March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
Follicular Lymphoma (FL) is a type of cancer of the white blood cells (WBCs). It is slow growing and often does not cause any symptoms in patients. Traditional therapies, while effective against many cases of FL, can often fail in the long term. The disease can also become resistant to these therapies during treatment. Such cases require novel therapeutics, some of which have been approved by the Food and Drug Administration (FDA). Many others are in development.
Bispecific antibodies are a promising new class of therapeutics against FL. These are proteins that can simultaneously bind two other proteins, one on the cancer cells and one on the immune system cells. This kicks the immune system into action against cancer.
What is a Lymphoma?
Lymphoma is cancer that starts with the body’s WBCs, also called lymphocytes. WBCs are produced in the bone marrow, which is the tissue that lines the insides of many of our long bones, including the hip bones and the vertebral column.
Broadly speaking, cancers of the WBCs are leukemias or lymphomas. Their names signify the location of the involved cancer cells. In leukemia, the cancer cells occupy the bone marrow and the blood. In lymphoma, the errant cells take up residence within the lymph nodes and the lymphatic system. They can often form masses that can be seen or felt in lymphoma patients.
The lymphatic system or tissue is an extensive network within the body. It consists of lymph nodes, which are rounded, bean-shaped collections of WBCs. These nodes are extensively interconnected through lymphatic channels. Lymph tissue is also found in the spleen, bone marrow, thymus gland, and gastrointestinal tract, among other locations. Lymphomas can start in any of these locations.
Follicular Lymphoma – A Type of Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is a collection of lymphomas that share some common features and are treated similarly. Around 20-30% of all non-Hodgkin lymphomas are follicular lymphomas (FL). This translates to around 15,000 new cases of follicular lymphoma diagnosed each year in the United States. Although this disease cannot usually be cured, it can be treated. The outlook for FL is generally favorable, with around 88% of people with the disease living for 5 or more years. Older adults in their 60s are most at risk for developing FL.
Because of its slow-growing nature, FL is oftentimes asymptomatic, especially in the earlier stages of the disease. Therefore, watchful waiting or active surveillance can be an appropriate initial treatment option for some patients. This approach requires regular follow-ups with their physicians, blood work, and other testing, such as whole-body imaging, as indicated. Unfortunately, FL will commonly advance to a more symptomatic stage, which will require conversion to active medical therapy.
The standard of care therapy for FL is usually R-CHOP, which combines chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine) with rituximab, an antibody against CD20, which is a protein found on certain immune system cells. R-CHOP can have a great response in patients, with over 90% of patients experiencing a significant reduction of their tumors with 50% surviving without any progression of their disease at 10 years! Despite these wins, this therapy is not curative, and most patients will relapse given enough time. Some patients can also develop a resistance to these drugs, rendering them effectively useless. Other shortcomings of this treatment include significant short-term side effects, such as nausea, vomiting, and hair loss, and long-term side effects, including heart toxicity.
Thus, better, more effective treatments, especially for people with relapsed or refractory disease are a dire need.
A Promising New Treatment for Relapsed/Refractor Follicular Lymphoma: Mosunetuzumab
Mosunetuzumab is a bispecific antibody, which is an artificial protein structure modeled after the naturally occurring antibodies of the human immune system. Naturally occurring antibodies are Y-shaped structures with two binding sites, both of which bind to the same unique, specific molecule called an antigen. Each bispecific antibody also has at least two binding sites. However, these arms can bind to two different antigens or two different sites on the same antigen.
“A bispecific antibody is an antibody that has at least two arms, usually one to [bind] to a T-cell, and one to [bind] to a tumor target,” says Dr. Catherine Diefenbach, Director of the Clinical Lymphoma program at Perlmutter Cancer Center. The arm that binds to the tumor usually engages a protein such as the CD20 surface protein, while the other couples with proteins present on immune system cells, such as the CD3 protein present on T-cells. When both arms engage their respective targets, the T-cells are brought into close proximity with the tumor cells. This activates the T-cells, impelling them into action against the tumor cells. In somewhat of a domino effect, several kinds of T-cells are activated en masse. All in all, the bispecific antibodies can help T-cells mount a vicious attack on the tumor cells that can ultimately result in cancer elimination.
Mosunetuzumab has been approved by the FDA for the treatment of relapsed/refractory FL after at least two lines of traditional therapies. This was based on the promising results of an important scientific study of 90 FL patients. Sixty percent of these patients had a complete response (total disappearance of their tumor) to therapy, while 80% achieved some response as a result of treatment with mosunetuzumab.
Other New Therapy Options
Mosunetuzumab is not the only new therapy for the treatment of difficult cases of FL. Obinutuzumab is an antibody against another protein (CD20) present on lymphoma cells, which, in combination with other drugs (rituximab, lenalidomide), has been shown to be highly effective for relapsed/refractory FL as well in another study. There are other treatments, some incorporating bispecific antibodies, that are being evaluated in clinical trials and are expected to produce positive results in the years to come.
- Follicular Lymphoma (FL) is a type of cancer of the white blood cells. It is a slow-growing, often asymptomatic cancer that can be treated but is not usually cured.
- Traditional therapies are effective at controlling the disease. However, FL tends to reoccur after therapy and can sometimes become resistant to these traditional therapeutics.
- “There are many new therapies that can control [follicular lymphoma], even for patients who have relapsed or resistant disease,” per Dr. Diefenbach.
- One such treatment is the bispecific antibody mosunetuzumab which has been approved by the FDA for FL treatment.
- Bispecific antibodies are proteins that can simultaneously bind two other proteins, one on the cancer cells and one on the immune system cells. This kicks the immune system into action against cancer.
- Many bispecifics and other new therapeutics are in development for FL.