Fatima Riaz Vaccinology UG-3

The leading immunotherapy against cancer

Cancer or malignant neoplasm has 200 or so types and is associated with the
uncontrollable division of cells followed by the rapid spread of the consequent abnormal cells all over the body (1)

Cancer and the immune system

Abnormal proteins displayed on cancer cells act as the red flags that are picked up by the immune surveillance mechanism and the subsequent activated immune cells act to eliminate these abnormal cells.This protection is not always extended as the cancer cells have adopted certain immune evasion mechanisms which are cited as follows Production of immunosuppressive agents Genetic change resulting in loss of tumor antigens Masking or hiding of tumor antigens The goal of immunotherapy is to assist the immune system in specifically targeting tumor antigens as a means of killing cancer cells (2) Below are listed certain tumor antigens specific to different cancer cell types
Tumor Antigen Carcinoembryonic antigen (CEA) Prostate-specific antigen (PSA) Tyrosinase protein Cancer Colon,breast,lung and pancreatic Prostrate Melanoma

 In contrast to chemotherapy and radiotherapy, cancer vaccines are not associated with any serious side effects and once a specific T cell response is generated against the particular tumor antigen, a group of memory cells will remain in the body, and provide a faster, more efficient response in case of a second threat. Cancer vaccines stimulate the bodys defense against cancer by priming and increasing the response of the immune system.They help mount antigen specific anti tumor responses that assists in the clearance of the mutated cancer cell from the body. There are two broad types of cancer vaccines: Preventive (or prophylactic) vaccines, which are intended to prevent cancer from developing in healthy people; and Treatment (or therapeutic) vaccines, which are intended to treat an existing cancer by strengthening the bodys natural defenses against the cancer (3)

 Their function principally resembles that of generic vaccines administered against an infectious agent.They prevent the occurrence of chronic viral, bacterial and parasitic infections that cause or contribute to cancer. Their major drawback is that they are only useful against cancers caused by infections as they do not target cancer cells directly. Microbes contribute to between 15 percent and 25 percent of all cancers diagnosed worldwide each year, with the percentage being lower in developed than developing countries.Some microbes and their associative cancers are listed as follows (3) Infectious agent hepatitis B virus (HBV) Epstein-Barr virus Organism type virus virus Associative cancer hepatocellular carcinoma Burkitt lymphoma; non-Hodgkin lymphoma;Hodgkin lymphoma; nasopharyngeal carcinoma stomach cancer; mucosa-associated lymphoid tissue (MALT) lymphoma bladder cancer

Helicobacter pylori

bacterium

schistosomes (Schistosoma parasite hematobium)

Cervical cancer vaccines

The U.S. Food and Drug Administration (FDA) has approved two vaccines that prevent infection of the Human Papillomavirus (HPV) type 16 and 18, which cause 70% of all cervical cancers Gardasil - Produced by Merck and Company and FDA approved in 2009, it is employed for the prevention of HPV types 6, 11, 16 and 18 in young women aged 9-26. It also prevents genital warts caused by HPV types 6 and 11 in young men . Gardasil, is a quadrivalent vaccine manufactured from 4 different types of virus like particles (or VLPs) that correspond to HPV types 6,11,16 and 18. Cervarix -Produced by GlaxoSmithKline and approved in 2009.It is a bivalent vaccine composed of VLPs made with proteins from HPV types 16 and 18.(4)

Hepatocellular carcinoma vaccines

Chronic infections with Hepatitis viruses are the leading cause of hepatocellular carcinoma. Engerix- B Produced by GlaxoSmithKline and approved in 1989, it is composed of noninfectious hepatitis B virus surface antigen (HBsAg) and is administered intramuscularly.It contains purified surface antigen of the virus obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus. (5)

Cancer treatment vaccines work closely with the immune system to treat cancers that have already developed. They help launch a specific ,long lasting response against the tumor cells by activating both CD4 and CD8 T cell responses.CD8 T cells are cytotoxic cells that directly kill cancer cells while CD4 or helper T cells support CD8 and B cells by reinforcing their activity with the help of chemical messengers. Non specific cells like natural killer cells and macrophages can also be spurred into action with the help of cancer vaccines.(2) A successful cancer vaccine must delay or stop cancer cell growth; cause tumor shrinkage; prevent cancer from reappearing; eliminate cancer cells that have not been killed by other forms of treatment. Cancer vaccines come in last as a form of cancer treatment to ensure there is no residual cancer left after surgery and to further enforce immune memory cells against a possible relapse. .
Diagnosis Surgery Tumor vaccination Treatment

Therapeutic vaccines

Whole cell

Soluble vaccines

Self (Autologous)

Donor(Allogenic)

Dendritic cell

1. Whole cell vaccines employ the use of whole inactivated tumor cells to help overcome the ambiguity of the various tumor antigens, most of which remain unknown.These inactivated tumor cells have a range of abnormal tumor proteins to which the patients immune cells respond by generating an anti-tumor response and clearing any persisting cancer cells after surgery. Autologous Vaccines: The tumor cells used in whole cell vaccines can be derived from the patients own (self or autologous) tumor after it has been removed during surgery. Allogenic Vaccines :Alternatively, these tumor cells can be obtained from a tumor sample removed from another individual with the same cancer type Dendritic Cell Vaccines: Dendritic cells are finger-like cells that pick up proteins from tumor cells (antigens) or invading organisms (bacteria, viruses, and parasites), and process and present them to young lymphocytes . Dendritic cell cancer vaccines are safe and well tolerated in humans. (3,6) 2. Synthetic protein antigens or soluble vaccines are mass-produced synthetic versions of abnormal proteins displayed by tumors, and can generate immune responses capable of destroying cells in the body that display these antigens . This type of vaccination is given to patients with immune system boosters (adjuvants).(7)

 Sipuleucel-T (Provenge),-manufactured by Dendreon and approved in 2010 , is approved for use in some men with metastatic prostate cancer, who are no longer responding to hormonal treatments. It is designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells. Unlike some other cancer treatment vaccines under development, sipuleucel-T is customized to each patient. The vaccine is created by isolating antigen-presenting cells (APCs) from a patients blood through a procedure called leukapheresis. The APCs are sent to Dendreon, where they are cultured with a protein called PAP-GM-CSF. This protein consists of PAP linked to another protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). The latter protein stimulates the immune system and enhances antigen presentation.(8)

 Vaccines intended to prevent or treat cancer appear to have safety profiles comparable to those of traditional vaccines but this trend is a varying one that differs from person to person and among vaccine formulations. The most commonly reported side effect of cancer vaccines is inflammation at the site of injection, including redness, pain, swelling, warming of the skin, itchiness, and occasionally a rash. People sometimes experience flu-like symptoms after receiving a cancer vaccine, including fever, chills, weakness, dizziness, nausea or vomiting, muscle ache, fatigue, headache, and occasional breathing difficulties. Blood pressure may also be affected. Other, more serious health problems have been reported in smaller numbers of people after receiving a cancer vaccine. These problems may or may not have been caused by the vaccine. The reported problems have included asthma, appendicitis, pelvic inflammatory disease, and certain autoimmune diseases, including arthritis and systemic lupus erythematosus. Vaccines, like any other medication affecting the immune system, can cause adverse effects that may prove life threatening. For example, severe hypersensitivity (allergic) reactions to specific vaccine ingredients have occurred following vaccination. However, such severe reactions are quite rare.(3)