Targeted Therapies for Lymphoma

IntroductionIn This Section: Targeted TherapiesOverview Lymphoma TutorialObjectives Lymphoma BackgroundTargeted TherapiesOverviewTargeted therapies are transforming the way people treat cancer. These carefully designed drugs have already begun to make personalized medicine a reality and will continue to help doctors tailor cancer treatment based on the characteristics of each individuals cancer.

It is important that health care professionals become familiar with the concept of targeted therapies so they can communicate with their patients about these new approaches and help patients make better-informed treatment decisions.Lymphoma TutorialObjectivesThis tutorial focuses on the variety of targeted therapies that have been and are being developed to treat lymphoma. By completing this tutorial, you will learn the answers to the following questions. What are some of the molecules and pathways that are being targeted inlymphomacells? What agents are being developed to target these molecules and pathways? Which targeted therapies are currently approved by the FDA for treatment of lymphoma? How can I find clinical trials of targeted therapies for lymphoma?Lymphoma BackgroundLymphoma is a cancer that begins in cells of the immune system calledlymphocytes. Lymphoma occurs when B orT cellsacquire changes that allow them to grow uncontrollably. The abnormal cells accumulate in thelymph nodesor other parts of the lymphatic system.

This image shows an outline of a human body on the left with the lymphatic system highlighted. To the right of the body, a normal B and T cell are shown with an arrow leading to a mass of green cancer cells.There are two types of lymphoma: Hodgkin andnon-Hodgkin lymphoma. The majority of Hodgkin lymphomas are classical Hodgkin lymphomas, which consist of characteristic cells called Reed-Sternberg cells. Another much more rare type ofHodgkin lymphomaisnodular lymphocyte-predominant Hodgkin lymphoma.There are several types of non-Hodgkin lymphoma. The most common areB cellcancers called diffuse large B cell lymphoma andfollicular lymphoma. Other B cell non-Hodgkin lymphomas includeBurkitt lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, andmantle cell lymphoma.T cellnon-Hodgkin lymphomas includemycosis fungoides,anaplastic large cell lymphoma, andprecursor T-lymphoblastic lymphoma.

Targeting CD20In This Section: CD20 in Normal Cells CD20 in Cancer Cells Targeting CD20 Self TestCD20 in Normal CellsB cells at almost every stage of development express a membrane-spanning protein called CD20. The function of CD20 is not fully understood, although it is suspected to play roles in calcium regulation and B cell development.

The head and torso of a human body are shown on the left, with the lymphatic system emphasized. A callout bubble coming from a lymph node shows a close-up view of a B cell. In the membrane of the B cell is an embedded protein labeled CD20.CD20 in Cancer CellsCD20 is an attractive therapeutic target for a number of reasons:Firstly, it is expressed by nearly 90 percent of all B cell non-Hodgkin lymphomas.

This image is titled, 'B Cell Non-Hodgkin Lymphoma Patients.' On the left are 9 green figures labeled CD20-positive. On the right is one green figure labeled CD20-negative. Screen text reads, 'Expressed by nearly 90 percent of B cell non-Hodgkin lymphomas.'Secondly, although CD20 is present on most normal B cells, thestem cellsthat give rise to B cells do not express the protein. This means that B cells damaged by a CD20-targeted therapy can be replaced.

In the background are several gray cells representing normal and malignant B cells that have been killed by a CD20-targeted therapy. In the foreground are several viable blue cells. One of these is labeled stem cell. The other blue cells represent CD20-positive B cells that have arisen from the stem cell. The screen text on this image reads, Normal B cells can be regenerated."Finally, CD20 is not present on any other cells in the body, which makes it less likely that drugs targeting this protein will damage other tissues and organs.

A human body is shown in the center of the screen. A call-out bubble on the right shows a close-up view of a CD20-positive malignant B cell. The transmembrane protein CD20 is labeled. A black label pointing to the body states, Not expressed by other cells in the body.Targeting CD20Several monoclonal antibodies have been designed to target CD20 on lymphoma cells. These includeRituxan (rituximab), Bexxar (tositumomab), andZevalin (ibritumomab tiuxetan). The mechanisms of these therapeutic antibodies vary, but all of them bind to CD20 on the surface of both normal and cancerous B cells. This tutorial discusses several proposed mechanisms of action for Rituxan (rituximab), includingantibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, andapoptosis.

This image shows a close-up view of the cell membrane of a malignant B cell. A protein labeled CD20 is present in the cell membrane. A purple monoclonal antibody is bound to the extracellular portion of CD20.Antibody-dependent cell-mediated cytotoxicity, orADCC, occurs when Rituxan (rituximab) that is bound to CD20 interacts with immune system effector cells. These cells release molecules that lyse the target cell.

This image is titled Antibody-Dependent Cell-Mediated Cytotoxicity. It shows a close-up view of the membrane of a malignant B cell. A CD20 protein is extruding from the B cell membrane and is bound to one of the short arms of a purple monoclonal antibody. The long arm of the antibody is bound to a protein embedded in the membrane of a blue cell that represents an immune cell. Molecules are being released from the immune cell.Rituxan (rituximab) is also thought to activate complement-dependent cytotoxicity, or CDC. CDC is an immune response that involves a series of proteins known as the complement system. Some of the complement proteins insert themselves into the cell membrane, compromising the integrity of the cell and leading to cell death.

This image is labeled Complement-Dependent Cytotoxicity. It shows a close-up view of the membrane of a malignant B cell. The extracellular portion of CD20 is shown bound to the short arm of a monoclonal antibody. The long arm of the monoclonal antibody is bound to a series of three proteins. Five cylindrical proteins are shown embedding into the cell membrane, forming a pore. Small molecules are being released from the cell through the membrane.Rituxan (rituximab) can also cause target cells to undergo apoptosis by shifting the balance of pro- and anti-apoptotic pathways in the cell.

A layer of pink normal cells is shown in the background and a mass of green cancer cells is shown in the foreground on the right. Several of the tumor cells are shrinking and breaking into small globules, indicating that they are undergoing apoptosis. A call-out bubble is emanating from the tumor mass; in it is a close-up view of a cancer cell beginning to undergo apoptosis.Rituxan (rituximab) was the first monoclonal antibody approved by the FDA for therapeutic use in cancer patients.

Several green figures are shown in the background. In the center is an icon containing a purple monoclonal antibody with a stamp over it reading, FDA approved. Rituxan is written beneath the icon.It has been approved for use in combination with standard chemotherapy for treatment of CD20-expressing diffuse large B cell and follicular B cell non-Hodgkin lymphomas.It is also approved as a single agent for certain types of CD20-positive B cell non-Hodgkin lymphomas that have relapsed or do not respond to other therapies.Rituxan (rituximab) and other drugs that target CD20 are also being tested inclinical trialsfor lymphoma.More InformationThis table lists several drugs that target CD20. Agents that have been approved by the FDA for treatment of lymphoma are marked with an asterisk. For more information on types of targeted therapies, seeUnderstanding Targeted Therapies: An Overview.Research NameGeneric NameTrade NameDrug Type

CD20 Targeted Drugs--Ofatumumab (also called HuMax-CD20)ArzerraMonoclonal antibody

--Tositumumab*Bexxar*Monoclonal antibody

--Rituximab*Rituxan*Monoclonal antibody

--Ibritumomab Tiuxetan*Zevalin*Monoclonal antibody

hA20Veltuzumab--Monoclonal antibody

AME-133v----Monoclonal antibody

R7159----Monoclonal antibody

* Agents that have been approved by the FDA for treatment of lymphomaSome monoclonal antibodies that target CD20 are conjugated to other molecules that will damage the CD20-expressing cell. For example, Zevalin (ibritumomab tiuxetan) is a monoclonal antibody against CD20 that is covalently bound to a radioactive molecule called Yttrium-90. Bexxar (tositumomab) is a monoclonal antibody conjugated to radioactive iodine.Self TestQuestions1. Which of the following are mechanisms of Rituxan (rituximab)-mediated death of lymphoma cells: .a. Antibody-dependent cell-mediated cytotoxicityb. Downregulation of CD20c. Apoptosisd. A and Be. A and CAnswers1. Correct Answer:e2. a. Partially correct.Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.b. Incorrect.Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity. It does not appear to cause downregulation of CD20.c. Partially correct.Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.d. Incorrect.Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity. It does not appear to cause downregulation of CD20.e. Correct.Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.