Chapter 3. Cancer Vaccines

Vaccines have been exceptionally effective against a number of diseases and have become one of the safest and most cost-effective weapons in medicine's arsenal against communicable disease. Vaccines generally induce both T cell and B cell responses.

Like vaccines that prevent infectious diseases, cancer vaccines work by stimulating the immune system to build an army of cells that recognize, attack, and kill the cancer cells. Differing from the vaccines for infectious diseases, most of the investigational cancer vaccines are designed for therapeutic purposes. It is very important to use tumor-specific or tumor associated antigens (proteins) displayed on tumor cells but not normal cells so that the induced immunity is directed against tumor cells.

Table 3. Cancer Vaccines

There are two classes of cancer vaccine, prophylactic and therapeutic. Prophylactic cancer vaccine is used to prevent occurrence of cancer. There are a number of pathogens which are known to cause cancers and these pathogens include human papilloma virus, hepatitis virus, Epstein-Bar virus, human T-cell leukaemia virus, helicobactor pylori, and human immunodeficiency virus etc. Cervical cancer vaccines, Cervarix and Gardasil, are prophylactic vaccine. Human papillomavirus (HPV) is the causative agent of cervical cancer. Cervarix and Gardasil are used to generate immune response and prevent the HPV infection, thus prevent development of cervical cancer. These two vaccines are based on virus-like particle (VLP) technology. The VLP is a structurally identical, non-infectious form of the virus.

Therapeutic cancer vaccine is used for treatment after cancer is developed. Majority of the cancer vaccines under development are therapeutic. So far, there are three therapeutic cancer vaccines reached market in limited countries. They are Avax Technologies' M-Vax, Corixa's Melacine, and IntraCel's OncoVax. M-Vax consists of autologous melanoma cells conjugated to a highly immunogenic hapten, dinitrophenyl, which makes the cancer cells more easily recognized by the immune system. Melacine contains lysed (broken) cells from two human melanoma cell lines combined with adjuvant, including monophosphoryl lipid A (MPL) and mycobacterial cell wall skeleton, both of which activate the human immune system in the context of vaccination. OncoVax is made of autologous colon cancer cells. However, these three therapeutic vaccines have performed poorly, and have only been marketed in limited geographic territories. M-Vax was marketed in Australia in 2000 and launched in Switzerland in October 2005, but was withdrawn from Australia in September 2002. Melancine was marketed in Canada in 2001, but was discontinued in Canada in July 2005, and is thus no longer marketed in any territory worldwide. OncoVax was marketed in Germany, Holland, and Switzerland in 2003. The reasons for the vaccine's failure of achieving commercial success may include: complex and expensive manufacturing procedure, lack of reimbursement status, lack of confidence in the vaccine, and extremely disappointing sales.

A number of cancer vaccine are made of whole tumor cells. The whole cell vaccine may stimulate a stronger immune response than other immunotherapy approaches that use cell fragments, peptides or antigens alone. These whole cancer cells have been irradiated to prevent replication, but they continue to produce antigens and stimulate the immune system for a period of days to weeks after they have been injected into a patient. In contrast, cell fragments, peptides and antigens are more likely to rapidly degrade in the body, which minimizes their ability to stimulate the immune system against cancer.

The whole cells also expose the immune system to multiple antigens that are associated with a wide range of solid tumors. These antigens appear in unpredictable patterns and concentrations among different people and within an individual's cancer as it evolves over time. The presentation of numerous antigens, termed polyvalence, is an important element in eliciting a therapeutic immune response in most patients and reducing a tumor cell's ability to escape the immune response. For example, Canvaxin contains at least 38 antigens that may be associated with tumor and may induce immune responses against tumor. However, Canvaxin was found no evidence of overall survival benefit for stage III melanoma compared to placebo. GVAX are comprised of tumor cells that have been irradiated and genetically modified to secrete granulocyte macrophage-clony stimulation factor (GM-CSF), an immune stimulating hormone, which activates the immune system to recognize and destroy the cancer cells.

A number of vaccines are based on the tumor associated antigens. BLP25 is synthetic MUC1 peptide vaccine, a liposomal vaccine specifically designed to generate a cellular immune response to the tumor associated antigen mucin MUC1. Theratope contains a synthetic form of a cancer-associated carbohydrate antigen, Sialyl Tn (STn). However, the phase III results indicated that the drug failed to improve survival. GMK incorporates an immune stimulant or adjuvant and the GM2 ganglioside, a cancer antigen present in approximately 95% of melanoma cells. MyVax Personalized Immunotherapy combines a protein derived from the patient's own tumor with an immunologic carrier protein keyhole limpet hemocyanin (KLH) and is administered with GM-CSF as an adjuvant.

Allovectin-7 is a DNA plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ࢸ microglobulin, which together form a Major Histocompatibility Complex, or MHC, Class I antigen. This type of antigen can trigger a potent immune response against cancer cells. Allovectin-7 is injected directly into tumors, and is designed to make malignant cells more visible to the immune system. The treatment may trigger an immune response against tumor cells, both locally and systemically, by enabling the immune system to recognize tumor cells.

Avicine, a therapeutic cancer vaccine, is a synthetic peptide formulation designed to elicit an anti-human chorionic gonadotropin (hCG) immune response targeting hCG-producing cancer cells. This peptide is composed of carboxy terminal 37 amino acids (CTP-37) of the beta-subunit of hCG that has been conjugated to diphtheria toxoid. It is effective in stimulating an immune response to hCG that does not cross-react with related glycoprotein hormones. hCG is a biochemical marker of malignancy associated with all the major types of cancer. The expression of hCG has been shown to correlate with tumor aggressiveness, i.e., the greater the hCG expression, the more aggressive the tumor. The antibody can be used to neutralize hCG, reduce level of hCG, and thus, inhibit tumor growth.