Since 2015, Dana-Farber researchers have been participating in clinical trials that evaluate the use of bispecific antibodies for patients with non-Hodgkin lymphoma. Three bispecific antibody therapies have been FDA approved with more on the horizon.

These are exciting new medicines that rally the immune system in a powerful way to fight blood cancers. But rolling out a new type of medicine is a project of its own.

Philippe Armand, MD, PhD

The experts at Dana-Farber who have been treating patients with these new medicines are now working on expanding their use. Philippe Armand, MD, PhD, chief of the Lymphoma Program, and Jennifer Crombie MD, Reid Merryman, MD, and Christine Ryan, MD, physicians and clinical investigators in the Lymphoma Program, are using what they have learned as clinical investigators to run new trials to determine if these medicines could have benefits earlier in treatment, in combination with other therapies, or in other types of lymphoma.

“The hope is that these drugs will help improve outcomes for patients with lymphoma,” says Crombie, who has been the principal investigator of a bispecific antibody trial for the past few years.

Double Trouble for Cancer Cells

Monoclonal antibodies treat cancer by binding to markers on cancer cells and rallying the immune system to destroy them. Bispecific antibodies are designed to recognize and bind to more than one cell marker. The bispecific antibodies approved for the treatment of B-cell non-Hodgkin lymphoma recognize CD20, a marker known to be on B cells, and CD3, a marker known to be on T cells, which are immune cells that can attack cancer cells.

Jennifer Crombie, MD

By binding to both, the bispecific antibody pulls the T cells closer to the cancerous B cells, increasing the chances that the T cells will recognize and kill the cancer.

“Bispecific antibodies can be a powerful immune-based mechanism because of their dual binding properties,” says Crombie.

These medicines are currently approved for use alone in patients with follicular lymphoma or diffuse large-cell lymphoma who have received three lines of treatment and need a new therapeutic option. Some patients may choose to try bispecific antibody therapy after CAR T-cell therapy. Others may opt to try bispecific antibodies before trying, or in lieu of, CAR T-cell therapy. Recommendations will vary depending on the type of lymphoma and other individual factors.

These new therapies are administered via infusion or an injection under the skin. However, these immunotherapies can cause side effects that many centers are learning how best to manage.

Reid Merryman, MD

Safety First

In clinical trials of bispecific antibodies, investigators noted side effects that are like those experienced by patients receiving CAR T-cell therapy. The reactions, however, are often less frequent and less severe.

For instance, some patients experience cytokine release syndrome, a potentially dangerous whole-body inflammatory reaction, though this reaction rarely becomes high grade and more serious. Some patients also experienced neurologic toxicities, though these were very rare.

With immediate intervention, these side effects can be managed. But oncologists at cancer centers that don’t offer CAR T-cell therapy may have limited experience managing them.

Armand, and Crombie joined together with an international team of experts with experience with bispecific antibodies and CAR T-cell therapies to apply what they have learned from managing these toxicities. The team, with support from the Lymphoma Research Foundation, have produced detailed recommendations to help cancer care centers develop an approach to treating patients with bispecific antibodies safely.

Christine Ryan, MD

“We hope that by having guidelines for managing these drugs, both academic and community cancer centers will feel more comfortable using them and access to these agents can increase,” says Crombie, who was one of four co-leaders of the consensus recommendations, which were published in Blood.

Under Investigation

Bispecific antibodies are currently approved as single agents for use in third line treatment for lymphoma. But Armand, Crombie, Merryman, and Ryan, have clinical trials underway to explore the possibility that these medicines could be effective in front-line treatment, in combination with other medicines, and for other subtypes of lymphoma.

Crombie is leading a trial for a subset of patients with previously untreated DLBCL. The phase 2 trial is investigating whether a combination of a bispecific antibody, and a standard chemotherapy regimen that includes an antibody-drug conjugate – another novel form of medicine that uses an antibody to guide a toxic therapy to cancer cells – could be an effective first line treatment.

Merryman is leading two trials for patients with previously untreated follicular lymphoma. One is testing a combination of a bispecific antibody with rituximab, a monoclonal antibody therapy that targets CD20 on B cells. The other is testing a different bispecific antibody in combination with a different anti-CD20 monoclonal antibody.

Ryan is leading a trial of a bispecific antibody for patients with Richter’s syndrome, which occurs when CLL transforms to an aggressive lymphoma.

Armand is also leading a trial for patients with relapsed or refractory Hodgkin lymphoma. The trial is testing a combination of a different type of bispecific antibody that blocks the immune checkpoints, PD-1 and TIM-3.

“We’re excited about these studies,” says Crombie. “We have a lot of interest in seeing how we can use these new immunotherapies to help patients.”