TABLE OF CONTENT

Cancer immunotherapy ........................................................................................................................... 2

1) What is immunotherapy? .................................................................................................................... 2

2) History of Cancer immunotherapy .................................................................................................... 2

3) Types of Cancer immunotherapy ....................................................................................................... 2 3.1) Active Immunity ............................................................................................................................... 2 3.1.1) Active Specific Immunotherapy ................................................................................................... 2 3.1.1.1) Cancer vaccines ........................................................................................................................... 2 3.1.1.1) Dendritic cell vaccines ................................................................................................................ 2 Tumor cell vaccines ..................................................................................................................... 2 Antigen vaccines .......................................................................................................................... 3 Anti-Idiotype vaccines ................................................................................................................ 4 DNA vaccines ............................................................................................................................... 4

3.1.2) Active non-specific immunotherapy ............................................................................................. 5 3.2) Passive Immunotherapy ................................................................................................................... 8 3.2.2) Passive combined immunotherapy ............................................................................................. 11 3.2.2.1) Lymphokine Activated Killer (LAK) Cell Therapy ....................................................... 11 3.2.2.2) Tumor infiltrating lymphocyte (TIL) therapy ................................................................... 11 3.2.2.3) NK Cell Therapy................................................................................................................... 11 4) Some other Cancer immunotherapies .................................................................................................. 12 4.1) Topical immunotherapy ..................................................................................................................... 12 4.2) Natural products ................................................................................................................................. 12

5) Conclusion............................................................................................................................................... 12

Cancer Immunotherapy
1) What is immunotherapy?
Immunotherapy is also sometimes called biologic therapy or biotherapy that uses certain parts of the immune system to fight diseases such as cancer by stimulating your own immune system to work harder or smarter to attack cancer cells & giving you immune system components, such as man-made immune system proteins.

2) History of Cancer immunotherapy

Immunotherapies of cancer began about 100 years ago when in 1922 Dr William Coley, at Sloan Kettering Institute, showed that he could control the growth of some cancers and cure a few advanced cancers with injections of a mixed vaccine of Streptococcal and Staphylococcal bacteria known as Coleys toxin 1, 2.

3) Types of Cancer immunotherapy

There are many types of cancer treatments that could be thought of as immunotherapy. They include 2 basic types namely, active immunotherapy and passive immunotherapy.

Fig.I: Classification of Cancer Immunotherapy 3.

3.1) Active Immunity Active immunotherapy is further classified into two systems of specific immunity and non-specific immunity that cooperates in important ways to form an effective barrier to tumor proliferation. 3.1.1) Active Specific Immunotherapy Active specific immunotherapy includes prophylactic approach towards the metastatic malignant cells. 3.1.1.1) Cancer vaccines Cancer vaccines stimulate the immune system to act in a tumor specific fashion. A cancer vaccine contains cancer cells, parts of cells or pure antigens. The vaccine increases the immune response against cancer cells that are already present in the body. Cancer vaccines cause the immune system to make antibodies to one or several specific antigens and/or make killer T-cells to attack cancer cells that have those antigens 4, 5. Tumor cell vaccines Tumor cell vaccines use cancer cells removed during surgery. The cells are killed, usually by radiation, so they cannot form more tumors. Adding chemicals or new genes often changes them. The cells are then injected into the patient to stimulate a specific immune response so that the immune system attacks similar cancer cells remaining in the body. Vaccines containing tumor cells fused with dendritic cells are also used to further stimulate the immune system. Whole tumor cells are used in vaccines instead of individual antigens, as not all cancer antigens have been identified and this will ensure that the immune system is exposed to a large number of important cancer vaccines, including some that have not been recognized 6. The two basic kinds of tumor cell vaccines are:
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a) Autologous vaccines: An autologous tumor vaccine is made from killed tumor cells taken from the same person in whom they will be used later. These vaccines may be reinjected shortly after surgery or they may be grown in the laboratory or preserved by freezing and reinjected later. But it can be expensive to create a new, unique autologous tumor cell vaccine for each patient. Cancer cells also tend to mutate over time, so an autologous vaccine may become less effective if the cancer cells in the patients body change. b) Allogenic vaccines: These vaccines use cells of a particular cancer type originally taken from another patient. The cells are grown in the laboratory. They are killed and injected along with adjuvant to stimulate the immune system. Some allogenic vaccines use a mixture of cells taken from several patients. Tumor cell vaccines are not routinely used to treat cancer. They are being studied in clinical trials against several types of cancer such as melanoma, ovarian cancer, breast cancer, colorectal cancer, lung cancer and leukemia. Antigen vaccines Antigen vaccines stimulate the immune system by using individual antigens rather than whole tumor cells that contain thousands of antigens. These vaccines are specific for a certain type of cancer. Scientists have unraveled the genetic codes of many antigens, so that they can be mass-produced from synthetic chemicals. It is possible to change the antigens to make them more easily recognized by the immune system. Thus very specific antigens can be given to patients. Often several antigens are combined in a vaccine to produce a response to more than one of the antigens that may be present on the cancer cells. E.g. Breast cancer.

 Anti-Idiotype vaccines Every B lymphocyte or plasma cell produces only one kind of antibody. The unique part of each antibody is called idiotype. The immune system also produces antibodies that treat other antibodies like antigens i.e. some antibodies themselves act as antigens, triggering an immune response. This phenomenon is important in regulating the immune system. Antibodies and antigens fit together like a lock and key so an antibody to a particular idiotype of another antibody (anti-idiotype) will usually look like the antigen that triggered production of the antibody. Due to this, the immune system attacks the anti-idiotype, along with the antigens themselves, when they are injected into the patient. Anti-idiotypes can be mass produced and be cancer specific. These vaccines are not unique for each patient. Researchers consider lymphomas to be the most promising targets for anti-idiotype vaccines. This is because all lymphomas have unique antigen receptors not present on normal lymphocytes. Preliminary studies have yielded promising results. DNA vaccines When antigens or anti-idiotypes are injected into the body as a vaccine, they may produce the desired immune response at first but become less effective over time. This is because antibodies recognize them as foreign and rapidly attach to them, after which the immune system cells destroy them. Without any further stimulation, the immune system returns to normal (pre-vaccine) state. To overcome this drawback a steady supply of antigens is required. DNA present in cells contains the genetic code for the proteins that cells make. Thus, if bits of DNA are injected the cells would take these up and the DNA would instruct them to continuously make specific antigens. These types of therapy are called DNA vaccines. Cells from the body are removed and are treated with the DNA containing instructions for making a particular antigen and are then reinjected into the body. These cells continuously make antigens to produce an immune response. DNA vaccines are being studied in clinical trials for use against melanoma, leukemia, prostate, kidney and head and neck cancer.
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3.1.1.2) Dendritic cell vaccines Dendritic cells are specialized antigen presenting cells (APCs) that help the immune system to recognize cancer cells. They break down the antigens from the cancer cells into smaller pieces and then present them to T-cells, making it easier for the immune system to react and attack them. Dendritic cells are patient specific and must be made individually for each patient. The process used to create them is as follows:

Dendritic cells are removed from the blood and treated in the laboratory so that they reproduce rapidly.

These cells are taught to recognize cancer antigens by exposing them to the antigens in a dish or by genetically modifying them so that they make their own antigens.

Cells are then injected back into the body. The trained dendritic cells are better able to help the immune system to recognize and destroy cancer cells that have those antigens on them.

These vaccines are available through clinical trials. They are being studied for treatment of melanoma, leukemia, non-Hodgkin lymphoma, prostrate, kidney, colorectal, lung and breast cancer 6. 3.1.2) Active non-specific immunotherapy Non-specific immunotherapies do not target a certain cell or antigen. They stimulate the immune system in a very general way, but this may still result in more activity against cancer cells. It utilizes, the components of the non-specific immune system of the body. These components include, cytokines like interleukins, interferons etc. Adjuvants Some non-specific immunotherapies can be given by themselves as cancer treatments. Others are used as adjuvants (along with a main treatment) to boost the immune system to improve how well another type of immunotherapy (such as a vaccine) works.

Cytokines Cytokines are chemicals made by immune system cells. They are crucial in controlling the growth and activity of other immune system cells and blood cells in the body. Man-made versions of some cytokines can be given alone to boost the immune system, or they can be given along with tumor vaccines as adjuvants. Some man-made cytokines are used to lessen the side effects of other treatments such as chemotherapy. They can help the bone marrow make more white blood cells, red blood cells, or platelets when their levels in the body have gotten too low. While this is important in cancer treatment, it isn't truly immunotherapy. Cytokines are injected, either under the skin, into a muscle, or into a vein. The most common ones are discussed here. a) Interleukins Interleukins are a group of cytokines that act as chemical signals between white bloodcells. Interleukin-2 (IL-2) helps immune system cells grow and divide more quickly. When a man-made version of IL-2 was approved by the US Food and Drug Administration in 1992 to treat advanced kidney cancer, it became the first true immunotherapy approved to be used alone in treating cancer. Since that time, it has also been approved to treat people with metastatic melanoma. IL-2 can be used as a single drug treatment for these cancers, or it may be combined with chemotherapy or with other cytokines such as interferon-alfa. Using IL-2 with these treatments might help make them more effective against some cancers, but the side effects of the combined treatment are also increased. Side effects of IL-2 may include flu-like symptoms such as chills, fever, fatigue, and confusion. Most people gain weight, develop low blood pressure, which can be treated with other medicines. Some have nausea, vomiting, or diarrhea. Rare but potentially serious side effects include an abnormal heartbeat, chest pain, and other heart problems.

Other interleukins, such as IL-7, IL-12, and IL-21, are now being studied for use against cancer too, both as adjuvants and as stand-alone agents. b) Interferons These cytokines, first discovered in the late 1950s, help the body resist virus infections and cancers. The types of interferon (IFN) are named after the first 3 letters of the Greek alphabet: IFN-alfa, IFN-beta, and IFN-gamma. Only IFN-alfa is used to treat cancer. It boosts the ability of certain immune cells to attack cancer cells. It may also slow the growth of cancer cells directly, as well as the blood vessels that tumors need to grow. The FDA has approved IFN-alfa for use against Hairy cell leukemia, Chronic myelogenous leukemia, Follicular non-Hodgkin lymphoma, Cutaneous (skin) T-cell lymphoma, Kidney cancer, Melanoma, Kaposi sarcoma. Side effects of interferons may include flu-like symptoms (chills, fever, headache, fatigue, loss of appetite, nausea, vomiting), low white blood cell counts (which increase the risk of infection), skin rashes, and thinning hair. These side effects can be severe and can make treatment with interferon hard to tolerate for many people. Most side effects do not last long after the treatment stops, but fatigue can last longer. Other rare long-term effects include damage to nerves, including those in the brain and spinal cord. c) Granulocyte-macrophage colony-stimulating factor GM-CSF is a cytokine that causes the bone marrow to make more of certain types of immune system cells and blood cells. A man-made version (known as sargramostim or Leukine) is often used to boost white blood cell counts after chemotherapy. GM-CSF is also being tested against cancer as a non-specific immunotherapy and as an adjuvant given with other types of immunotherapies. Clinical trials of GM-CSF, alone or with other immunotherapies, are being done in people with many different types of cancer. Common side effects of GM-CSF include flu-like symptoms (fever, headaches, muscle aches), rashes, facial flushing, and bone pain 7.

3.2) Passive Immunotherapy Passive immunotherapy is composed of antibody therapy and usage of a combination of both active and passive components to generate anti-tumor responses e.g. lymphocyte activated natural killer cells and tumor infiltrating activated T-cells. Passive immunotherapy involves the creation of specific immune elements in a laboratory that are administered to patients to fight cancer. 3.2.1) Monoclonal Antibody Therapy Monoclonal antibody (mAb) therapy is a form of passive immunotherapy because these treatments do not require the persons immune system to take an active role in fighting the cancer 9. Two types of monoclonal antibodies are used in cancer treatments: 1. Naked monoclonal antibodies are those without any drug or radioactive material attached to them. Naked antibodies attach themselves to specific cancer cells. They can be used to mark the cancer cell for the immune system to destroy it. The others attach to certain antigen sites, called receptors, where other molecules that stimulate the cancer cells growth might otherwise attach. By blocking the other molecules from attaching there, the monoclonal antibodies prevent the cancer cells from growing rapidly e.g Trastuzumab (Herceptin), a naked mAb used against breast cancer 8. 2. Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells) 9. Conjugated (tagged/ labeled/ loaded) mAbs are joined to drugs, toxins or radioactive atoms. and are used as delivery vehicles to take those substances directly to the cancer cells. The mAb circulates throughout the body to find a cancer cell with a matching antigen. It delivers the toxic substances to the cancerous cells thus avoiding damage to normal cells. mAbs with chemotherapy drugs attached are termed as chemolabelled. mAbs with radioactive particles attached are radiolabelled and the therapy is known as radio immunotherapy (RIT)
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. mAbs attached to toxins are called immunotoxins

. Antibodies can also be

fused with lipids and polyethylene glycols to enhance in vivo delivery and pharmacokinetics and to direct drug- loaded liposomes 12.
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Table 1: Tumor-associated antigens targeted by monoclonal antibodies

Antibody enzyme fusions have also been developed for pro-drug activation, primarily for cancer therapy 13. Radiolabelled antibodies against tumor-associated molecules have been used for detection of tumors but the method is not more sensitive than modern methods of computerized tomography or nuclear magnetic resonance imaging (NMRI) scan 14. Side effects of the monoclonal antibody therapy include allergic reaction, fever, chill, weakness, headache, nausea, vomiting, diarrhoea, low blood pressure and rashes.

Table 3: Monoclonal antibodies currently FDA-approved in oncology

Limitations of the Passive Antibody Therapy 1. Poor penetration into large tumor masses. This might be overcome by smaller molecules that retain specific antigen binding.

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2. Normal cells expressing a target antigen as well as cells bearing receptors for immunoglobulin carbohydrates bind to antibodies thereby creating problems

of specificity. Chemical modification or genetic engineering of antibodies may overcome these difficulties. 3. Antibodies are immunogenic and maybe attacked by immune system. Humanized antibody can be used to avoid this 16. 3.2.2) Passive combined immunotherapy This therapy involves destruction of cancer cells by cell recruitment of cytotoxic T-cell, natural killer (NK) cells or macrophages that can be targeted by encoding cell surface antibodies 49. It may also include alternative cell recruitment strategies using bifunctional antibodies fused to cytokines for T cell stimulation at tumor site 17. 3.2.2.1) Lymphokine Activated Killer (LAK) Cell Therapy Cancer- fighting T-cells can be produced in the laboratory by treating a small number of T-cells in a test tube with interleukin-2, a cytokine. After being returned to a patients blood stream, these special cells, called LAK cells become effective against cancer cells. LAK cell therapy has shown promising results in animal studies, where shrinkage of tumors of lung, liver was seen 18. 3.2.2.2) Tumor infiltrating lymphocyte (TIL) therapy Tumors contain lymphocytes that have infiltrated the tumor and presumably are taking part in an anti- tumor response. These lymphocytes are obtained from the tumors and expanded in vitro with IL-2.Such activating tumor-infiltrating lymphocytes are

called TILs. The TILs show more specificity towards autologous tumors than LAK. TIL action was studied and used for renal cell carcinomas and malignant melanomas 19. 3.2.2.3) NK Cell Therapy Lymphocytes called Natural killer (NK) cells are not specific as killer T-cells, but are drawn to areas with cancer cells by substances given off by other cells. They attach to
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cancer cells and release substance that split the cells open. After killing the cancer cells, the NK cells then find other cancer cells to attack. Anti-tumor activity of NK cells is still under study 20.

4) Some other Cancer immunotherapies

4.1) Topical immunotherapy Dermatologists use immune enhancement creams and injections which are interferon producer causing the patient's own killer T cells to destroy warts, basal cell carcinoma, squamous cell carcinoma, cutaneous T cell lymphoma, and Superficial spreading melanoma i.e. in the management of benign and malignant skin tumors. 4.2) Natural products Some types of natural products have shown promise to stimulate the immune system. Research suggests that the compounds in medicinal mushrooms like Reishi i.e. a diverse collection of polysaccharide compounds, particularly proteoglucans and beta-glucans are most responsible for up-regulating the immune system and providing an anti-cancer effect by stimulating macrophage, NK cells, T cells, and immune system cytokines & activate the immune system by interacting with the Macrophage-1 antigen (CD18) receptor on immune cells 21, 22.

5) Conclusion
Pharmaceutical companies worldwide are allocating a large part of their capital for finding a cure for cancer, a seemingly incurable disease. The advent of cancer immunotherapy gave fascinating implications in this search. The need of the hour is a synchronized approach to harness the gains made in this field, overcome the drawbacks of immunotherapy and develop a coherent therapy with a high success rate.

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