Targeted Therapies for Lymphoma

Introduction
In This Section:

Targeted TherapiesOverview

Lymphoma TutorialObjectives

Lymphoma Background

Targeted TherapiesOverview
Targeted 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 TutorialObjectives
This 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
in lymphoma cells?

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 Background
Lymphoma is a cancer that begins in cells of the immune system called lymphocytes. Lymphoma
occurs when B or T cells acquire changes that allow them to grow uncontrollably. The abnormal
cells accumulate in the lymph nodes or 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 and non-Hodgkin lymphoma. The majority of Hodgkin
lymphomas are classical Hodgkin lymphomas, which consist of characteristic cells called ReedSternberg cells. Another much more rare type of Hodgkin lymphoma is nodular lymphocytepredominant Hodgkin lymphoma.
There are several types of non-Hodgkin lymphoma. The most common are B cell cancers called
diffuse large B cell lymphoma and follicular lymphoma. Other B cell non-Hodgkin lymphomas
include Burkitt lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic
lymphoma, and mantle cell lymphoma. T cell non-Hodgkin lymphomas include mycosis
fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma.

Targeting CD20
In This Section:

CD20 in Normal Cells

CD20 in Cancer Cells

Targeting CD20

Self Test

CD20 in Normal Cells

B 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 Cells

CD20 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, the stem cells that 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 closeup 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 CD20
Several monoclonal antibodies have been designed to target CD20 on lymphoma cells. These
includeRituxan (rituximab), Bexxar (tositumomab), and Zevalin (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), including antibody-dependent cell-mediated cytotoxicity,
complement-dependent cytotoxicity, and apoptosis.

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, or ADCC, 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 CD20expressing 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 in clinical trials for
lymphoma.

More Information
This 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, see Understanding Targeted Therapies: An Overview.

Research
Name
CD20
Targeted
Drugs

Generic
Name

Trade
Name

Drug Type

--

Ofatumuma
b (also
called
HuMaxCD20)

Arzerra

Monoclonal
antibody

--

Tositumum
ab*

Bexxar*

Monoclonal
antibody

--

Rituximab*

Rituxan*

Monoclonal
antibody

--

Ibritumoma
b Tiuxetan*

Zevalin*

Monoclonal
antibody

hA20

Veltuzumab

--

Monoclonal
antibody

AME-133v

--

--

Monoclonal
antibody

R7159

--

--

Monoclonal
antibody

* Agents that have been approved by the FDA for treatment of lymphoma

Some 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 Test
Questions
1. Which of the following are mechanisms of Rituxan (rituximab)-mediated death of
lymphoma cells: .
a. Antibody-dependent cell-mediated cytotoxicity
b. Downregulation of CD20
c. Apoptosis
d. A and B
e. A and C
Answers
1. Correct Answer: e
2.
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.