory response to CAR-T. Others were neurological symptoms, ranging from confusion to hallucinations to difficulty communicating to seizures. The side effects tend to manifest five to seven days after the CAR-T cell injections. Rochelle, son Mike and daughter Betsy watched as Brennan encountered an increasing number of them with passing hours and days. Brennan’s other son, Bill Jr., had returned home to California and was about to board a flight from San Francisco to Shanghai when he got the call from Mike: “You’ve got to come now. This is it.”
‘Exactly what should happen’
Bill boarded a much shorter flight to Colorado, where he found his father to be suffering from “every single thing on the list, to a very high degree. He was completely out of it.”
“It got to the point where he wasn’t there mentally; he couldn’t move physically and was completely disoriented. He was unconscious a lot of the time, and when he’d wake up, there was this strange stare,” Bill says.
The family summoned Purev. She considered her patient, who was indeed in a desperate state. Then she told the family: “This is exactly what should happen.”
The CAR-T cell therapy was working, and what they were seeing was a body hosting total war against an entrenched and lethal invader. A dose of anti-inflammatory dexamethasone helped. Purev told them she was confident that he was going to have a good result.
Her confidence emboldened the family and, as Brennan became lucid, the patient himself. And indeed, the tumors near his ears and the swelling on his neck had begun shrinking. On May 16, he left the UCH in a wheelchair for a stay at an inpatient rehabilitation facility near his home.
His 30-day PET scan showed no sign of cancer. Brennan says the result was “thrilling,” but he kept his excitement in check when friends and family asked how things were going. “I’d say ‘The last scan was positive and encouraging; the next one will be more of a determinant,’” he says. A man who had spent his life exercising five to six days a week still wasn’t quite himself physically until mid-July, two-and-a-half months after the CAR-T cell injection, when he noticed a cloud of lingering fatigue to have evaporated.
To Del Mar
The next scan happened 90 days post-injection. The short history of CAR-T cell therapy (the first patient was in 2007) has shown that clean scans at 90 days can mean complete remission. And indeed, as Purev had suspected, so it was. Brennan asked Haverkos if it was OK to go on vacation – the annual Brennan family reunion in Del Mar, California, was happening in early August. Absolutely, she said.
There, he walked the beach, took photos, and hung out with, among others, his nine-month-old great-granddaughter, Macy. It was, in a way, a victory lap, and surely not the only one powered by the Juno CAR-T trial at UCH.
The trial has enrolled 14 patients, Purev says. For two of the patients, their cancer was so aggressive that the three-week wait for the CAR-T cells’ return proved to be too long. Of the 12 who received CAR-T cells, 11 responded to the treatment. Of those, nine, like Brennan, went into complete remission.
New trials are testing the relative effectiveness of CAR-T cell therapy on blood cancers for patients who have failed only one round of chemotherapy. After that, trials will be testing CAR-T cell therapy as the go-to approach from the beginning.
“My hope is that we can move immunotherapy to a frontline therapy,” Purev says.
That will take years and a lot of science. Those advances will not only relate to CAR-T cell therapies and the potential combinations of those therapies with existing and new anti-cancer drugs, but also to tuning the immune system to tame extreme side effects Brennan and others must overcome as their augmented immune systems subdue their cancers.
Bill Brennan won’t have to mind such things. Haverkos is keeping an eye on him while, as Brennan puts it, he enjoys “a new lease on life” with his family and all those friends.