The goal of this section is to provide an overview of the immune system in laymen's terms and related the components and functions to potential and existing therapies for lymphoma.
Background on Cancer Vaccines
The focus of immunotherapy is to wake a sleeping force of immune cells so that they seek and destroy cancer cells that have managed to evade or suppress immunity.
Basic approach to cancer vaccines
- First identify and isolate antigens (protein fragments) specific to the tumor.
- Deliver these tumor antigens into the body in ways that induce the immune system to recognize and attack cancer cells.
- Add adjuvants to increase immune effects and attention to the tumor antigens.
- Add additional therapies to offset evasion or protection tactics by cancer cells.
- Add treatments to decrease tumor burden and increase antigen fallout, without compromising immunity. (Antigens in dying cells could enhance immune response in some circumstances.)
- Alter the immune profile to favor anti-cancer immune action. An immune profile is the predominance of types of immune cells and cell signaling.
- Alter the expression of cancer cells so that they become more visible to the immune system. For example, virally infecting b-cell lymphomas could change how these cells look to the immune system, making them more immunogenic (capable of evoking an immune response).
Potential settings for cancer vaccines
As the safety profile of vaccines becomes established, and it appears to be doing so, the settings in which it can be tried will increase. Indeed, Patients Against Lymphoma advocates for the routine application of strategies to safely induce immune response lymphomas.
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Frontline early stage disease – taking advantage of immune competence.
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Following treatment – taking advantage of minimal disease state.
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During treatment – taking advantage of antigen fallout and diminishing tumor burden.
Targeting tumor cells selectively
Just as we might recognize a criminal by they way he acts or looks (profiling), the immune system has the potential to identify and kill cancers cells because by definition cancer cells express abnormal proteins that distinguish them from normal cells.
Targets: Tumor Associated Antigens (TAA) and Receptors
Tumor Associated Antigens are peptide sequences (fragments of proteins) that make a tumor distinct from normal cells. Tumors may express unique receptors based on normal or abnormal gene expression. Two examples of targets based on normal gene expression:
Normal antigen target: Rituxan targets CD20, which is normally expressed on mature b-cells.
Normal antigen target: Induce immunity against the Idiotype (Id) -- a unique marker normally expressed on the surface of the lymphoma cells that distinguish them from all other lymphocytes and other cells in the body. The Id, is a receptor that's specific to an antigen (bacteria, virus, etc.) that particular immune cell was designed to recognize and kill. The idiotype is typically clonally expressed, meaning that each malignant cell has the same idiotype receptor. The goal of Idiotype vaccine treatment is to "teach" the immune system to target and attack this protein.
Abnormal antigen target - One example could be if all the malignant cells were infected by a virus. A vaccine could then be prepared to "teach" the immune system to recognize and kill cells that have this viral antigen. We could imagine a therapy that intentionally infects malignant cells with a virus, and then induces an immune response against the virus.
The search for tumor antigens is becoming industrialized and automated, and therefore far more efficient. Some antigen types include: Differentiation antigens, Mutated tumor antigens, Over expressed antigens, Viral antigens
Some technologies that utilize or identify TAAs: DNA chips to identify tumor specific genes, Autologous cell therapy: multiple antigen approach, cross priming of TAAs with antigen presenting cells.
Background Terminology
Antibodies - are proteins (glycoproteins) with a specific shape that corresponds to an antigen or cell receptor. B cells produce antibodies that lock onto pathogens. There are ??
Antigens (Ag) - a general term for a protein or protein fragment considered foreign or abnormal that elicits an immune response in the body.
Epitope - smallest structural part of an antigen to which an antibody can bind. Also called the antigenic determinant.
Receptors - A protein shape on the surface of cells that have a shape specific to an antigen or protein signal. Both B- and T-cells have surface receptors for antigens. Each cell has thousands of receptors of a single specificity; that is, with a binding site for a particular epitope.
Signaling - Immune cells coordinate actions by sending and receiving messages.
T-cell receptors (TCRs) - enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope presented by specialized antigen-presenting cells or APCs.
B-cell receptors (BCRs) enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope on molecules of a soluble antigen. The response ends with descendants of the B cell secreting vast numbers of a soluble form of its receptors. These are antibodies.
Humoral Antibody System - B lymphocytes
- each B lymphocyte produces a distinct antibody molecule (immunoglobulin or Ig)
- over a million different B lymphocytes are produced in each individual
- thus, each individual can recognize over a million different antigens
- the antibody molecule is composed of 2 copies of 2 different proteins
- there are two copies of a heavy chain - over 400 amino acids long
- there are two copies of a light chain - over 200 amino acids long
- each antibody molecule can bind 2 antigens at one time
- thus, a single antibody molecule can bind to 2 viruses which leads to clumping
- when a new antigen comes into the body
- it binds to the B-cell which is already making an antibody that matches the antigen
- the antigen-antibody complex is engulfed into the B-cell and partially digested
- the antigen is displayed on the cell surface by a special receptor protein (MHC II) for recognition by helper T-cells
- the B-cell is activated by the helper T-cell to divide and produce secreted antibodies which circulate in the serum and lymph
- some B-cells become memory cells to produce antibody at a low rate for a long time (long term immunity) and to respond quickly when the antigen is encountered again
- the response is regulated by a class of T-cells called suppressor T-cells
Cellular System - T lymphocytes
- T-cells mature in the thymus (thus the name T-cell)
- over a million different kinds of T-cells; each producing a different receptor in the cell membrane
- each receptor is composed of 1 molecule each of two different proteins
- each receptor binds a specific antigen but has only one binding site
- receptors only recognize antigens which are "presented" to it within another membrane protein of the MHC type (major histocompatibility complex)
- recognizes antigens presented by B-cells, macrophages, or any other cell type
- T-cells, B-cells, and macrophages use MHC-II receptors for presentation; all other cells use MCH-I (responsible for most of tissue graft rejection)
- when a T-cell is presented with an antigen, its recpetor binds to the antigen and it is stimulated to divide and produce
- helper T-cells - activate B-cells with bound antigen
- suppressor T-cells - regulate the overall response
- cytotoxic "killer" T-cells - kill cells with antigen bound in MHC-I
Source: http://www.people.virginia.edu/~rjh9u/imresp.html
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