1.  What is a cancer vaccine?

Cancer vaccines are intended either to treat existing cancers (therapeutic vaccines) or to prevent the development of cancer (prophylactic vaccines). Both types of vaccines have the potential to reduce the burden of cancer. Treatment or therapeutic vaccines are administered to cancer patients and are designed to strengthen the body's natural defenses against cancers that have already developed. These types of vaccines may prevent the further growth of existing cancers, prevent the recurrence of treated cancers, or eliminate cancer cells not killed by prior treatments. Prevention or prophylactic vaccines, on the other hand, are administered to healthy individuals and are designed to target cancer-causing viruses and prevent viral infection.

2.  Is any cancer vaccine currently available in the United States?

Yes. The single cancer vaccine licensed by the Food and Drug Administration is a prophylactic vaccine against hepatitis B virus, an infectious agent associated with liver cancer. There are no licensed therapeutic vaccines to date. However, several treatment vaccines are in large-scale testing in humans. If clinical trial results are favorable, additional cancer vaccines may be approved for use in the United States within the next few years.

3.  How are therapeutic vaccines designed to treat cancer?

Vaccines used to treat cancers take advantage of the fact that certain molecules on the surface of cancer cells are either unique or more abundant than those found on normal or non-cancerous cells. These molecules, either proteins or carbohydrates, act as antigens, meaning that they can stimulate the immune system to make a specific immune response. Researchers hope that when a vaccine containing cancer-specific antigens is injected into a patient, these antigens will stimulate the immune system to attack cancer cells without harming normal cells.

4.  Why does the immune system need a vaccine to help fight cancer?

The immune system generally doesn't "see" tumors as dangerous or foreign, and doesn't mount a strong attack against them. One reason tumor molecules do not stimulate an effective immune response may be that tumor cells are derived from normal cells. So, even though there are many molecular differences between normal cells and tumor cells, cancer antigens are not truly foreign to the body, but are normal molecules, either altered in subtle ways or more abundant.

Another reason tumors may not stimulate an immune response is that cancer cells have developed ways to escape from the immune system. Scientists now understand some of these tricks, which include shedding tumor antigens, and reducing the number of molecules and receptors that the body normally relies on to activate T cells (specific immune cells) and other immune responses. Reducing these molecules makes the immune system less responsive to the cancer cells; the tumor become less "visible" to the immune cells. Hopefully, this knowledge can be used by researchers to design more effective vaccines.

5.  What strategies are used to design effective cancer treatment vaccines?

Researchers have developed several strategies to stimulate an immune response against tumors. One is to identify unusual or unique cancer cell antigens that are rarely present on normal cells. Other techniques involve making the tumor-associated antigen more immunogenic, such as (a) altering its amino acid structure slightly, (b) placing the gene for the tumor antigen into a viral vector (a harmless virus that can be used as a vehicle to deliver genetic material to a targeted cell), and (c) adding genes for one or more immuno-stimulatory molecules into vectors along with the genes for the tumor antigen. Another technique is to attach something that is definitely foreign, known as an adjuvant, to tumor molecules (see Question 8). By using the adjuvant as a decoy, the immune system may be tricked into attacking both the antigen/adjuvant complex (the vaccine) and the patient's tumor.

6.  What types of treatment vaccines are currently under investigation?

The types of vaccines listed below represent various methods investigators have devised for presenting cancer antigens to the body's immune system. This list is not meant to be comprehensive.

Antigen/adjuvant vaccines
Antigen vaccines were some of the first cancer vaccines investigated. Antigen vaccines commonly use specific protein fragments or peptides to stimulate the immune system to fight tumor cells. One or more cancer cell antigens are combined with a substance that causes an immune response, known as an adjuvant. A cancer patient is vaccinated with this mixture. It is expected that the immune system, in responding to the antigen-carrying adjuvant, will also respond to tumor cells that express that antigen.

Whole cell tumor vaccines
Taken either from the patient's own tumor (autologous) or tumor cells from one or more other patients (allogeneic), these whole cell vaccine preparations contain cancer antigens that are used to stimulate an immune response.

Dendritic cell (DC) vaccines
Specialized white blood cells known as dendritic cells (DCs) are taken from a patient's blood through a process called leukapheresis. In the laboratory, the DCs are stimulated with the patient's own cancer antigens, grown in petri dishes, and re-injected into the patient. Once injected, DC vaccines activate the immune system's T cells. Activation by DCs is expected to cause T cells to multiply and attack tumor cells expressing that antigen.

Viral vectors and DNA vaccines
Viral vectors and DNA vaccines use the nucleic acid sequence of the tumor antigen to produce the cancer antigen proteins. The DNA containing the gene for a specific cancer antigen is manipulated in the laboratory so that it will be taken up and processed by immune cells called antigen-presenting cells (APCs). The APC cells then display part of the antigen together with another molecule on the cell surface. The hope is that when these antigen-expressing APC cells are injected into a person, the immune system will respond by attacking not only the APC cells, but also tumor cells containing the same antigen. Vector-based and DNA vaccines are attractive because they are easier to manufacture than some other vaccines.

Idiotype vaccines
Since antibodies are molecules containing protein and carbohydrate, they can themselves act as antigens and induce an antibody response. Antibodies produced by certain cancer cells (i.e., B-cell lymphomas and myelomas), called idiotype antibodies, are unique to each patient and can be used to trigger an immune response in a manner similar to antigen vaccines.

7.  Which antigens are commonly found in cancer vaccines?

Treatment Vaccines

Patient-specific vaccines use a patient's own tumor cells to generate a vaccine intended to stimulate a strong immune response against an individual patient's malignant cells. Each therapy is tumor-specific so, in theory, cells other than tumor cells should not be affected. There are several kinds of patient-specific vaccines that use antigens from a patient's own tumor cells but deliver the antigen differently.

Prostate Specific Antigen (PSA) is a prostate-specific protein antigen that can be found circulating in the blood as well as on prostate cancer cells. PSA is present in small amounts in men who do not have cancer, but the quantity of PSA generally rises when prostate cancer develops. Patients have been shown to mount T-cell responses to PSA.

Sialyl Tn (STn) is a small, synthetic carbohydrate that mimics the mucin molecules (the primary molecule present in mucus) found on certain cancer cells.

Heat Shock Proteins (HSPs) (e.g., gp96) are produced in cells in response to heat, low sugar levels and other stress signals. Besides protecting against stress, these molecules are also involved in the proper processing, folding, and assembling of proteins within cells. In laboratory experiments, HSPs from mouse tumors, in combination with small peptides, protected mice from developing cancer. The human vaccine consists of heat shock protein and associated peptide complexes isolated from a patient's tumor. HSPs are under investigation for treatment of several cancers including liver, skin, colon, lung, lymphoma and prostate cancers.

Ganglioside molecules (e.g., GM2, GD2, and GD3) are complex molecules containing carbohydrates and fats. When ganglioside molecules are incorporated into the outside membrane of a cell, they make the cell more easily recognized by antibodies. GM2 is a molecule expressed on the cell surface of a number of human cancers. GD2 and GD3 contain carbohydrate antigens expressed by human cancer cells.

Carcinoembryonic antigen (CEA) is found in high levels on tumors in people with colorectal, lung, breast and pancreatic cancer as compared with normal tissue. CEA is thought to be released into the bloodstream by tumors. Patients have been shown to mount T-cell responses to CEA.

MART-1 (also known as Melan-A) is an antigen expressed by melanocytes -- cells that produce melanin, the molecule responsible for the coloring in skin and hair. It is a specific melanoma cancer marker that is recognized by T cells and more abundant on melanomas than normal cells.

Tyrosinase is a key enzyme involved in the initial stages of melanin production. Studies have shown that tyrosinase is a specific marker for melanoma and more abundant on melanomas than normal cells.

Prevention Vaccines

Viral proteins on the outside coat of the cancer-causing viruses are commonly used as antigens to stimulate the immune system for prevention vaccines.

8.  What are adjuvants? Which adjuvants are commonly used in treatment vaccines?

To heighten the immune response to cancer antigens, researchers usually attach a decoy substance, or adjuvant, that the body will recognize as foreign. Adjuvants are weakened proteins or bacteria which "trick" the immune system into mounting an attack on both the decoy and the tumor cells. Several adjuvants are described below:

Keyhole limpet hemocyanin (KLH) is a protein made by a shelled sea creature found along the coast of California and Mexico known as a keyhole limpet. KLH is a large protein that both causes an immune response and acts as a carrier for cancer cell antigens. Cancer antigens often are relatively small proteins that may be invisible to the immune system. KLH provides additional recognition sites for immune cells known as T-helper-cells and may increase activation of other immune cells known as cytotoxic T-lymphocytes (CTLs).

Bacillus Calmette Guerin (BCG)is an inactivated form of the tuberculosis bacterium routinely used for decades to vaccinate against TB. BCG is added to some cancer vaccines with the hope that it will boost the immune response to the vaccine antigen. It is not well understood why BCG may be especially effective for eliciting immune response. However, BCG has been used for years with other vaccines, including the vaccine for tuberculosis.

Interleukin - 2 (IL-2) is a protein made by the body's immune system that may boost the cancer-killing abilities of certain specialized immune system cells called natural killer cells. Although it can activate the immune system, many researchers believe IL-2 alone will not be enough to prevent cancer relapse. Several cancer vaccines use IL-2 to boost immune response to specific cancer antigens.

Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF) is a protein that stimulates the proliferation of antigen-presenting cells.

QS21 is a plant extract that, when added to some vaccines, may improve the immune response.

Montanide ISA-51 is an oil-based liquid intended to boost an immune response.

9.  Why are some vaccines used to treat specific kinds of cancer?

Many cancer vaccines treat only specific types of cancers because they target antigens found on specific cancers. For example, a vaccine against prostate cancer may be able to attack cancer cells within the prostate itself or cells that have spread to other parts of the body, but would not affect cancers originating in other tissues.

Vaccines that target antigens found on several different kinds of cancer cells are used to treat multiple cancers. The effectiveness of the vaccine would be expected to differ according to the amount of antigen on different kinds of cancer cells. Researchers also are investigating a possible "universal" cancer vaccine that might cause an immune response against cancer cells that originate from any tissue.

10.  Are there vaccines under development to prevent cancer?

Yes, some vaccines currently under investigation have the potential to reduce the risk of cancer. These vaccines target infectious agents that cause cancer and are similar to traditional prophylactic vaccines, which target other disease-causing infectious agents such as those that cause polio or measles. Non-infectious components of cancer-causing viruses, commonly the viral coat proteins (proteins on the outside of the virus), serve as antigens for these vaccines. It is hoped that these antigens will stimulate the immune system in the future to attack cancer-causing viruses, which should, in turn, reduce the risk of the associated cancer.

For example, the human papilloma virus (HPV) causes nearly all cases of cervical cancer. Preventing infection by HPV is expected to dramatically reduce the risk of cervical cancer. One promising vaccine against HPV is expected to enter large-scale human trials in the near future. Another promising prevention vaccine targets the hepatitis C virus, linked to the development of liver cancer.

11.  Which vaccines have reached Phase III testing?

The results from ongoing Phase III trials, listed in the table on the next page, will determine whether vaccines will play a role in the treatment and prevention of different cancers. The information is derived from government databases including the National Cancer Institute's clinical trials database, http://cancer.gov/search/clinical_trials/, and the National Institute's of Health clinical trials Web site, http://clinicaltrials.gov. Information on each trial can also be obtained by clicking the link in the far right column of the chart on the next page.

Further information about cancer vaccines can be found at: http://www.nci.nih.gov/clinicaltrials/understanding/treating-cancer-with-vaccine-therapy.

Type of Cancer Prevented	Title of Study	Vaccine Name (if applicable)	Lead Institution	Nature of Vaccine	Purpose of the Study	Start Date and Links
Breast	Study of Theratope Vaccine in Metastatic Breast Cancer Patients	Theratope	Biomira Inc.EMD Pharmaceuticals Merck KGaA	Theratope vaccine contains a synthetic version of a carbohydrate antigen, sialyl Tn, (STn), which is frequently found on the outer surface of many cancer cells. Synthetic STn is fused to KLH to promote an immune response.	Compare disease progression and survival of women being treated with aromatase inhibitors or Faslodex to those treated with Theratope plus aromatase inhibitors or Faslodex.	2001 NCT00046371
Follicular B-cell Non-Hodgkin's Lymphoma	Randomized Trial of Patient-specific Vaccination With Conjugated Follicular Lymphoma-derived Idiotype With Local GM-CSF in First Complete Remission	Not Named	National Cancer Institute	The vaccine is composed of portions of antibodies that are unique to a patient's own tumor cells. These iodiotype proteins are chemically attached to KLH. GM-CSF is used to enhance the immune response.	To compare two vaccination groups: Group I patients receive injections of the vaccine plus GM-CSF. Group II patients receive injections containing only KLH and GM-CSF.	January 2000 www.ncilymphomavaccine.org Protocol:00-C-0050
Follicular B-cellNon-Hodgkin's Lymphoma	Combination Chemotherapy Followed by Vaccine Therapy Plus Sargramostim in Treating Patients With Stage III or Stage IV Non-Hodgkin's Lymphoma	GTOP-99	Genitope Corporation	The vaccine consists of portions of antibodies that are unique to a patient's tumor. This idiotype protein is chemically attached to the adjuvant protein, KLH. GM-CSF (Sargramostim) is also used to enhance the immune response.	To evaluate time to tumor progression in patients who receivevaccines compared to controls who receive adjuvant alone and GM-CSF alone.	November 2000 NCT00017290
Kidney	Survival Study of Oncophage® vs. Observation in Patients With Kidney Cancer	Oncophage (HSPPC-96)	Antigenics	The vaccine -- heat shock proteins(gp 96 ) and associated peptides -- is made from individual patients' tumors.	To determine whether patients receiving Oncophage treatment for surgically removed non-metastatic renal cell carcinoma survive longer than patients who do not receive vaccine treatment.	December 2002 NCT00033904
Lung	Survival in a Randomized Phase III Trial in Patients With LD Small Cell Lung Cancer Vaccinated With Adjuvant BEC2 and BCG	BEC2 Vaccine	European Cooperative (EORTC)	The vaccine contains a mouse antibody engineered to resemble the human protein GD3 ganglioside, found on small cell lung cancers. The vaccine combines the antibody, BEC2, with the adjuvant, BCG.	To determine whether vaccinated patients survive longer than patients who do not receive vaccine.	September 1998 NCT00037713
Melanoma	Study of Heat Shock Protein-Peptide Complex (HSPPC-96) vs. IL-2/DTIC for Stage IV Melanoma	Oncophage (HSPPC-96)	Antigenics	The vaccine -- heat shock proteins and associated peptides -- is made from individual patient's tumor.	To determine if people with metastatic melanoma who receive Oncophage after surgery live longer than people who may or may not have surgery but who receive conventional chemotherapy including interleukin-2 /dacarbazine/temozolomide-based therapy.	March 2002 NCT0003900
Melanoma	Vaccine Therapy in Treating Patients With Primary Stage II Melanoma	Not Named	European Cooperative (EORTC)	The vaccine consists of GM2, a common antigen on melanoma cells, which is conjugated to the adjuvant, KLH. QS21 is used to enhance the immune response.	To compare the disease-free and overall survival of stage II melanoma patients receiving the vaccine to those not receiving the vaccine.	February 2002 NCT00005052
Melanoma	Vaccine Therapy in Treating Patients With Melanoma of the Eye	Not Named	European Cooperative (EORTC)	The vaccine contains several melanoma differentiation peptides.	To determine the effectiveness of vaccine therapy in preventing liver metastasis and increasing survival in patients at high risk for recurrent melanoma of the eye.	February 2002 NCT00036816
Melanoma	Vaccine Therapy and/or Sargramostim in Treating Patients With Locally or Advanced Metastatic Melanoma	Not Named	National Cancer Institute	The vaccine contains a combination of 3 melanocyte-specific antigens: tyrosinase, gp100, and MART. GM-CSF (Sargramostim) is used to enhance the immune response.	To determine the effectiveness of peptide vaccine therapy and/or GM-CSF in treating patients with locally advanced or metastatic melanoma.	December 1999 NCT00005034
Melanoma	Vaccine Therapy Compared With Interleukin-2 and/or Chemotherapy in Treating Patients With Stage IV Melanoma	Heat Shock protein-peptide complex (HSPCC-96)	Jonsson Comprehensive Cancer Center	Heat shock protein gp96 plus associated peptides is prepared from surgically removed melanoma tissue.	To compare the effectiveness of heat shock protein vaccine to IL-2 therapy and/or chemotherapeutic agents, dacarbazine and temozolomide.	October 2002 NCT00047359
Melanoma	A Phase III Multi-Institutional Randomized Study of Immunization With the gp100: 209-217 (210M) Peptide Followed by High Dose IL-2 vs. High Dose IL-2 Alone in Patients With Metastatic Melanoma	Not Named	National Cancer Institute	The vaccine contains gp100, IL-2, and Montanide ISA-51. Montanide ISA-51 is an oil used to enchance the immune response.	Since high dose IL-2 is currently approved by the FDA for treating patients with metastatic melanoma, the protocol will compare the use of the vaccine plus IL-2 to L-2 alone.	February 1999 NCT00001801
Multiple Myeloma	Active Immunization of Sibling Bone Marrow Transplant Donors Against Purified Myeloma Protein of the Recipient Undergoing Allogeneic Bone Marrow Transplantation	Not Named	National Cancer Institute	Patient-derived vaccine consists of the myeloma immunoglobulin idiotype protein attached to KLH. GM-CSF is used to enhance the immune response.	Bone marrow transplantation is used to treat multiple myeloma. In one group, both the donor and recipient of bone marrow transplant are vaccinated with the patient-derived vaccine before transplantation. This group is compared to one where only patients (recipients of transplant) receive the vaccine. The goal is to see if the added immune boost to the donor can be transferred to the recipient to enhance the anti-tumor effect of the vaccine.	November 1996 NCT00001561
Prostate	Vaccine Therapy in Treating Patients With Metastatic Prostate Cancer		Northwest Biotherapeutics	Cells from patient's blood (peripheral blood mononuclear cells) plus interleukin-4 and GM-CSF are used to generate dendritic cells, which are then treated with the adjuvant BCG and stimulated with prostate-specific membrane antigen.	To compare disease progression and survival in patients receiving dendritic vaccines to those receiving peripheral blood mononuclear cells.	November 2002 NCT00043056

Type of Cancer Prevented	Title of Study	Vaccine Name (if applicable)	Lead Institution	Nature of Vaccine	Purpose of the Study	Start Date
Cervival Cancer		HPV (human papilloma virus) quadravalent vaccine	Merck & Co., Inc.	The HPV quadravalent vaccine contains viral proteins from four HPV strains: HPV 16 & 18, the types that account for about2/3 of the world-wide cases of cervical cancer, and HPV 6 & 11, the types most commonly associated with genital warts.	To see whether the vaccine prevents HPV cervicalinfection and precancerous cervical lesions.	2002 Merck public information: (215) 652-0059

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