In English | En español
Questions About Cancer? 1-800-4-CANCER

Advances in Targeted Therapies Tutorial

< Back to Main

Page Options

  • Print This Page
  • Print This Document
  • View Entire Document
  • Email This Document

Popular Resources

NCI Highlights

Targeted Immunotherapies

In This Section:

Introduction

The therapies discussed in the previous section target many processes and pathways used by cancer cells to survive and grow. We saw how antibodies, such as Herceptin® (trastuzumab), Avastin® (bevacizumab), and TRAIL-like antibodies, can disrupt cancer as it signals for uncontrolled growth. Monoclonal antibodies can also be used to design immunotherapies to attack cancer cells.

Monoclonal Antibodies

Overview

Monoclonal antibodies can directly trigger an immune response against cancer cells.

Example: Rituxan® (rituximab)

Rituxan® (rituximab) is a good example of a monoclonal antibody that can activate the immune system to attack a cancer cell. It binds to a surface protein, called CD20, located on mature B lymphocytes (B cells). Once bound, the antibody activates the body's immune system, which then attacks the cancer cells. Rituxan® (rituximab) may also make cells more susceptible to chemotherapy, promoting more cell death by apoptosis.

This image shows a cut-away of the surface and cytoplasm of a malignant B cell. A cell surface receptor labeled 'CD20' spans the cell membrane. In a circle, there is a close-up view of the extracellular portion of a cell surface receptor. Attached to the receptor is a purple monoclonal antibody targeted therapy molecule.

Because CD20 is on all B cells, Rituxan® (rituximab) kills normal as well as cancer cells. However, patients can regenerate normal B cells from their own or transplanted blood stem cells.

This image shows dead malignant B cells as well as blue normal B cells that have been regenerated.

More Information

Rituxan® (rituximab)

Clinical trials have shown that Rituxan® (rituximab) can be effective against cancer cells that express CD20 when used with standard chemotherapy regimens such as CHOP—which includes cyclophosphamide, doxorubicin, vincristine, and prednisone—or CVP—which includes cyclophosphamide, vincristine, and prednisone. Combination therapy with Rituxan® (rituximab) and chemotherapy has been approved by the Food and Drug Administration (FDA) for the treatment of certain types of non-Hodgkin lymphoma. Three possible mechanisms of Rituxan-mediated cell lysis have been proposed: (1) antibody-dependent cell-mediated cytotoxicity, (2) complement-dependent cytotoxicity, and (3) apoptosis (independent of immune system). Antibody-dependent cell-mediated cytotoxicity occurs when immune cells (including natural killer cells, T cells, and macrophages) bind to Rituxan and release chemicals that result in cell lysis. Complement-dependent cytotoxicity occurs when Rituxan recruits complement proteins, which disrupt the cell's plasma membrane, leading to cell lysis. Rituxan may also induce target cells to undergo apoptosis independent of the immune system.

Radioimmunotherapy

Overview

Monoclonal antibodies can be chosen for their ability to target specific receptor proteins on the outside of cancer cells and then be modified to also deliver lethal molecules to these cancer sites. Radioactive isotopes can be attached—or conjugated—to carefully chosen monoclonal antibodies. When the conjugated antibody binds to a specific target on the cancer cell's surface, the radiation will fatally damage the cell.

Example: Bexxar® (tositumomab)

Bexxar® (tositumomab) is an example of a radioactive immunotoxin. It is a monoclonal antibody that binds to CD20. Radioactive iodine attached to the antibody releases high doses of radiation that will kill the cell.

This image shows a cut-away view of the cell surface of a malignant B cell. There are cell surface receptors, labeled CD20, spanning the cell membrane. Bexxar®, which is represented by a purple antibody with a yellow and black radioactivity symbol, is attached to the extracellular portion of one of the cell surface receptors.

Because CD20 is on all B cells, Bexxar® (tositumomab) kills normal cells as well as cancer cells. The radiation released from Bexxar® (tositumomab) may also damage nearby cells that do not have CD20 on their surface. However, patients can create new normal B cells from their own stem cells or transplanted stem cells.

More Information

Bexxar® (tositumomab)

Bexxar® (tositumomab and iodine I 131 tositumomab) has been approved by the FDA for the treatment of patients with follicular non-Hodgkin lymphoma whose disease is refractory to Rituxan® (rituximab) and who have relapsed following chemotherapy. Bexxar® (tositumomab) is also being evaluated for use as a first-line therapy in clinical trials.

Immunotoxin Therapy

Overview

Monoclonal antibodies can also be conjugated to other types of molecules that are toxic to cells.

Example: Mylotarg® (gemtuzumab)

Mylotarg® (gemtuzumab) is a monoclonal antibody that binds to a protein called CD33. CD33 is on the surface of cancer cells of almost all patients with acute myeloid leukemia (AML).

This image shows a cut-away view of a green cancer cell labeled 'Acute Myeloid Leukemia (AML)'. A cell surface receptor labeled 'CD33 Protein' is spanning the cell membrane. Attached to the extracellular portion of the receptor is Mylotarg, which is represented by a purple antibody attached to a skull-and-bones symbol. The skull-and-bones symbol indicates that a toxic antibiotic is attached to the antibody.

When Mylotarg® (gemtuzumab) binds CD33, the cell's plasma membrane folds in and the antibody is brought inside the cell.

This is a cut-away view of a green cancer cell. A cell surface receptor is bound to Mylotarg. The cell membrane surrounding the Mylotarg-bound receptor folds in, causing the receptor to be internalized by the cell.

Once inside, Mylotarg® (gemtuzumab) releases its secret weapon—a cytotoxic antibiotic. The drug travels into the nucleus, where it binds DNA. Like some standard chemotherapy drugs, this drug causes breaks in the DNA. If the breaks remain unrepaired they eventually lead to cell death.

This image shows the cytoplasm and nucleus of a cancer cell. The folding-in of the membrane around the cell surface receptor has been completed, resulting in a membrane-enclosed sphere in the cytoplasm. The cell surface receptor is embedded in the membrane of the sphere. Mylotarg, which is bound to the part of the receptor enclosed within the sphere, has released its toxic antibiotic (represented by a skull-and-crossbones symbol). The antibiotic has entered the nucleus and damaged the cell's DNA, as shown by a close-up view of a broken DNA strand with a red starburst.

CD33 is expressed on some normal blood cells, but not on stem cells. This means that, although a patient's normal cells may be killed along with the cancer cells, the stem cells will be able to replace the normal cells over time.

More Information

Mylotarg® (gemtuzumab)

Mylotarg® (gemtuzumab ozogamicin) is currently approved by the FDA for treatment of some AML patients who have relapsed and are unable to undergo treatment with standard chemotherapy. It is also being tested in clinical trials for earlier stage AML and other types of cancer.

Vaccines

Overview

Vaccines can also be used to activate a patient's immune system to attack cancer. Unlike monoclonal antibodies and other types of targeted therapies, cancer vaccines do not act directly on cancer cells. Instead, they work systemically to activate the body's immune system.

This image shows a male torso. A vaccine has been administered and purple targeted therapy molecules are circulating through the body's lymphatic system. A close-up view of a lymph node is shown. In it is a clump of green cancer cells. There are also three blue immune cells that have been activated by the vaccine. They are releasing immune substances (multicolored particles). Some of the cancer cells are turning black, indicating they are dying.

No vaccine has yet been approved by the FDA to treat cancer. However, researchers are actively testing several approaches for therapeutic cancer vaccines.

Example: Dendritic Cell Vaccines

One therapeutic cancer vaccine approach takes advantage of a specialized type of immune cell called a dendritic cell.

Dendritic cells detect and chew up foreign "invader" proteins and then "present" pieces of the invaders on their surface.

This is an image of a dendritic cell, which has several arm-like extensions projecting from the main body of the cell. A yellow 'foreign invader' substance (a protein) is being absorbed by the dendritic cell.

Certain populations of killer T cells—another type of immune cell—recognize these foreign pieces and increase in number, creating an army of immune cells to attack cells bearing the invader protein.

In this image, the dendritic cell has processed the foreign invader protein, and pieces of the protein are presented on the extensions of the dendritic cell. An immune cell, labeled 'Killer T Cell', is interacting with several of the dendritic cell extensions. After recognizing pieces of the foreign 'invader' protein, the killer T cell has become activated, as indicated by the fact that it is turning the same color as the invader protein pieces.

To make a dendritic cell vaccine, the blood of the cancer patient is collected and enriched to increase the population of dendritic cells. These cells are then grown in the laboratory in the presence of a protein or part of a protein that is present in or on the patient's tumor cells.

The patient's dendritic cells digest the protein and transport tiny pieces of it to the cell surface. When the dendritic cells are put back into the patient, they signal certain populations of killer T cells to destroy all cells with the telltale protein, including cancer cells.

This image shows three activated killer T cells surrounding a cancer cell that expresses a protein used to make a dendritic cell vaccine against that protein.

Self Test

Questions

  1. The primary mechanism by which Mylotarg® (gemtuzumab) kills cancer cells is by blocking CD33 signaling.
    1. True
    2. False
    Check answer.

  2. Monoclonal antibodies are a type of vaccine.
    1. True
    2. False
    Check answer.

Answers

  1. Correct answer to Question 1: b
    1. True - Incorrect answer. Mylotarg® (gemtuzumab) simply uses CD33 to localize a cytotoxic drug to the cancer cell. It is this cytotoxic drug—not the interaction of Mylotarg® (gemtuzumab) with CD33—that actually kills the cell.
    2. False - Correct answer. The primary mechanism by which Mylotarg® (gemtuzumab) kills cancer cells is the toxic effect of the drug that is conjugated to the antibody.

  2. Go to Question 2.
    Correct answer to Question 2: b
    1. True - Incorrect answer. Antibodies are a form of immunotherapy, but they are not a vaccine. Antibodies are sometimes referred to as passive immunotherapy because they are not produced by the patient's body. In contrast, vaccines involve the administration of a substance that causes the patient's immune system to mount a targeted attack on a specific antigen.
    2. False - Correct answer. Although they are a form of immunotherapy, monoclonal antibodies are not considered vaccines. Antibodies are sometimes referred to as passive immunotherapy because they are not produced by the patient's body. In contrast, vaccines involve the administration of a substance that causes the patient's immune system to mount a targeted attack on a specific antigen