Howard Chew had no idea he was sick.
Living in Pomona, California, with family since the start of the COVID-19 pandemic, the 54-year-old Bay Area waiter’s heart condition was his only medical concern. A few months into isolation, he ran out of medication, so he made an appointment with a local physician.
After receiving his refill, it occurred to Chew to ask the doctor about a small lump on his neck.
The doctor’s response was more serious than Chew expected. He ordered bloodwork, a biopsy and a scan. Chew ended up staying overnight in the hospital.
In the morning, the doctor told him, “Howard, you have Stage 4 lymphoma.”
“That hit me hard. I was just going there for medicine,” Chew said. Having survived quadruple bypass surgery 10 years earlier, Chew thought he had already been through the worst.
Looking back over the previous months, he realized he had been feeling a bit fatigued and that he had lost some weight. But it was the height of the pandemic, when “everyone was feeling off.”
Stage 4 Mantle Cell Lymphoma Diagnosis
Chew was diagnosed with mantle cell lymphoma, a rare and aggressive form of non-Hodgkin lymphoma that attacks the B lymphocytes and has a strong tendency to infiltrate the gastrointestinal tract and bone marrow. It accounts for only about 6% of non-Hodgkin lymphoma cases in the U.S., can be difficult to treat and tends to recur. It typically occurs in people over age 60 and is three times more common in men. It is often diagnosed at a late stage.
“When I finally got a chance to look at the scans, that’s when it kind of hit me,” Chew said. “My body is kind of going through hell, with all the darkness in the bones. Something really is wrong with me.”
Chew’s family had experience with City of Hope. “They got me in right away,” he said. The confident demeanor of his physician, Elizabeth Budde, M.D., Ph.D., associate professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation, immediately put Chew at ease.
“We never talked about my life expectancy,” Chew recalled. “Everything was put in a positive light. She said, ‘We’re going to get you well.’ That calmed me down.”
Chemotherapy, Then CAR T Cell Therapy
Dr. Budde, also executive medical director of the Enterprise Immune Effector Cell Therapy Program, first ordered two rounds of chemotherapy. Unfortunately, the treatment didn’t have the effect she was hoping for. She told Chew it was time to try a different approach. In April 2021, Chew received CD19 CAR T cell therapy, a powerful form of immunotherapy that simulates a patient’s own immune cells to attack their cancer.
That put his cancer into remission for about a year. He was also placed on two oral medications, which helped keep his lymphoma at bay. At one point, his level of detectable cancer cells was only .2%.
But his next bloodwork showed a leap to 20% malignant cells in the bone marrow.
“Dr. Budde said, ‘Let’s go back and change the formula and do another CAR T,’” Chew recalled. What he didn’t realize was that he was about to become the first patient to receive an entirely novel form of CAR T cell therapy developed at City of Hope. “She used to call me her No. 1 patient,” Chew said, laughing. At the time, he didn’t understand that he was literally the first person to undergo this therapy.
The CD19 CAR T cell therapy that Chew initially received has revolutionized the treatment landscape of B cell lymphoma. By genetically altering patients’ T cells in the lab, scientists can program the immune cells to seek and destroy cancer cells with the CD19 antigen.
Unfortunately, a significant number of patients with aggressive B cell lymphoma, mantle cell lymphoma or follicular lymphoma still relapse or don’t respond after this therapy — like Chew.
Seeking a better approach, Larry Kwak, M.D., Ph.D., deputy director of City of Hope's comprehensive cancer center and the Dr. Michael Friedman Professor in Translational Medicine, and his lab focused on B cell-activating factor receptor (BAFFR) signaling, a driver of B cell and cancer growth. Reducing BAFFR expression, they hypothesized, could limit the ability of B cell tumors to dodge therapy.
Malignant B cells express BAFFR independently of CD19 expression, their studies found, and CAR T cells targeting BAFFR were able to eliminate B cell tumors in a preclinical setting.
In the latest study, City of Hope researchers tested their BAFFR CAR T cell product created by modifying T cells taken from Chew. After receiving just one infusion in City of Hope’s Phase 1 trial of the new therapy, called PMB-CT01, Chew has now been in complete remission for over 20 months and continues to have undetectable cancer as determined by sensitive molecular tests for minimal residual disease. Five other patients in the trial have experienced similar remissions. Dr. Budde, the trial’s principal investigator, presented the initial results at the American Society of Hematology conference in December 2023.
So far, all patients have done well on the treatment. There were only low-grade side effects, which resolved safely with time or medication. No dose-limiting toxicities were seen. The study, sponsored by PeproMene Bio Inc., is now enrolling patients in its next cohort. (Dr. Kwak is PeproMene’s scientific founder, compensated chair of its Scientific Advisory Board and has an equity interest in PeproMene. City of Hope holds an interest in the investigational therapy being studied in this research.)
“I was fine for a few days [after the BAFFR CAR T cell infusion], and then you kind of pick up that your body’s reacting and then you don’t feel so good after that,” said Chew, who stayed at the Judy & Bernard Briskin Hope Village for two weeks after his treatment, watching World Cup 2022 and enjoying the breakfast buffet while he recovered. “Just a few days of nausea, then you feel OK and it’s just a matter of time until you’re walking and eating and getting better,” he said. “It was really easy to feel better there.”
After 14 days, it was back home, and then weekly visits for blood draws. “Then it was, ‘Hey you’re all clear.’ It was a big relief to hear that,” Chew said. “That’s been a beautiful thing. I’m thankful I’m here with the help of City of Hope.”
BAFFR CAR T After CD19 Therapy
“We developed BAFFR-CAR T therapy as another treatment option for the significant number of patients with lymphomas and leukemias who relapse after receiving commercial CD19 CAR T cell therapy. Our results so far represent the ideal maximal efficacy with minimal toxicity,” Dr. Kwak said.
“It’s exciting to say that all five patients with non-Hodgkin lymphoma and one with B cell acute lymphoblastic leukemia treated with PMB-CT01 have demonstrated durable responses,” Dr. Budde added.
These days, Chew, now 58, is a frequent visitor to City of Hope, where he sees a therapist, a cardiologist and an endocrinologist. He meets with Dr. Budde about every three months for monitoring. He also has started to volunteer at City of Hope events, such as food drives. “After four years you kind of get a relationship beyond the cancer. It’s a nice thing to have,” he says.
A “people person” who loves to try new restaurants, window shop and travel, Chew celebrated his remission with a Mediterranean cruise with stops in Italy and Greece. Next up: A four-day cruise to Ensenada with friends.
Budde has urged him to “enjoy life and take things as they come.” While he knows there is always a chance his cancer might come back, “Let’s hope it doesn’t,” he said. “But if it does, I’m positive that City of Hope will be there to support me.”