Types of Immunotherapy for Lymphoma

Medically Reviewed by Arefa Cassoobhoy, MD, MPH on September 20, 2023
8 min read

Your doctor may talk to you about using immunotherapy to help treat your lymphoma. It’s a newer type of cancer treatment that works with your natural immune system to find and kill cancer cells in your body.

After successful immunotherapy, your cancer's not as likely to return because your immune system has learned to recognize and target that type of tumor cell if it comes back.

Some forms of it are quite high-tech, and some side effects can be serious or life-threatening.

These are the different kinds of immunotherapy you may get for lymphoma:

  • Monoclonal antibodies
  • Immunomodulating drugs
  • Immune checkpoint inhibitors
  • CAR T-cell therapy

Normally, your immune system makes antibodies to help fight infection. The antibodies stick to proteins called antigens on the surfaces of cells. Different kinds of cells have different antigens. That's why your body can find things that can make you sick, like viruses and bacteria. Only one kind of antibody fits each antigen, like a key in a lock. The antibodies mark the "bad" cells so your immune system can go after and destroy them.

Monoclonal antibodies are made in a lab. They’re designed to lock onto certain antigens that cancer cells make too much of. This means that they affect mostly cancer cells with little damage to normal cells.

Monoclonal antibodies can work in these ways:
1. They keep cancer cells from growing by blocking signals sent out by the cancer cells. These signals may do things like tell the cancer cells to grow and multiply, or they may tell nearby blood vessels to grow toward them so they can get nutrients they need to grow. Blocking the signals stops these processes.

2. They can also bind to the cancer cells and trigger your immune system to kill them. They may do this by marking the cells so your immune system attacks them. Or they can block the signals the cancer cells send out to tell your immune system to leave them alone.

3. Monoclonal antibodies can be attached to toxins, chemo, or radioactive substances. They then carry these cell-killing materials to the cancer cells and lock onto the antigen. This leads to the death of the cancer cells, with little to no effect on your normal cells that don’t have the antigen.

Rituximab (Rituxan) is the monoclonal antibody that doctors most often use to treat lymphoma. This drug targets the CD20 antigen, which many types of lymphoma make too much of. CD20 is found on a type of white blood cell called a B cell. This kind of monoclonal antibody will go after all B cells, not just the ones that have cancer. But your body will grow healthy new ones when you finish your treatment.

You get it by IV or an injection under your skin. You may get just rituximab, or you might get it along with chemo.

Doctors can also use other monoclonal antibodies that target CD20. Examples are ibritumomab tiuxetan (Zevalin), obinutuzumab (Gazyva), and ofatumumab (Arzerra).

CD20 monoclonal antibodies rev up your immune system, so you might feel like you have the flu during or after the infusion. You're also more likely to get a serious infection later on.

If you've had hepatitis B, the drugs that target the CD20 antigen can make it flare up again, so your doctor may check for signs of an old infection before your treatment.

You might get a monoclonal antibody that targets a different antigen that’s found on your lymphoma cells. For instance, you may get alemtuzumab (Campath) if your cells have the CD52 antigen.

Doctors mainly use alemtuzumab to treat T-cell lymphoma.

You get it as an infusion about three times a week for up to 3 months. It can cause fever, chills, nausea, and other side effects, so your doctor may start with a low dose and workup.

Alemtuzumab can give you very low blood cell counts, and there's a higher chance you'll get a serious infection.

There are also monoclonal antibodies that target cancer cells and deliver cancer-killing drugs to lymphoma cells. -- called antibody-drug conjugates. Your lymphoma cells might have the CD30 antigen, in which case brentuximab vedotin (Adcetris), a monoclonal antibody attached to chemo, might be part of your treatment plan. Polatuzumab vedotin is is another drug that binds with cancer cells and then kills with chemo. It is used to treat diffuse large B cell lymphoma, the most common type of non-Hodgkin lymphoma in the US. 

Here are some of the ways monoclonal antibodies can be used, depending on the type of lymphoma you have:

Follicular lymphoma: If you have a large stage I or II, or a certain kind of stage III or IV follicular lymphoma, your first treatment will likely be rituximab and chemo. You might get radiation, too. Then, if the lymphoma shrinks or goes away, you may get rituximab alone as maintenance therapy.

You can get rituximab alone or along with different chemo if the lymphoma comes back after treatment or stops responding to the treatment you’re getting.

Ibritumomab (Zevalin) or obinutuzumab (Gazyva) are other monoclonal antibodies you might get instead of rituximab. Tazemetostat may be an option for patients who have failed or are resistant to treatments and can be used for FL with specific types of mutations.

Mantle cell lymphomas: You might get rituximab along with chemo as the first treatment for mantle cell lymphoma. You can also get rituximab as a maintenance treatment or if the lymphoma comes back.

Diffuse large B-cell lymphoma:  You will get rituximab along with chemo for any stage of diffuse large B-cell lymphoma (DLBCL). You may also get radiation afterward.

If the lymphoma comes back or doesn’t respond to the treatment with rituximab, you may get a monoclonal antibody called polatuzumab vedotinis which is used for the initial treatment to treat DLBCL that has come back a second or later time or after at least 2 other medicines did not work well. Another option if treatment has not been working is pembrolizumab (Keytruda). Loncastuximab tesirine-lpyl (Zynlonta), is a single-agent treatment to be prescribed after two or more lines of systemic therapy.

Burkitt lymphoma: Doctors can use rituximab to treat Burkitt lymphoma as your first treatment or as a later treatment. You’ll get it along with chemo.

Marginal zone lymphomas: Both gastric and nongastric MALT lymphomas can be treated with rituximab. So can nodal and splenic marginal zone lymphomas. If you have any stage of one of these cancers, you might get rituximab, often along with chemo, as one of your treatments. You may also get it if the cancer comes back.

Rituximab, alone or with chemo, might be the first treatment you get for lymphoma in your skin (cutaneous B-cell lymphoma). You’ll get this medicine by IV if the lymphoma is in more than one area of your skin. Doctors can also combine it with the drug hyaluronidase (this is called Rituxan Hycela) and give it as a shot right into the skin lymphoma if it’s only in one area.

You might get a different monoclonal antibody, brentuximab vedotin (Adcetris), by IV if other treatments haven’t worked. Alemtuzumab (Campath) is another option if the lymphoma comes back after other treatments. You might get it by IV or as a shot into the skin lymphoma.

Hodgkin's lymphoma: You may get a monoclonal antibody called brentuximab vedotin (Adcetris) if you can’t have a stem cell transplant or classic Hodgkin's lymphoma comes back after treatment. You might get this as part of your first treatment if you have certain symptoms and blood test results. This drug binds to the CD30 antigen, which is common on Hodgkin's lymphoma cells. It’s attached to a chemo drug, which then kills the cell.

You can get rituximab along with chemo and radiation if you have early stage nodular lymphocyte predominant Hodgkin's disease (NLPHD) that’s causing symptoms or large tumors. You can also get it if you have more advanced-stage NLPHD, either alone or with chemo, and maybe radiation.

T-cell lymphomas: If your lymphoma stops responding to chemo, your doctor may talk to you about trying the monoclonal antibody called alemtuzumab (Campath) or brentuximab vedotin (Adcetris).

These drugs help your immune system work better, but doctors don’t know exactly how they work. The two drugs used are lenalidomide (Revlimid) and thalidomide (Thalomid).

You may get one of these drugs if you have one of these types of non-Hodgkin's lymphoma (NHL): a T-cell lymphoma, or a follicular, marginal zone, mantle cell, or diffuse large B-cell lymphoma. You might also get one of these drugs if you have Hodgkin's lymphoma that hasn’t responded to other treatments or that came back after treatment.

These immunomodulators are pills you take every day. They can have painful side effects that might not go away after treatment.

You can only get these drugs if you agree to take special precautions to prevent pregnancy because they cause severe birth defects. Your doctor will talk to you about this.

Cells have proteins on them called checkpoints. They help your immune system know the difference between good and bad cells. Lymphoma cells can make these checkpoints and trick your immune system into not killing them. These drugs help keep this from happening.

For example, PD-1 is a checkpoint on your T cells. When it binds to the protein called PD-L1 on another cell, the T cell is stopped from killing that cell. Your Hodgkin's lymphoma cells may make a lot of PD-L1. This tells your T cells to leave them alone. There are drugs that can block PD-1. This means your T cells aren’t turned off and your immune system can attack the cancer cells.

Classic Hodgkin's lymphoma: If the lymphoma has continued to grow while you’re getting other treatment that includes a monoclonal antibody, nivolumab (Opdivo) may be an option.

If you have a stage III or IV Hodgkin's lymphoma that’s not responding to chemo or monoclonal antibodies, or has come back after a transplant, nivolumab or pembrolizumab (Keytruda) might be helpful.

This is a very new treatment used for some types of B-cell lymphoma. CAR stands for chimeric antigen receptor. CARs are made in the lab. They’re designed to lock onto antigens found on your lymphoma cells. Each patient has their own CAR T cells made just for them.

To do this, you get some T cells filtered out of your blood. A lab then changes those T cells so they make CARs. Then the lab grows lots of those cells. Later, you get them back and the CAR T cells travel through your blood to find, lock onto, and kill the cancer cells. They continue to grow and multiply in your body so that CAR T cells can go on to kill cancer cells for months, or maybe even years.

The FDA has approved two CAR T-cell therapies for people with non-Hodgkin’s lymphoma. Axicabtagene ciloleucel (Yescarta) is for certain types of large B-cell lymphoma that haven't responded to or have come back after at least two other kinds of treatment. Tisagenlecleucel (Kymriah) is for relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL), high-grade B-cell lymphoma, and DLBCL that started as follicular lymphoma.

CAR T can have severe side effects, so you can get it only in special cancer centers. It also costs more than almost any other medical treatment, and your insurance may not pay for it.