Immunotherapy for Lymphoma

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  • Lymphoma
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

How is Immunotherapy for Lymphoma Changing the Outlook for Patients?

Reviewed By: Joshua D. Brody, M.D.
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Icahn School of Medicine at Mount Sinai
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Immunotherapy for lymphoma provides multiple treatment options for both adults and children, including checkpoint inhibitors and adoptive cell therapy. 

Lymphoma is a type of cancer that arises in the infection-fighting cells of the immune system called lymphocytes (a type of white blood cell made in the bone marrow). Lymphocytes circulate throughout the body via blood and the lymphatic system. Lymph nodes, a key structure of the lymphatic system, are found throughout the body and filter lymph fluid to remove foreign particles. When bacteria and other invaders are found in the lymph fluid, lymphocytes multiply within the lymph nodes, including B cells, T cells, and natural killer (NK) cells. Lymphomas develop when these lymphocytes transform from healthy to malignant cells, therefore lymphomas can be partly classified as B cell lymphomas (the majority), T cell lymphomas, or NK cell lymphomas (rare).

Diagram of Circulatory and Lymphatic System (c) Terese Winslow

Lymphoma is one of the primary cancers that affect children and young adults. The two main types are:

  • Hodgkin lymphoma, affecting only about 10% of patients diagnosed
  • non-Hodgkin lymphoma (NHL), accounting for the vast majority (90%) of lymphoma diagnoses

Hodgkin lymphoma has several characteristics that distinguish it from NHL, including the presence of Reed-Sternberg cells. These are large, cancerous, B cell-derived cells with a distinct appearance, named for the scientists who first identified them. Hodgkin lymphoma is considered one of the most treatment-responsive cancer types with a majority of patients—even those with advanced disease—being cured with standard therapies.

Non-Hodgkin lymphoma represents a diverse group of diseases distinguished by the characteristics of the cancer cells associated with each disease type. Most people with NHL have a B cell type (about 85%). The others have a T cell type or a natural killer (NK) cell type of lymphoma. While NHL represents a more aggressive cancer diagnosis, some patients with fast-growing NHL can be completely cured. Treatments for slow-growing NHL are effective in stabilizing the disease for long periods of time, even years and decades.

Each year, there are an estimated 590,000 new cases of lymphoma diagnosed and 270,000 deaths due to the disease globally. In the United States alone, there will be roughly 86,000 new cases and 21,000 deaths in 2020.

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Lymphoma Treatment Options

Treatment for lymphoma depends on type of lymphoma diagnosed (e.g., Hodgkin lymphoma vs non-Hodgkin lymphoma) and disease stage. Chemotherapy, radiation, or combinations of the two are typically used to treat both types of lymphoma. Stem cell treatment is an option when initial courses of treatments are ineffective. Radiotherapy is used less often and typically when the disease is localized to a single site in the body.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are currently nine FDA-approved immunotherapy options for lymphoma.

Targeted Antibodies

  • Brentuximab vedotin (Adcetris®): an antibody-drug conjugate that targets the CD30 pathway and delivers toxic drugs to tumors; approved for subsets of patients with either Hodgkin or non-Hodgkin lymphoma, including as a first-line therapy
  • Ibritumomab tiuxetan (Zevalin®): an antibody-drug conjugate that targets the CD20 pathway and delivers toxic drugs to tumors; approved for subsets of patients with non-Hodgkin lymphoma
  • Mogamulizumab (Poteligeo®): a monoclonal antibody that targets the CCR4 pathway; approved for subsets of patients with two rare types of non-Hodgkin lymphoma—mycosis fungoides and Sézary syndrome—that affect the skin
  • Obinutuzumab (Gazyva®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with non-Hodgkin lymphoma, including as a first-line therapy
  • Polatuzumab vedotin (Polivy): an antibody-drug conjugate that targets the CD79b pathway and delivers toxic drugs to tumors; approved for subsets of patients with non-Hodgkin lymphoma
  • Rituximab (Rituxan®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with CD20-positive non-Hodgkin Lymphoma (NHL), including as a first-line therapy
  • Tafasitamab-cxix (Monjuvi®): a monoclonal antibody that targets the CD19 pathway; approved for subsets of patients with diffuse large B-cell lymphoma

Immunomodulators

  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with classical Hodgkin lymphoma
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with classical Hodgkin lymphoma
  • Interferon alfa-2b (Intron A®): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with follicular lymphoma

Adoptive Cell Therapy

  • Axicabtagene ciloleucel (Yescarta®): a CD19-targeting CAR T cell immunotherapy; approved for subsets of patients with non-Hodgkin lymphoma
  • Brexucabtagene autoleucel (Tecartus™): a CD19-targeting CAR T cell immunotherapy; approved for subsets of patients with mantle cell lymphoma
  • Tisagenlecleucel (Kyrmriah®): a CD19-targeting CAR T cell immunotherapy; approved for subsets of children and young adult patients with acute lymphoblastic leukemia (ALL)

New immunotherapies for lymphoma are currently being tested in clinical trials and several have shown impressive results for both children and adults.

Find a lymphoma clinical trial

CRI's Impact in Lymphoma

Since 1953, the Cancer Research Institute has dedicated more than $24 million in funding to develop and discover immunotherapies that can treat blood cancers, including lymphoma. CRI-funded scientists are dedicated to discovering more about the causes and immunotherapeutic treatment of Hodgkin and non-Hodgkin lymphoma across all subtypes and stages. Examples of our impact on lymphoma include:

See what lymphoma cancer-specific research we’re currently funding. With your help, we can fund more research and transform the way lymphoma is treated—saving more lives.

Donate to lymphoma research

Featured Patient

There's life during cancer, too. Especially when I was doing immunotherapy.

Jenny
Lymphoma  |  Diagnosed
Read My Story
Featured Scientist
Baochun Zhang, M.D., Ph.D.
Dana-Farber Cancer Institute
CLIP Investigator  |  2020
View Funding Profile

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Lymphoma Statistics

90% Non-Hodgkin lymphoma
60% 10-year overall relative survival rate for patients with Non-Hodgkin lymphoma
590k Newly diagnosed patients each year globally

Lymphoma Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Therapies
  • Targeted Antibodies
  • Cancer Vaccines
  • Adoptive Cell Therapy
  • Immunomodulators
  • Oncolytic Virus Therapy

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells, in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in lymphoma clinical trials include:

  • BCMA: an important signaling receptor found mainly on mature B cells; often expressed by lymphoma and myeloma cells
  • CD19: a receptor found on the surface of almost all B immune cells that influences their growth, development, and activity; often expressed by leukemia, lymphoma, and myeloma cells
  • CD20: a receptor found on the surface of B immune cells during their development; often expressed by leukemia, lymphoma, and myeloma cells
  • CD22: a receptor found primarily on the surface of mature B immune cells; often expressed by leukemia and lymphoma cells
  • CD25 (also known as IL2-R):  a cytokine receptor involved in the growth and expansion of immune cells; often expressed by leukemia and lymphoma cells
  • CD30: a receptor that is expressed on certain types of activated immune cells; often expressed by leukemia and lymphoma cells
  • CD37: a protein found on many types of immune cells; often expressed by leukemia and lymphoma cells
  • CD52: a protein found on the surface of mature immune cells as well as other cell types
  • CD123 (also known as IL-3R): a receptor found on immune cells that is involved in proliferation and differentiation, and often expressed by leukemia and lymphoma cells
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • SLAMF7: a surface protein found on plasma B cells; often expressed by lymphoma and myeloma cells
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in lymphoma clinical trials include:

  • In situ vaccination: immune stimulants can be injected directly into one tumor site to ‘trick’ the immune system to perceive tumor cells as foreign invaders and then target and eliminate them throughout the body 
  • Personalized neoantigens: these abnormal proteins arise from mutations and are expressed exclusively by tumor cells
  • Survivin: a protein that can prevent cellular death and is overexpressed by a number of cancer cell types
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in lymphoma clinical trials include:

  • CD19: a receptor found on the surface of almost all B immune cells that influences their growth, development, and activity; often expressed by leukemia, lymphoma, and myeloma cells
  • CD20: a receptor found on the surface of B immune cells during their development; often expressed by leukemia, lymphoma, and myeloma cells
  • CD22: a receptor found primarily on the surface of mature B immune cells; often expressed by leukemia and lymphoma cells
  • CD30: a receptor that is expressed on certain types of activated immune cells; often expressed by leukemia and lymphoma cells
  • CD123 (also known as IL-3R): a receptor found on immune cells that is involved in proliferation and differentiation, and often expressed by leukemia and lymphoma cells
  • Epstein-Barr Virus (EBV)-related antigens: foreign viral proteins expressed by EBV-infected cancer cells
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but can become reactivated in cancer cells, flagging them as abnormal to the immune system
  • NY-ESO-1: a protein that is normally produced only before birth, but is often abnormally expressed in cancer
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in lymphoma clinical trials include:

  • CD47: this surface protein acts as a “don’t eat me!” signal that protects cancer from being consumed by certain immune cells; blocking CD47 can improve their cancer-eating activity
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages      
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STAT3: activating this intracellular signaling protein can help stimulate adaptive immune responses
  • STING: activating this protein in the DNA-sensing pathway can help stimulate immune responses against threats such as viruses and cancer
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses viruses that are often, but not always, modified in order to infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in lymphoma clinical trials include:

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Herpes simplex virus: a virus that can cause the formation of sores on the mouth and genitals
  • Vesicular stomatitis virus: a virus that belongs to the same family as the rabies virus; can cause flu-like symptoms in humans
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Sources: ACS Facts and Figures 2020; ClinicalTrials.gov; CRI documents; GLOBOCAN 2018; Leukemia and Lymphoma Society

Updated August 2020

*Immunotherapy results may vary from patient to patient. Consult a healthcare professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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