Lymphoma is characterized by the uncontrolled growth of abnormal immune system cells (T cells or B cells), which travel through the body.  Some of the immunotherapy drugs used in lymphoma are designed to recognize unique proteins on the surface of lymphoma cells.  These drugs become attached to the lymphoma cells, enabling the immune system to find and destroy them.  Other immunotherapy drugs prevent lymphoma cells from suppressing the immune system, thereby restoring the immune system’s ability to destroy them.  Ultimately, how lymphomas respond to immunotherapy depends on how well the immune system can target the lymphoma cells.

Immunotherapy Types

Antibody-Drug Conjugates (ADC) is a monoclonal antibody attached to a chemotherapy drug. These agents target lymphoma cells by attaching to a protein on the cell surface, such as CD30. The ADC then enters the cell, where the chemotherapy drug separates from the antibody portion and kills the cell by targeting a critical cell function, such as cell division. Similar to monoclonal antibodies, ADC is given intravenously. An example of an FDA-approved ADC is brentuximab vedotin (Adcetris). Side effects are caused both by the antibody and the chemotherapy portion of the drug, and may include low blood cell counts, nerve damage leading to neuropathy, anemia, fatigue, and nausea. Approved antibody-drug conjugates include:

• Brentuximab Vedotin (Adcetris)
• Loncastuximab Tesirine-lpyl (ZYNLONTA)

Biosimilar therapies are biologic therapies that after modeled after an existing biologic therapy, or reference product, that has already been approved by the FDA. A biosimilar is expected to be just as effective as its reference product, but due to the complexities of making medications from natural sources, the two are not exactly the same. Manufacturers of biosimilars must show that minor differences in their chemical makeup do not change the safety and effectiveness of the biosimilar compared to the reference product. Biosimilars should not be confused with generic drugs, which are chemically identical to the original branded drug after which they are modeled. The manufacturer of a generic drug must show that it is equivalent to the branded drug after which it is modeled. Approved biosimilars include:

• Rituximab-abbs (Truxima) and rituximab-pvvr (Ruxience), both of which are Rituximab (Rituxan) biosimilars

Bispecific antibodies (bsAbs) are an innovative class of immunotherapy drugs designed to recognize two different targets expressed on the cell surface, called antigens. Like standard monoclonal antibodies (such as rituximab, a monoclonal antibody that targets B cells), bsAbs can be administered intravenously (IV) or subcutaneously (SC) i.e., underneath the skin. Once in the bloodstream, bsAbs travel throughout the body and attach themselves to the cell(s) that express their specific antigens. Approved bispecific antibodies include:

• Mosunetuzumab-axgb (Lunsumio)
• Epcoritamab-bysp (Epkinly)

To learn more about Bispecific Antibodies, download the Bispecifc Antibodies Fact Sheet.

CAR T Cell Therapy includes the chimeric antigen receptor (CAR) T cell therapies. These directly provide engineered molecules called chimeric antigen receptors (CARs) that recognize and destroy antigens present on the surface of lymphoma cells. T cells are removed from patients and genetically modified to produce CARs. The genetically engineered CAR-T cells are grown in the laboratory until they number in the billions and are then infused back into the patient. Approved CAR-T Cell therapies include:

• Axicabtagene Ciloleucel (Yescarta)
• Brexucabtagene Autoleucel (Tecartus)
• Lisocabtagene Maraleucel (Breyanzi)
• Tisagenlecleucel (Kymriah)

Learn more about CAR T cell therapy >

Checkpoint Inhibitors are a new class of immunotherapy that block signaling through checkpoints, which are used by some cancers to evade detection by the immune system. Approved checkpoint inhibitors include:

• Nivolumab (Opdivo)
• Pembrolizumab (Keytruda)

Cytokines drugs, such as interferon alfa-2b (Intron A) and denileukin diftitox (Ontak), are synthetic versions of naturally occurring cytokines (proteins used by immune system cells to communicate with each other). They are not commonly used today for the treatment of lymphoma. Cytokine drugs boost the body’s immune response to lymphoma cells. They may be given subcutaneously or intravenously. Common side effects of cytokines include flu-like symptoms, low white cell counts, rashes, and thinning hair. Approved cytokines include:

• Denileukin Diftitox (Ontak)

Immunomodulatory Drugs are treatments that have many ways of working against tumor cells. Approved immunomodulatory drugs include:

• Lenalidomide (Revlimid)
• Interferon Alfa-2b (Intron A)

Monoclonal antibodies are the most common biologic agents used for lymphoma therapy. Antibodies produced by our immune system recognize and destroy “foreign” invaders such as bacteria and viruses. Scientists can now produce monoclonal antibodies in the laboratory that are designed to recognize antigens (specific molecules) that are present on the surface of certain cancer cells. Once in the bloodstream, monoclonal antibodies travel throughout the body and attach themselves to their specific target antigens. Approved monoclonal antibodies include:

• Brentuximab Vedotin (Adcetris)
• Ibritumomab Tiuxetan (Zevalin)
• Ofatumumab (Arzerra)
• Obinutuzumab (Gazyva)
• Polatuzumab Vedotin-Piiq (Polivy)
• Rituximab (Rituxan)
• Rituximab and Hyaluronidase Human (Rituxan Hycela)
• Tafasitamab (Monjuvi)

Radioimmunotherapy (RIT) consists of a monoclonal antibody attached to a source of radiation. RIT acts as a “guided missile” to destroy lymphoma cells by attaching to a specific molecule on the surface of the lymphoma cell, such as CD20, and delivering small doses of radioactivity, which is intended to kill the cell. The only FDA-approved RIT for lymphoma is ibritumomab tiuxetan (Zevalin). RIT is given intravenously. Side effects of RIT include fever/chills, pneumonia, lung inflammation, arrhythmias, and low blood counts.

To learn more about radioimmunotherapy, download the Radioimmunotherapy Fact Sheet.