Immunotherapy for Non-Hodgkin Lymphoma

Immunotherapy is treatment that either boosts the patient’s own immune system or uses man-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth.

Monoclonal antibodies

Antibodies are proteins made by your immune system to help fight infections. Man-made versions, called monoclonal antibodies, can be designed to attack a specific target, such as a substance on the surface of lymphocytes (the cells in which lymphomas start). 

Several monoclonal antibodies are now used to treat non-Hodgkin lymphoma (NHL). 

Antibodies that target CD20

A number of monoclonal antibodies target the CD20 antigen, a protein on the surface of B lymphocytes. These include:

• Rituximab (Rituxan, other brand names): This drug is often used along with chemotherapy (chemo) for some types of NHL, but it may also be used by itself.
• Obinutuzumab (Gazyva): This drug is often used along with chemo as a part of the treatment for small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). It can also be used along with chemo in treating follicular lymphoma.
• Ofatumumab (Arzerra): This drug is used mainly in patients with SLL/CLL that is no longer responding to other treatments.
• Ibritumomab tiuxetan (Zevalin): This drug is made up of a monoclonal antibody that is attached to a radioactive molecule. The antibody brings radiation directly to the lymphoma cells.

These drugs are given into a vein (IV), often over several hours. They all can cause reactions during the infusion (while the drug is being given) or several hours afterward. Most reactions are mild, such as itching, chills, fever, nausea, rashes, fatigue, and headaches. More serious reactions can include chest pain, heart racing, swelling of the face and tongue, cough, trouble breathing, feeling dizzy or lightheaded, and feeling faint. Because of these kinds of reactions, drugs to help prevent them are given before each infusion. 

There is also a form of rituximab called rituximab and hyaluronidase injection (Rituxan Hycela) that is given as a shot under the skin. It can take 5-7 minutes to inject the drug, but this is much shorter than the time it normally takes to give the drug by vein. It is approved for use in patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Possible side effects include local skin reactions, like redness, where the drug is injected, infections, low white blood cell counts, nausea, fatigue, and constipation.

All of these drugs can cause inactive hepatitis B infections to become active again, which can lead to severe or life-threatening liver problems. Your doctor may check your blood for signs of an old hepatitis B infection before you start treatment. These drugs can also increase your risk of certain serious infections for many months after the drug is stopped. Other side effects can depend on which drug is given. Ask your doctor what you can expect.

T-cell engaging bispecific antibodies

Some newer antibodies are designed so they can attach to two different targets. These are known as bispecific antibodies.

An example are T-cell engaging bispecific antibodies. Once in the body, one part of these antibodies attaches to the CD3 protein on immune cells called T cells. Another part attaches to a target on lymphoma cells, such as the CD20 protein. This brings the two cells together, which helps the immune system attack the lymphoma cells.

• Mosunetuzumab (Lunsumio) can be used to treat follicular lymphoma that has returned or that is no longer responding after treatment with at least 2 other types of drugs. This drug is given as an IV infusion, typically once a week for the first 3 weeks, then once every 3 weeks.
• Epcoritamab (Epkinly) can be used to treat diffuse large B-cell lymphoma (DLBCL) or other high-grade B-cell lymphomas, typically after other treatments have been tried. This drug is given as an injection under the skin (subcutaneously), usually once a week for the first 3 months, then once or twice a month.
• Glofitamab (Columvi) can be used to treat diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, typically after two or more other treatments have been tried. This drug is given as an IV infusion, typically once a week for the first 3 weeks, then once every 3 weeks.

These drugs can cause some of the same side effects as other antibodies that target CD20. For example, mosunetuzumab can cause infusion reactions (see above).

These drugs can also cause some other, more serious side effects, including:

Cytokine release syndrome (CRS): This side effect can occur when T cells in the body release chemicals (cytokines) that ramp up the immune system. This happens most often within the first day after treatment, and it can be serious or even life-threatening.

Symptoms of CRS can include high fever and chills, muscle weakness, trouble breathing, low blood pressure, a very fast heartbeat, headache, nausea or vomiting, and feeling dizzy, light-headed, or confused.

Your health care team will watch you closely for possible signs of CRS, especially during and after the first few treatments. You may get medicines before these treatments to help lower your risk of CRS. Be sure to contact your health care team right away if you have any symptoms that might be from CRS.

Nervous system problems: These drugs might affect the nervous system, which could lead to symptoms such as headaches, numbness or tingling in the hands or feet, feeling dizzy or confused, trouble speaking or understanding things, memory loss, abnormal sleep patterns, tremors, or seizures.

Serious infections: Some people might get a serious infection while getting one of these drugs. Tell your health care team right away if you have a fever, cough, chest pain, shortness of breath, sore throat, rash, or pain when urinating.

Low blood cell counts: These drugs might lower your blood cell counts, which can increase your risk of infections or bleeding. Your doctor will check your blood cell counts regularly during your treatment.

Tumor flare: These drugs might cause your tumor to grow or cause more symptoms for a time, which is known as tumor flare. Tell your health care team if you notice tender or swollen lymph nodes, chest pain, cough, trouble breathing, or pain or swelling around a known tumor.

Other side effects can include feeling tired, muscle or bone pain, rash, fever, nausea, diarrhea, and headaches.

Antibodies that target CD19

Tafasitamab (Monjuvi) is an antibody directed at the CD19 antigen, a protein on the surface of B lymphocytes. This drug can be used along with lenalidomide (see Immunomodulating drugs, below) to treat diffuse large B-cell lymphoma (DLBCL) that has come back or is no longer responding to other treatments, in people who can’t have a stem cell transplant for some reason.

This drug is infused into a vein (IV), typically about once a week for the first few months, and then once every two weeks.

Some people have infusion reactions while getting this drug, which can cause symptoms like chills, flushing, headache, or shortness of breath during the infusion. You’ll likely get medicines before treatment to help lower this risk, but it’s important to tell your healthcare provider right away if you have any of these symptoms.

Other side effects can include low blood cell counts (with an increased risk of bleeding and serious infections), feeling tired or weak, loss of appetite, diarrhea, cough, fever, and swelling in the hands or legs.

Antibody-drug conjugate with CD19 antibody

An antibody-drug conjugate (ADC) is a monoclonal antibody linked to a chemotherapy drug. In this case, the antibody directed against CD19 acts like a homing signal by attaching to the CD19 protein on cancer cells, bringing the chemo directly to them.

Loncastuximab tesirine (Zynlonta): This antibody-drug conjugate is used by itself to treat some types of large B-cell lymphoma (including diffuse large B-cell lymphoma, or DLBCL) after at least 2 other treatments (not including surgery or radiation) have been tried. This drug is given in a vein (IV) every 3 weeks.

Common side effects include abnormal liver function tests, low blood counts, feeling tired, rash, nausea, and muscle and joint pain. More serious side effects include infection, fluid collection in the lungs, around the heart, or in the abdomen (belly), very low blood counts, and very severe skin reactions when out in the sun.

Antibodies targeting CD52

Alemtuzumab (Campath) is an antibody directed at the CD52 antigen. It is useful in some cases of SLL/CLL and some types of peripheral T-cell lymphomas. This drug is infused into a vein (IV), usually 3 times a week for up to 12 weeks.

The most common side effects are fever, chills, nausea, and rashes. It can also cause very low white blood cell counts, which increases the risk for serious infections. Antibiotic and antiviral medicines are given to help protect against them, but severe and even life-threatening infections can still occur. Rare but serious side effects can include strokes, as well as tears in the blood vessels in the head and neck.

Antibodies that target CD30

Brentuximab vedotin (Adcetris) is an anti-CD30 antibody attached to a chemotherapy drug (an antibody-drug conjugate). The antibody acts like a homing signal, bringing the chemo drug to lymphoma cells, where it enters the cells and kills them. 

Brentuximab can be used to treat some types of T-cell lymphoma, either as the first treatment (typically along with chemo) or if the lymphoma if it has come back after other treatments. This drug is infused into a vein (IV), typically every 3 weeks.

Common side effects can include nerve damage (neuropathy), low blood counts, fatigue, fever, nausea and vomiting, infections, diarrhea, and cough. 

Antibodies that target CD79b

Polatuzumab vedotin (Polivy) is an anti-CD79b antibody attached to a chemotherapy drug (an antibody-drug conjugate). The antibody finds the lymphoma cell and attaches to the surface protein CD79b. Once connected, it is drawn into the lymphoma cell where the chemo is released and destroys it.

This drug can be used along with chemotherapy and rituximab to treat diffuse large B-cell lymphoma (DLBCL). This drug is infused into a vein (IV), typically every 3 weeks.

Common side effects can include numbness or tingling of hands/feet (peripheral neuropathy), low blood counts, fatigue, fever, decreased appetite, diarrhea, and pneumonia.

Immune checkpoint inhibitors

Immune system cells normally have substances that act as checkpoints to keep them from attacking other healthy cells in the body. Cancer cells sometimes take advantage of these checkpoints to avoid being attacked by the immune system.

Drugs such as pembrolizumab (Keytruda) work by blocking these checkpoints, which can boost the immune response against cancer cells. Pembrolizumab can be used to treat primary mediastinal large B-cell lymphoma (PMBCL) that has not responded to or has come back after other therapies.  

Immunomodulating drugs 

Drugs such as thalidomide (Thalomid) and lenalidomide (Revlimid) are thought to work against certain cancers by affecting parts of the immune system, although exactly how they work isn’t clear. They are sometimes used to help treat certain types of lymphoma, usually after other treatments have been tried. Lenalidomide can be given with or without rituximab, or along with tafasitamab.

These drugs are taken daily as pills.

Side effects of can include low white blood cell counts (with an increased risk of infection) and neuropathy (painful nerve damage), which can sometimes be severe and may not go away after treatment. There is also an increased risk of serious blood clots (that start in the leg and can travel to the lungs), especially with thalidomide. Thalidomide can also cause drowsiness, fatigue, and severe constipation.

These drugs can cause severe birth defects if taken during pregnancy. Given this risk, the company that makes these drugs puts restrictions on access to them to prevent women who are or might become pregnant from being exposed to them.

Chimeric antigen receptor (CAR) T-cell therapy

In this treatment, immune cells called T cells are removed from the patient’s blood and altered in the lab to have specific receptors (called chimeric antigen receptors, or CARs) on their surface. These receptors can attach to proteins on the surface of lymphoma cells. The T cells are then multiplied in the lab and given back into the patient’s blood, where they can seek out the lymphoma cells and launch a precise immune attack against them.

Axicabtagene ciloleucel (Yescarta, also known as axi-cel) is a type of CAR T-cell therapy approved to treat people with:

• Large B-cell lymphoma (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma) that hasn’t responded to initial treatment with chemotherapy plus immunotherapy, or that comes back within a year of this treatment.
• Follicular lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma, after at least two other kinds of treatment have been tried.

Tisagenlecleucel (Kymriah, also known as tisa-cel) is approved to treat people with diffuse large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma, as well as follicular lymphoma that hasn’t responded to or has come back after other therapies, after trying at least two other kinds of treatment.

Lisocabtagene maraleucel (Breyanzi, also known as liso-cel) is approved to treat adults with diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and follicular lymphoma grade 3B, after at least one other kind of treatment has been tried.

Brexucabtagene autoleucel (Tecartus, also known as brexu-cel) is approved to treat adults with mantle cell lymphoma that has come back or is no longer responding to other treatments.

Side effects of CAR T-cell therapy  

Because CAR T-cell therapy can have serious side effects, it is only given in medical centers that have special training with this treatment. 

• These treatments can sometimes cause cytokine release syndrome (CRS), in which immune cells in the body release large amounts of chemicals into the blood. Symptoms of this life-threatening syndrome can include fever, chills, headache, nausea and vomiting, trouble breathing, very low blood pressure, a very fast heart rate, swelling, diarrhea, feeling very tired or weak, and other problems. 
• These treatments can also sometimes cause serious neurological (nervous system) problems, such as confusion, trouble speaking, seizures, tremors, or changes in consciousness.
• Other serious side effects of these treatments can include severe infections, low blood cell counts, and a weakened immune system.

To learn more, see CAR T-Cell Therapies.