Cancer Immunotherapy

Lymphoma

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 cancer treatments to people with lymphoma.
 

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 2014, it is estimated that there will be 77,800 new cases of non-Hodgkin lymphoma and 9,190 new cases of Hodgkin lymphoma, for a total of 79,990 cases. An estimated 20,170 deaths from lymphoma will occur in 2014, most of which are NHL (18,990). In 2013, about 731,277 people were living with lymphoma or were 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 (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 atom. 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 disease 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 it is under investigation as part of the primary therapy.
 

Immunotherapies in Development

Current immunotherapies for lymphoma fall into four broad categories: therapeutic cancer vaccines, checkpoint inhibitors / immune modulators, adoptive T cell transfer (including chimeric antigen receptor T cell therapy), and monoclonal antibodies.

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 include:

  • BiovaxID® (dasiprotimut-T), produced by Biovest International, is an anti-lymphoma vaccine that targets follicular non-Hodgkin lymphoma and potentially other B cell cancers. It demonstrated a 15.4 month improvement in remission in a multi-center, randomized phase III clinical trial. It is under review by the European Medicines Agency (EMA) for approval for non-Hodgkin follicular lymphoma for patients who have achieved complete remission following frontline therapy (NCT00091676).
  • Imprime PGG is made by Biothera and is in a phase II trial for non-Hodgkin lymphoma (NCT02086175, not yet recruiting).
  • CDX-301 (anti-Flt3L), made by Celldex, plus Poly-ICLC, made by Oncovir, is enrolling patients with B cell lymphoma (NCT01976585).
  • Immunotransplantation is under investigation for mantle cell lymphoma at Stanford University. The patient’s own tumor cells are activated with an immune modulator and used as the vaccine for patients in remission after chemotherapy. Immune T cells are taken from the patient and then given back along with the stem cells after high dose chemotherapy (NCT00490529).
     

Checkpoint Inhibitors / Immune Modulators

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, checkpoint inhibitors are designed to unleash or enhance pre-existing anti-cancer immune responses. This promising new approach was envisioned by CRI Scientific Advisory Council director James P. Allison, Ph.D., who developed the first checkpoint inhibitor, ipilimumab (anti-CTLA-4), for the treatment of metastatic melanoma. Several clinical trials of immune modulators are currently enrolling patients:

  • 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) and a phase II trial for patients with adult T cell leukemia/lymphoma (NCT01626664).
  • Nivolumab (BMS-936558) is an anti-PD-1 antibody made by Bristol-Myers Squibb (BMS). Clinical trials of nivolumab are enrolling patients with follicular lymphoma (NCT02038946) or diffuse large B cell lymphoma (NCT02038933). 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 hematological cancers (NCT01592370).
  • Ipilimumab (Yervoy) is an anti-CTLA-4 antibody made by Bristol-Myers Squibb and is in two phase I trials in adult patients with lymphoma (NCT01729806; NCT01822509) and a phase I trial in Hodgkin lymphoma (NCT01896999).
  • Urelumab (BMS-663513, anti-4-1BB/CD137), made by Bristol-Myers Squibb, is in two phase I trials in adult patients with lymphoma (NCT01471210; NCT01775631).
  • Anti-LAG-3 (BMS-986016) is in a phase I trial that is enrolling adult patients with hematologic cancers (NCT02061761).
  • CDX-1127 (varlilumab) is an anti-CD27 antibody made by Celldex and is in a phase I trial for adult patients with several cancers, including lymphoma (NCT01460134).
  • Pembrolizumab (MK-3475) is an anti-PD-1 antibody being developed by Merck and is in a phase I trial for lymphoma (NCT01953692).
  • PF-05082566 is an anti-4-1BB/CD137 antibody developed by Pfizer and is in a phase I trial for adult patients with non-Hodgkin lymphoma (NCT01307267).
     

Adoptive T Cell Transfer

In this immunotherapy approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.

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 is not naturally found on T cells. The genetically modified T cells are then put back into the patient so his or her immune system can begin fighting the cancer.

In 2011, Carl H. June, M.D. (a CRI clinical investigator and member of the CRI Scientific Advisory Council), Michael Kalos, Ph.D. (a former CRI postdoctoral fellow), and colleagues at the University of Pennsylvania School of Medicine achieved clinical responses in patients with chronic lymphocytic leukemia, including two complete, durable clinical responses[i]. Studies at the Surgery Branch of the National Cancer Institute (NCI), led by Steven A. Rosenberg, M.D., Ph.D., have reported that administration of the anti-CD19-CAR T cells resulted in complete remissions in 12 out of 13 patients with advanced B cell malignancies enrolled in a phase I/IIa clinical trial. Many companies are now engaged in CAR T cell drug development, including Novartis Pharmaceuticals, Juno Therapeutics, Cellectis/Pfizer, Kite Pharma, and Lion Biotechnologies.

Organizations with trials enrolling patients include:

  • Baylor College of Medicine, where they are enrolling both adult and pediatric patients with lymphoma (NCT00840853; NCT01316146; NCT01192464; NCT01853631; NCT00586391; NCT02050347)
  • City of Hope Medical Center, where they are enrolling adult patients with lymphoma (NCT02051257; NCT02153580, not yet recruiting)
  • Fred Hutchinson Cancer Research Center, where they are enrolling adult patients with lymphoma (NCT01865617)
  • MD Anderson Cancer Center is enrolling pediatric and young adult patients with lymphoma (NCT00968760; NCT01497184)
  • Memorial Sloan Kettering Cancer Center is enrolling adult patients with lymphoma (NCT01840566)
  • Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute are enrolling pediatric and young adult patients with lymphoma (NCT01260937)
  • National Institutes of Health Clinical Center, where they are enrolling adult patients with lymphoma (NCT00924326; NCT01087294) and pediatric and young adult patients with lymphoma (NCT01593696)
  • The Christie NHS Foundation Trust (UK) is enrolling adult patients with lymphoma (NCT01493453)
  • University of Pennsylvania is enrolling patients with non-Hodgkin lymphoma (NCT02030834)
  • University of Pennsylvania and the Children’s Hospital of Philadelphia are enrolling pediatric and young adult patients with lymphoma (NCT01626495)
     

Monoclonal Antibodies

Monoclonal antibodies are designed to target cancer cells and recruit immune cells to attack. They were the first successful forms of immunotherapy for lymphoma, with Rituximab, a monoclonal antibody against the CD20 target, now the standard of care for all B cell lymphomas.  Some new antibodies in clinical trials for lymphoma are:

  • Several anti-CD19 antibodies: MOR00208 in two phase II trials for non-Hodgkin lymphoma (NCT02005289; NCT01685008); 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).

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:

  • 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[ii] (lymphoma, breast cancer, and multiple myeloma).
  • 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.[iii]
  • 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.[iv]
  • 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.[v]
  • 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 July 2014

Sources: Leukemia and Lymphoma Society; American Cancer Society Cancer Facts & Figures 2014; GLOBOCAN 2012; ClinicalTrials.gov; CRI grantee progress reports and other CRI grantee documents.
 


[i] Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011 Aug 10; 3: 95ra73. (PMID: 21832238) Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011 Aug 25; 365: 725-33. Epub 2011 Aug 10. (PMID: 21830940)

[ii] 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)

[iii] 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

[iv] 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)

[v] 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

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    September 18, 2014

  • Cancer Research Institute to Honor Leaders in Cancer Immunotherapy

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    September 16, 2014

  • 32 Years and Counting

    CRI trustee Jacques Nordeman has been steering the course against cancer for more than three decades.

    September 16, 2014

Reviewed By:

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

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