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.