Cancer Immunotherapy


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Lymphoma is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on lymphoma and immunotherapy clinical trials for lymphoma patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based treatments to people with this type of cancer.

Urgent Need

Lymphoma is the name for a group of blood cancers that develop in certain immune cells. The two main types are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). About 90% of lymphomas are the non-Hodgkin type, while about 10% are Hodgkin.

In 2015, in the U.S., it is estimated that there will be 71,850 new cases of non-Hodgkin lymphoma and 9,050 new cases of Hodgkin lymphoma, for a total of 80,900 cases. An estimated 20,940 deaths from lymphoma will occur in the U.S. in 2015, most of which are NHL (19,790). In 2014, there were 761,659 people living with lymphoma or in remission (no sign of the disease).

Hodgkin lymphoma has characteristics that distinguish it from NHL, including the presence of Reed-Sternberg cells. These are large, cancerous cells with a distinct appearance, named for the scientists who first identified them. Hodgkin lymphoma is one of the most curable forms of cancer.

NHL 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. Some patients with fast-growing NHL can be cured. For patients with slow-growing NHL, treatment may keep the disease in check for many years.

Current Treatment

Non-Hodgkin lymphoma patients are usually treated with rituximab (Rituxan®, a monoclonal antibody) in combination with chemotherapy. Radiotherapy is used less often and typically when the disease is localized to a single site in the body. Other monoclonal antibodies directed at lymphoma cells are used for some types of NHL, as are antibodies linked to a radioactive molecule. In addition, new small molecule drugs are being used that target important survival pathways in NHL tumor cells. If NHL persists or recurs after initial treatments, high dose chemotherapy followed by stem cell transplantation may be an option.

Hodgkin lymphoma is usually treated with chemotherapy, radiation therapy, or a combination of the two, depending on the stage and cell type. Stem cell transplantation may be an option if these are not effective. The targeted drug brentuximab vedotin (Adcetris®)—a monoclonal antibody linked to a chemotherapy drug—is approved to treat Hodgkin lymphoma in patients whose disease has failed to respond to other treatment and, as of August 2015, to prevent relapse following a stem cell transplant.

ImmunotherapY for lymphoma

Current immunotherapies for lymphoma fall into four broad categories: checkpoint inhibitors, adoptive cell therapy, monoclonal antibodies, and therapeutic cancer vaccines.

Checkpoint Inhibitors 

A promising avenue of clinical research in lymphoma is the use of immune checkpoint inhibitors. These drugs work by targeting molecules that serve as brakes on the immune response. By blocking these inhibitory molecules or, alternatively, activating stimulatory molecules, checkpoint inhibitors are designed to unleash or enhance pre-existing anti-cancer immune responses. Several different checkpoint inhibitors are currently being tested in clinical trials for patients with lymphoma:

Nivolumab (Opdivo®) is an anti-PD-1 antibody made by Bristol-Myers Squibb (BMS). Nivolumab was granted FDA “Breakthrough Therapy” designation status for Hodgkin lymphoma based on a cohort of patients in a phase Ib trial testing nivolumab alone or with ipilimumab (see below) for blood cancers (NCT01592370). In that trial, 87% (20/23) of Hodgkin lymphoma patients responded to the treatment. The following nivolumab trials are open to patients with lymphoma:

  • A phase II study of nivolumab for patients with relapsed or refractory follicular lymphoma (NCT02038946)
  • A phase II study of nivolumab for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after failure of autologous stem cell transplant or after failure of at least two prior chemotherapy regimens (NCT02038933)
  • A phase I/II study of INCB24360 (an IDO inhibitor) in combination with nivolumab for B cell NHL or Hodgkin lymphoma including DLBCL (NCT02327078)
  • A phase II study of nivolumab in Hodgkin lymphoma after failure of autologous stem cell transplant (NCT02181738)

Pembrolizumab (Keytruda®) is an anti-PD-1 antibody made by Merck. The following pembrolizumab trials are open to patients with lymphoma:  

  • A phase Ib trial of pembrolizumab in patients with hematologic malignancies including Hodgkin lymphoma and non-Hodgkin lymphoma (NCT01953692)
  • A phase II study of pembrolizumab in relapsed or refractory low grade B cell non-Hodgkin lymphoma (NCT02332980)
  • A phase II study of pembrolizumab after autologous stem cell transplantation in patients with relapsed or refractory Hodgkin lymphoma and diffuse large B cell lymphoma (NCT02362997)
  • A phase Ib/II study of pembrolizumab with chemotherapy in patients with advanced lymphoma (PembroHeme) (NCT02408042)
  • A phase I/II study of pembrolizumab in children with PD-L1 positive advanced, relapsed or refractory lymphoma (KEYNOTE-051) (NCT02332668)

Atezolizumab (MPDL3280A) is an anti-PD-L1 antibody made by Genentech/Roche. The following trials are recruiting lymphoma patients:

  • A phase I study of MPDL3280A in patients with locally advanced or metastatic solid tumors (NCT01375842)
  • A phase Ib study of MPDL3280A in combination with obinutuzumab (an anti-CD20 antibody) in patients with relapsed or refractory follicular lymphoma or diffuse large B cell lymphoma (NCT02220842)

Ipilimumab (Yervoy®) is an anti-CTLA-4 antibody made by Bristol-Myers Squibb. The following ipilimumab trials are open to lymphoma patients:

  • A phase I study of ipilimumab in combination with rituximab in patients with relapsed or refractory CD20+ B-cell lymphoma (NCT01729806)
  • A phase I/Ib study of ipilimumab in patients with relapsed hematologic malignancies after a stem cell transplant (NCT01822509)
  • A phase I study of the combination of ipilimumab and brentuximab vedotin (Adcetris®, an antibody drug conjugate) in patients with relapsed or refractory Hodgkin lymphoma (NCT01896999)
  • A pilot study of lenalidomide (Revlimid®, an angiogenesis inhibitor) in combination with ipilimumab for patients with lymphoma who have had a stem cell transplant (NCT01919619)

Urelumab (BMS-663513, anti-4-1BB/CD137), made by Bristol-Myers Squibb, is an immune activator. It is being tested in the following trials that are open to lymphoma patients:

  • A phase I study urelumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NCT01471210)
  • A phase Ib study of urelumab combination with rituximab in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NCT01775631)
  • A phase I/II study of urelumab in combination with nivolumab in B-cell non-Hodgkin lymphoma (NCT02253992)

Other checkpoint inhibitors and immune activators:

  • A phase I trial of PF-05082566 (anti-4-1BB/CD137 antibody, developed by Pfizer, that stimulates the immune system) in adult patients with non-Hodgkin lymphoma (NCT01307267).
  • A phase Ib/II study of MEDI6469 (an anti-OX40 antibody, made by AstraZeneca/MedImmune, that stimulates the immune system) in combination with tremelimumab (anti-CTLA-4), durvalumab (MEDI4736, anti-PD-L1), or rituximab in patients with aggressive B-cell lymphomas (NCT02205333)
  • A phase Ib/II study of MEDI-551 (anti-CD19, made by AstraZeneca/MedImmune) in combination MEDI0680 (anti-PD-1) in patients with relapsed or refractory aggressive B-cell lymphomas (NCT02271945)
  • A phase I study of BMS-986016 (anti-LAG-3) in adult patients with hematologic cancers (NCT02061761)
  • A phase I study of varlilumab (CDX-1127, anti-CD27 antibody made by Celldex that stimulates the immune system) for adult patients with several cancers, including lymphoma (NCT01460134)

Checkpoint inhibitors in combination with targeted therapies:

Combining checkpoint inhibitors with small molecule targeted therapies has shown promise in laboratory studies. This concept is now being tested in clinical trials for lymphoma:

  • A phase I/II study of the ibrutinib (a targeted therapy) and nivolumab (anti-PD-1) in patients with hematological cancers (NCT02329847)
  • A phase Ib/II study of the combination of ACP-196 (a targeted therapy) and pembrolizumab (anti-PD-1) in patients with B-cell malignancies (NCT02362035)
  • A phase I/II study of ibrutinib (a targeted therapy) in combination with durvalumab (MEDI4736, anti-PD-L1) in patients with relapsed or refractory lymphoma (NCT02401048)

Adoptive Cell Therapy

In adoptive cell therapy, immune cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient, often in vastly increased numbers. The immune cells then seek out and destroy the cancer.

One specific form of this approach, called chimeric antigen receptor (CAR) T cell therapy, has been shown in early clinical trials to be particularly effective at treating lymphoma. In CAR T cell therapy, T cells from a patient are removed and then genetically modified to express a protein receptor that recognizes a particular antigen found on lymphoma cells. The receptor is called “chimeric” because it consists of two different proteins joined together—an antibody and a T cell receptor. Most existing CARs are designed to recognize a specific marker, called CD19, found on white blood cells called B cells. Both normal B cells and the cancerous B cells from which some lymphomas arise express CD19.

CAR T cell therapies for lymphoma are currently being tested in clinical trials at various institutions: 

  • Baylor College of Medicine is enrolling both adult and pediatric patients with non-Hodgkin lymphoma (NCT00840853; NCT01853631; NCT02050347)
  • City of Hope Medical Center is enrolling adult patients with non-Hodgkin lymphoma (NCT02051257; NCT02153580)
  • Fred Hutchinson Cancer Research Center is enrolling adult patients with non-Hodgkin lymphoma (NCT01865617)
  • Memorial Sloan Kettering Cancer Center is enrolling adult patients with non-Hodgkin lymphoma (NCT01840566)
  • NCI/National Institutes of Health Clinical Center is enrolling adult patients with B cell lymphoma (NCT00924326; NCT01087294) and pediatric and young adult patients with B cell lymphoma (NCT01593696)
  • The Christie NHS Foundation Trust (UK) is enrolling adult patients with non-Hodgkin lymphoma (NCT01493453)
  • University of Pennsylvania is enrolling patients with non-Hodgkin lymphoma (NCT02030834), relapsed or refractory Hodgkin lymphoma (NCT02277522), and small lymphocytic lymphoma (NCT01747486)
  • University of Pennsylvania and the Children’s Hospital of Philadelphia are enrolling pediatric and young adult patients with B cell lymphoma (NCT01626495)
  • Four medical centers (MD Anderson, City of Hope, Washington University in St. Louis, and Moffitt Cancer Center) are enrolling patients with refractory diffuse large B cell lymphoma, refractory primary mediastinal B cell lymphoma, and refractory transformed follicular lymphoma (NCT02348216

Monoclonal Antibodies

Monoclonal antibodies are molecules, generated in the lab, that are designed to target cancer cells and recruit immune cells to attack. They were the first successful forms of immunotherapy for lymphoma, with rituximab (Rituxan), a monoclonal antibody against the CD20 target, now the standard of care for all B cell lymphomas. Several other anti-CD20 monoclonal antibodies are now approved for lymphoma, including obinutuzumab (Gazyva™), ofatumumab (Arzerra®), and ibritumomab tiuxetan (Zevalin®). Some new antibodies in clinical trials for lymphoma are:

  • KW-0761 (mogamulizumab) is an anti-CCR4 antibody produced by Kyowa Hakko Kirin Pharma. The antibody is being tested in a phase III trial for patients with cutaneous T cell lymphoma (NCT01728805).
  • Several anti-CD19 antibodies: MOR00208 in a phase II trial for non-Hodgkin lymphoma (NCT02005289); MEDI-551 is in a phase II trial for diffuse large B cell lymphoma (DLBCL) (NCT01453205); and DI-B4 in a phase I trial for patients with B cell lymphoma (NCT01805375).
  • Milatuzumab (IMMU-115), an anti-CD74 antibody being developed by Immunomedics, Inc., is in a phase I/II trial for non-Hodgkin lymphoma (NCT01585688).

Therapeutic Vaccines

Therapeutic 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. Some vaccines are administered intravenously (into a vein), while others are injected directly into a single site of lymphoma (in situ vaccination) to induce an immune response that travels throughout the body to attack lymphoma wherever it resides. Vaccines in clinical testing include:

  • Imprime PGG, an intravenous vaccine made by Biothera is being tested a phase II trial for patients with non-Hodgkin lymphoma (NCT02086175).
  • An in situ vaccine made up of CDX-301 (aka Flt3L, a dendritic cell growth factor, made by Celldex) plus Poly-ICLC (a Toll-like receptors agonist, made by Oncovir) is being tested in patients with B cell lymphoma (NCT01976585).
  • An in situ vaccine made up of SD-101 (a Toll-like receptor agonist, made by Dynavax) is being tested for patients with previously untreated low grade lymphomas (NCT02266147)
  • An in situ vaccine made up of SD-101, given in combination with ipilimumab and radiation, for patients with for patients with relapsed low grade lymphoma (NCT02254772)
  • A type of vaccination in combination with stem cell transplant referred to as immunotransplantation is under investigation for mantle cell lymphoma at Stanford University. The patient’s own tumor cells are activated with CpG (a Toll-like receptor agonist) and used as the vaccine for patients in remission after chemotherapy. This stimulates the immune system to make T cells that target the tumor cells. The T cells are then taken from the patient and given back along with the stem cells after high dose chemotherapy (NCT00490529).

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for lymphoma that are currently enrolling patients.


CRI Contributions and Impact

Studies by CRI scientists that are shedding light on the understanding and treatment of lymphoma include:

  • In 1996, CRI Scientific Advisory Council director James P. Allison, Ph.D., and Matthew F. Krummel, Ph.D., a CRI investigator award recipient, established checkpoint blockade as a powerful new approach to cancer immunotherapy, by showing that an antibody which blocked the activity of a receptor on T cells called CTLA-4 could enhance tumor immunity. This work led directly to clinical trials and paved the way for the FDA approval in 2011 of Yervoy® (ipilimumab). 
  • Chimeric antigen receptor (CAR) technology, a form of adoptive T cell therapy, was made possible by decades of research by CRI scientists, including Scientific Advisory Council members Philip D. Greenberg, M.D.Carl H. June, M.D., and Michael Kalos, Ph.D., who was also a CRI postdoctoral fellow, and CRI postdoctoral fellow Isabelle Rivière, Ph.D
  • Jordan Gutterman, a CRI grantee and a member of the Scientific Advisory Council, and colleagues in 1980 reported the first demonstration of the ability of alpha interferon to induce regression of metastatic solid tumors and consistent remissions of blood cancers (lymphoma, breast cancer, and multiple myeloma).[i]
  • In 2000, Louis M. Staudt, a CRI investigator, and colleagues used DNA microarrays to conduct a systematic characterization of gene expression in diffuse large B cell lymphomas (DLBCL), identifying two molecularly distinct forms of DLBCL, which had gene expression patterns indicative of different stages of B cell differentiation. Their results demonstrated that the molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.[ii]
  • Micromet (now Amgen), building on the work of Gert Riethmuller (a member of the CRI Scientific Advisory Council), developed a recombinant antibody fragment that is bispecific (bispecific T cell engager, BiTE) designed to target the CD19 antigen on B cell lymphoma and the CD3 antigen on T cells, effectively using the T cells to kill the lymphoma cells.[iii]
  • Anjana Rao, a former CRI fellow and a member of the Scientific Advisory Council, and colleagues discovered the enzymatic activity of TET proteins and showed that they alter gene expression in stem cells, cancers, and the brain among others. Loss-of-function mutations in TET2 are shown to be frequent in lymphomas.[iv]
  • CRI investigator Hiroyoshi Nishikawa, M.D., Ph.D., at Osaka University, is working to identify novel targets for immunotherapy against adult T cell leukemia/lymphoma (ATLL), a virus-related blood cancer that is resistant to conventional chemotherapies and is characterized by a poor prognosis. In one study, he found that several cancer-testis antigens, including NY-ESO-1, were highly expressed in ATLL and that they could be recognized by killer T cells, providing proof-of-principle for cancer-testis antigens as a novel and potentially promising target for ATLL immunotherapy.
  • Changchun Xiao, Ph.D., a CRI investigator at The Scripps Research Institute, La Jolla, CA, has generated a mouse model in which a miR-17~92 (a micro RNA cluster) transgene can be turned on conditionally in a cell type-specific manner. The miR-17~92 cluster is known to be highly expressed in cancer cells, but the mechanisms of action of this microRNA in cancer and lymphocyte development are largely unknown. The effects of turning on the transgene in both B and T lymphocytes were tested in a large cohort of mice, about two-thirds of which developed B cell lymphoma. These results show that dysregulation of miR-17~92 expression is sufficient to cause cancer, and suggest that this defect may be one of the primary triggers of human lymphoma.

Updated and reviewed August 2015

Sources: Leukemia and Lymphoma Society; American Cancer Society Cancer Facts & Figures 2015; GLOBOCAN 2012;; CRI grantee progress reports and other CRI grantee documents.

[i] Gutterman JU, Blumenschein GR, Alexanian R, Yap HY, Buzdar AU, Cabanillas F, Hortobagyi GN, Hersh EM, Rasmussen SL, Harmon M, Kramer M, Pestka S. Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma, and malignant lymphoma. Ann Intern Med 1980 Sep; 93: 399-406. (PMID: 6159812)

[ii] Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Jr., Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. 2000. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403: 503-11

[iii] Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M, Einsele H, Brandl C, Wolf A, Kirchinger P, Klappers P, Schmidt M, Riethmüller G, Reinhardt C, Baeuerle PA, Kufer P. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008 Aug 15; 321: 974-977. (PMID: 18703743)

[iv] Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by the MLL fusion partner, TET1. Science 2009 May 15; 324: 930-935. (PMID: 19372391) Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, Ahn J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski J, Rao A. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010 Dec 9; 468: 839-843. (PMID: 21057493)


Lymphoma News & Stories

Reviewed By:

Ronald Levy, M.D.
Professor and Chief, Division of Oncology, Stanford University

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