Combination therapy may boost survival for people with aggressive lymphoma

A new clinical trial suggests that pairing bispecific antibodies and antibody-drug conjugates with CAR T-cell therapy may sharply boost one-year progression-free survival for people with aggressive lymphoma.

In just a few years, treatment options for aggressive lymphoma have rapidly advanced. However, many patients show a consistent pattern: powerful new therapies act quickly but often fail to keep the lymphoma at bay permanently, says Jay Spiegel, M.D., a transplant and cellular therapy physician at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.

Spiegel will present the early findings Dec. 8 at the 2025 American Society of Hematology (ASH) annual meeting in Orlando.

We have made huge improvements in lymphoma care. But there are still many patients where the current approaches are not curative."

Jay Spiegel, M.D., a transplant and cellular therapy physician, Sylvester Comprehensive Cancer Center

That challenge inspired a new clinical trial - the researchers, led by senior author Lazaros Lekakis, M.D., professor of clinical medicine at the Miller School, combined three of the most promising lymphoma treatments, aiming to improve outcomes.

The clinical trial data indicate that combining these treatments may significantly enhance progression-free survival at one year.

Layered therapies extend responses

Large B-cell lymphoma is the most common aggressive lymphoma in adults. Its most frequent subtype, diffuse LBCL, affects about 25,000 people in the U.S. each year. First-round treatments work for approximately 70% of patients. 

For the 30% whose lymphoma comes back or never fully disappears, the next step is often CAR T-cell therapy, such as axicabtagene ciloleucel, approved in 2017. It trains a patient's immune cells to target lymphoma.

"CAR T works incredibly well upfront," Spiegel said, "but we've learned that it often falls short in the long-term - only about 40% of patients remain in remission after five years."

So, researchers have designed other new therapies. Mosunetuzumab is a two-headed bispecific antibody that links a T-cell to a lymphoma cell, activating the immune system to attack. Polatuzumab is an antibody–drug conjugate, meaning it delivers a small dose of chemotherapy directly into lymphoma cells. Both are effective initially but don't reliably keep the disease away when used alone.

To boost the durability of these new treatments, the Sylvester team integrated all three approaches. "Attacking three different antigens at once could help overcome several of the reasons CAR T fails," Spiegel said. "The hope was that combining them could really jump the efficacy, and so far, it has been quite something."

The phase 2 study enrolled 25 adults with relapsed or refractory LBCL. They received mosunetuzumab and polatuzumab before and after the CAR T treatment. Of the 24 patients who reached day 90, 90% were in complete remission. At one year, about 80% were still in remission, a significant increase from an estimated 50% at one year with CAR T alone.

"I did not think it would work this well," Spiegel said. "To take patients with this type of aggressive disease and have so many still in remission at one year, that really surprised me."

The Sylvester trial might provide a way to achieve longer remissions. "We have an exciting result," Spiegel said, "but now we need to show it can be done on a larger scale. That is the goal of the next study, to prove the juice is worth the squeeze."

As encouraging as the findings are, they arrive in a field moving at an extraordinary pace as researchers are continually testing new immunotherapies, improving CAR T treatments, and exploring fresh drug targets. "Everything in lymphoma is happening all at once," Spiegel said. "It makes the field exciting but also complicated."

That pace presents both opportunity and complexity as clinicians work to understand how each advancement fits into the broader treatment landscape - and how they can work together. The current challenge is figuring out the best sequences and combinations for these new treatments - and how to use each without exhausting the immune system, Spiegel said.

In this surge of treatment options, the message for patients is increasingly hopeful. "If you have relapsed disease, even aggressive disease, there are multiple approaches now that can still cure your lymphoma," Spiegel said. "That was not true seven years ago."