1/9/16

CTLA-4

Cytotoxic T lymphocyte-associated antigen-4

cancer immunoediting

a dynamic process composed of three phases: elimination, equilibrium, and escape. Elimination represents the classical concept of cancer immunosurveillance. Equilibrium is the period of immune-mediated latency after incomplete tumor destruction in the elimination phase. Escape refers to the final outgrowth of tumors that have outstripped the immunological restraints of the equilibrium phase.

Allogeneic

coming from another patient. These vaccines use cells of a particular cancer type that originally came from a cancer patient.

PD-1

programmed death receptor-1

Tumor associated antigens (TAA) on viral tumors

A number of viruses cause different types of tumors in animals (HPV, EBV). Virus-induced tumors express cell surface antigens, which are shared by all tumors induced by the same virus. These antigens are characteristic of the tumor-inducing virus, regardless of tissue origin of the tumor or animal species in which the tumor exists.

Naked Monoclonal Antibodies

Attach themselves to specific antigens on cancer cells. Can be used in different ways: -Some mark the cancer cell for the immune system to destroy it -Others attach to certain receptors, where other molecules that stimulate the cancer cells' 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. TRASTUZUMAB (HERCEPTIN) is a naked MAb used against advanced breast cancer and works in this way.

Chronic HIV Infection

Continued viral replication and persistent immune activation during chronic infection soon leads to the exhaustion of T cells. Studies in chronic viral infections, like HIV

LAK cells

IL-2 enhances the tumoricidal activity of both NK cells and killer T cells to produce what are called lymphokine-activated killer cells (LAK) cells. The infusion of autologous LAK cells has produced clinical remissions in some cancer patients.

Interferons

Important in the body's resistance to virus infections and cancers. Some interferons directly slow the growth of cells in many cancers. Others can slow down angiogenesis, the growth of new blood vessels that tumors must have to continue to grow. Still other properties of interferons result in cancer cells producing more antigens, making them easier for the immune system to recognize and destroy. Interferons can also boost the ability of NK cells and cytotoxic T cells

Tumor antigens

In order for the immune system to react against a tumor, the latter must have antigens that are recognized as foreign. Tumor-associated antigen (TAA): an antigen that is relatively restricted to tumor cells Tumor-specific antigen (TSA): antigen unique to tumor cells

DNA Vaccines

Known individual tumor antigens could be synthesized (as peptides) and used as vaccines to stimulate the immune system instead of using whole tumor cells that contain many thousands of antigens. While antigen vaccines may be specific for a certain type of cancer, they are not made for a specific patient like autologous cell vaccines. This type needs to either be infused regularly or have DNA inserted into cells so that it would continually be produced.

Dendritic Cell Vaccines

Like autologous cell vaccines, are patient-specific and must be made individually for each patient.

Monoclonal Antibody Therapy (Passive immunotherapy)

Monoclonal antibody therapy is a passive immunotherapy because the antibodies are produced in large quantities outside the body rather than by the immune system. This type of therapy can be effective even if the immune system is weakened. These treatments do not require the immune system to take an "active" role in fighting the cancer. Antibodies are mass-produced in the lab and can be made to react with specific antigens on certain types of cancer cells. NAKED monoclonal antibodies are those without any drug or radioactive material attached to them CONJUGATED monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells)

Alemtuzumab

Naked, antibody against the CD52 antigen, which is present on both B and T cells. It is used to treat B cell chronic lymphocytic leukemia (B-CLL) in patients who have already had chemotherapy

Cetuximab

Naked, antibody against the EGFR protein, which is present in high amounts on some tumor cells. It is used along with the chemotherapy drug irinotecan to treat advanced colorectal cancer

Trastuzumab

Naked, antibody against the HER2 protein, which is present in large numbers on cells in some cases of breast cancer. Used to treat advanced cases of the disease

Rituximab

Naked, used to treat B cell non-Hodgkin's lymphoma. it contains a monoclonal antibody against the CD20 antigen, found on B cells

Bevacizumab

Naked, works against the VEGF protein, which normally helps tumors develop new blood vessels in order to get nutrients. This antiangiogenesis therapy is used along with chemotherapy to treat metastatic colorectal cancer

TIM-3

T cell immunoglobulin domain and mucin domain 3. Associated with a hierarchical loss of T cell funciton: Decreased proliferation of T cells Decreased cytolytic activity Decreased secretion of inflammatory cytokines

Tumor vaccine

Take tumor cell removed via surgery, kill it via radiation, inject into host along with non-specific adjuvants. One reason for using whole tumor cells in vaccines, instead of individual antigens, is that not all cancer antigens have been identified yet. using the whole tumor cell ma expose the immune system to a large number of important cancer antigens, including som ethat have not yet been recognized.

Immune effectors in response to tumors

The T cell is the primary cell thought to be responsible for direct recognition and killing of tumor cells. T cells carry out an immunological surveillance, destroying newly transformed tumor cells after recognizing TAA. They recognize intracellular material presented via an APC (and therefore the peptide presented need not be a cell surface peptide). CTLs kill cells with the foreign antigen. Natural killer (NK) cells, which can kill tumor cells, are also found in persons without tumors. They do not require prior sensitization, and lack MHC restriction. NK cells also mediate antibody dependent cell-mediated cytotoxicity (ADCC). The cytotoxic activity of NK cells is increased by various interferons, IL-15, and IL-2. Macrophages can kill specific tumor cells when activated in the presence of TAA, cytokines produced by T cells, or interferon-gamma. Macrophages have natural cytolytic activity against tumor cells, in either the absence or presence of T cells, and also mediate antibody-dependent cellular cytotoxicity (ADCC). Macrophages are less effective than T cell-mediated cytotoxic mechanisms Dendritic cells are of the utmost importance! They present antigens and are present in the barrier tissues

HIV Life Cycle

The viral glycoprotein binds to CD4+ T helper cells, macrophages, and dendritic cells (DCs) When CD4 binds to gp120, its causes a conformational change in the glycoprotein allowing it to further bind to the chemokine co-receptors, CCR5 or CXCR4. R5 viruses use the CCR5 receptor and infect CD4+ T cells, macrophages, and DCs X4 viruses use the CXCR4 receptor and infect only CD4+ cells Binding to the chemokine coreceptor exposes the fusion domain of gp41, allowing the fusion of viral and host membranes and subsequent viral entry. The viral genome is released in the cytoplasm and the associated enzymes are activated. The reverse transcriptase enzyme transcribes the HIV RNA to a double stranded DNA which is called the proviral DNA. The integrase enzyme integrates the proviral DNA into the host DNA. Of note, unintegrated viral DNA may survive, especially in quiescent cells. Transcription of the viral DNA then occurs followed by the production of viral proteins. The protease enzyme cleaves the newly synthesized viral polypeptide into functional viral protein components which are assembled in the cytoplasm to make new viral particles that are then released form the cell. CCR5 T cells are the first to be targeted (first exposed to virus in the mucosal cells). Th17 (cells that produce IL-17) are preferentially depleted. These cells play an important role in mucosal immunity through neutrophil recruitment. Their depletion early in infection plays a significant role in the immunopathogenesis of chronic HIV infection. Follicular helper T cells (Tfh) activate B cells to initiate the formation of germinal centers. They are exposed to high concentrations of HIS particles and expand during infection. The expansion leads to follicular hyperplasia and hypergammaglobulinemia early in infection and might predispose infected individuals to autoimmunity. Despite the expansion, Tfh function is impaired and thus these cells are unable to provide adequate B cell help.

HIV structure

The virus consists of two identical stands of RNA with associated enzymes that are enclosed in a cone-shaped p24 capsid protein. The envelope consists of a lipid bilayer membrane containing viral glycoproteins. The envelope viral glycoprotein is a trimeric complex consisting of a transmembrane gp41 and an external gp120 subunit

Tumor-Infiltrating Lymphocyte (TIL)

There are a number of immune cells trafficking and homing within the tumor mass including tumor-infiltrating lymphocytes (TILs). These cells can be removed from tumor samples taken from a patient and forced to reproduce in vitro by treating them with IL-2. When injected back into the patient, these cells may be active cancer fighters.

Lymphokine-Activated Killer (LAK) Cell Therapy

Treat a small number of patients' cells with cytokines like IL-2. Return these cells to the patient's bloodstream, and these special cells (called lymphokine-active killer cells) are more effective against cancer cells.

Escape from immunosurveillance

Tumors may not express neo-antigens that are immunogenic or they may fail to express co-stimulatory molecules for the activation of T-cells. In addition, certain tumors are known to lack or be poor expressers of MHC antigen. Tumors also shed their tumor antigens which blocks antibodies and T cells from reacting with malignant cells. Tumor cell antigens may change their structure spontaneously (antigenic variation) to avoid immune system elimination. Antibodies to tumor surface antigens may promote tumor survival (enhancing antibodies) if they bind without being cytotoxic, hiding the tumor antigens from T cells and inducing the tumor to downregulate tumor antigen expression Another reason for failure of immunosurveillance may be the fact that in the early development of a tumor, the amount of antigen may be too small to stimulate the immune system and, due to the rapid proliferation of malignant cells, the immune system is quickly overwhelmed. In addition, some tumors may evade the immune system by secreting immunosuppressive molecules and others may induce suppressor cells. Some tumors actively suppress the immune response by producing TGF-beta or IL-10, suppressive cytokines that inhibit cellular immunity. Some tumors, including myeloma and HTLV-1 T cell leukemia, also produce cytokines that stimulate their own proliferation. Finally, tumor-derived factors have been shown to polarize the immune responses in the tumor microenvironment. TUmor growth, for instance, was associated with increased formation of so-called regulatory immune cells, which directly suppress activity of antitumor CTLs and NK cells Among regulatory immune cells, myeloid-derived suppressor cells (MDSC), regulatory dendritic cells (regDC) and regulator T cells (Treg) are the most known

Immune Gene Therapy

an experimental treatment that involves introducing genetic material (DNA or RNA) into a person's cells to fight disease.

Interleukins

can be used as a single drug treatment for certain cancers such as metastatic melanoma and metastatic renal cell cancer, or it may be combined with other forms of immunotherapy, such as vaccines. The use of IL-2 together with chemotherapy or with other cytokines may increase their effectiveness against some cancers. unfortunately, IL-2-based therapy has some side effects, including flu-like symptoms such as chills, fever, fatigue, and confusion.

Cytokines

have a crucial role in regulating the growth and activity of immune cells. Used as nonspecific therapy or adjuvant. Some cytokines have important roles in cancer treatment. These cytokines, also known as hematopoietic growth factors, help the bone marrow start making blood cells again after chemotherapy has destroyed them. Granulocyte-colony-stimulating factor (G-CSF) stimulates the bone marrow to make granulocytes Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes production of both granulocytes and macrophages Erythropoeitin causes the bone marrow to produce RBCs Interleukin-11 (IL-11) promotes the production of platelets to reduce the risk of bleeding

Conjugated Monoclonal Antibodies

joined to drugs (chemolabeled), toxins (immunotoxins), or radioactive atoms (radiolabeled, part of radioimmunotherapy), and used as delivery vehicles to take those substances directly to the cancer cells. The MAb acts as a homing device, circulating in the body until it is attracted by, and attaches itself to, a cancer cell with a matching antigen. it delivers the toxic substance to where it is needed most, minimizing damage to normal cells in other parts of the body.

Onco-fetal antigens

may appear due to de-repression of genes that were only expressed early in life. Two major onco-fetal antigens: alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA). AFP is produced only as a secreted protein, whereas CEA is found both on cell membranes and in secreted fluids.

Nonspecific immunotherapies and adjuvants

stimulate the immune system in a very general way. This overall boost in immune system activity can result in more activity against any cancer cells present. Can be main therapy or as an adjuvant to boost the immune system and improve the effectiveness of another therapy. Cytokines, interleukins, and interferons are all nonspecific immunotherapies and adjuvants

immune surveillance

the immune system continually recognizes and eliminates tumor cells; when a tumor escapes immune surveillance and grows to large for the immune system to kill, cancer is the result

Autologous vaccines

tumor cells taken form the same person in whom they will later be used