Biological Therapies to Cancer

First line of defense against disease, mediated by cells (cellular immunity)

Immunity aquired from a previous infection, mediated by antibodies (humoral immunity)

Antigen presenting cells (dendritic cells/macrophages)
Natural killer cells (NK)

T-cells (thymus)- killer/helper/memory / regulatory
B-cells (bone marrow) - naive b cells/plasma cells

They pick up forgein protein (antigens) (such as mutated protein from cancer cells) and break them down, presenting them on their with class I or II MHC glands, and present them to CD8 or CD4 cells respectively to activate them.

They bind to MHC I found on healthy cells, which inhibits it and stops it from destroying the cell. If there is not enough MHC I presented by the cell, the NK cell will destroy it. In many cancer cells, MHC1 is low, and they are destroyed by NK cells.

killer/cytotoxic T-lypmocytes (CTLs), they recognize antigens fragments bound to MHC I molecules on APCs, and are activated. After activation, they bind to the MHC I of other cells, and if it find a matching antigen fragment, it destroys the cell.

CTLs require binding to MHC I of a cell in order to check if they have a matching antigen fragment as the presenting APC. Because of this, many cancer cells will downregulate their production of MHC I, as if they don't present their antigen fragments CTLs won't be able to detect them. However, NK cells will destroy any cell that doesn't present MHC I to it, so downregulation of MHC I by cancer to decrease destruction by t-cells will increase their rate of destruction by NK cells.

Helper T-cells, they stimulate B-cells to make antibodies and help CTLs develop. They bind to antigen fragmens bound to MHC II on APCs or B cells.

Recognizes antigens that have previously been in the body and will initiate a quick response to them.

They shut down the immune response and prevent autoimmunity

They absorb foreign antigens and break them down into fragments which they present on their MHC II. T-helper cells will bind to these MHC IIs, and stimulate the B-cell to differentiate into a plasma cell that creates antibodies against the absorbed antigen. These antibodies are against the antigen itself, not an antigen fragment bound to MHC I such as with T-killer cells, so they will be active against their target regardless of MHC I presentation.

Also regulatory B-cells which shut down the immune response.

They will bind to a cancer specific protein, usually external, such as an ER, and either antagonize or agonize it's function. These are very similar in function to a typical drug.

A very toxic drug is attached to an antibody, so that when the antibody finds and binds to the cancer cell, it will release the drug to kill the cancer. In order for this to be effective, the antibody-drug conugate must be internalized into the cell it is binding to, and after internalization the toxic drug must split off and become active, but not before.

It is the process used by the body where antibodies will flag a target cell with IgG, which signals to cytotoxic cells (CD8+ and NK) to destroy that cell.

They have an intact IgG domain which causes the rest of the immune system to mount a response to whatever they bind to. Unlike agonist/antagonist antibodies, which need to target some sort of receptor or transporter or something where the blocking or enhancement of it's activation would kill the cell, these antibodies can target any protein on the cancer cells. As long as they are able to bind to that protein, and they have an intact IgG domain, the rest of the body's immune system like CD8+ lymphocytes and NK cells will kill whatever cell that protein is on.

They are a fusion of two antibodies, one which binds to whatever target protein on cancer cells, and another which binds to CD3 receptors on CD8+ t-cells. This causes destruction of the bound cell simply by proximity to the cytotoxic T-cell. Very similar to immunomodulatory antibodies, but it has the advantage of being independent of co-stimulatory modules or MHC1 proteins.

Cancer cells which are immunoevasive do not express antigens which are recognized by the immune system as foreign. Prevents the immune system from building antibodies against these cancers.

Cancer cells which are immunosupressive do get targeted by the immune system, but have mechanisms which turn the immune system off when it gets attacked.

It is the idea that selective pressure from the immune system encourages the growth of cancer that is immune system resistant, either through immunoevasion or immunosuppression.

These therapies target cancer cells which are resistant to destruction by the immune system, and remove their mechanisms of resistance, allowing the immune system to do it's job of destroying the cancer cells.

The first cytotoxic antibody therapy. It binds to the CD20 receptor, which is found on B-cells, and flags the cell for destruction by NK cells. Will target all B-cells whether cancerous or not.

When the antibody is correctly targeting and causing the destruction of what it was designed to bind to, but that target is being found on non-cancerous cells causing their destruction as well. For instance with rituximab, it has the on-target off-tumor toxicity of destroying healthy B-cells as well as cancerous ones.

A conjugation of trastuzumab and DM1, which is a highly toxic drug which binds to tubulin and prevents polymerization. It is too toxic to use on its own. Trastuzumab binds to HER2 receptors and blocks them, which already is effective on it's own against HER2+ breast cancer. Then, when it is internalized, the DM1 breaks off and becomes active, also working to kill the cell.

A BiTE antibody which binds to CD19 on B-cells and CD3 on T-cells, causing destruction of the B-cell.

It is a receptor found on CD8+ t cells which when bound to APCs prevents T-cell activation. Some cancers will cause t-cells to express higher levels of CTLA-4, meaning they are less likely to be activated against these cancers.

It is an immune checkpoint regulator that binds to CTLA-4 and antagonizes it. This prevents immunosupression by cancers which enhance CTLA-4 expression, and still requires a foreign antigen to be present for activation so it is specific, however there is toxicity associated with extreme immune system activation.

A T-cell receives an antigen from an APC, and will activate and target cells with that antigen for destruction. PD-1 (programmed death protein 1) is a receptor on t and b cells that binds to PDL-1 which is typically expressed on healthy cells. When a t-cell binds to a cell presenting it's target antigen for destruction, it will be halted if it binds to PDL-1. Some cancers express very high levels of PDL-1, as a way of immunosupression. Even if the T-cells target and bind to the cancer cells, they won't destroy the cancer cell if PD-1/PDL-1 binding happens.

Immune checkpoint modulators. They are antibodies that target PD-1 on T-cells and prevent it from binding to PDL-1. Since the t-cells must already be activated with their target foreign antigen, this doesn't increase the rate of immune system activation, just the rate of target cell destruction. Relatively few side effects and high specificity.

pembrolizumab (Keytruda)
nivolumab (Opdivo)

DNA viruses will integrate into our DNA in order to replicate. With some viruses, such as HPV, this integration can be inserted in the middle of a genes (like the tumor supressor gene p53) and stop it from being made properly. Viruses that do this increase the risk of cancer and are called oncoviruses.

Vaccines against oncoviruses, by gaining immunity against the virus, you reduce the likelyhood you get cancer from it.

Vaccines against tumors specifically, which are made specific to each patient.

In a typical vaccine, antigens are injected, allowing the body's APCs to bind to them and mount and remember an immune response to a disease that isn't actually present in the body. However with tumors, they are actually in the body, and the body will mount an immune response to them if it is able to. However through, immunoediting and immunoevaison, some cancer antigens are not recognized as foreign antigens, and the body doesn't mount an immune response to them.

Cancer vaccines, such as Sipuleucel-T, take APCs from the patient, and incubate them with the target cancer antigen that they do not recognize as foreign. They are then treated and forced to bind to these antigens. Then these APCs which are bound to the cancer antigen are injected back into the body, which allows them to react with T killer and helper cells to mount an immune response against that antigen, including antibodies.

CD8 T-cells are either taken from the patient or another donor. They are then modified in some way, engineered to recognize cancer antigens, multiplied, etc, and then injected into the patient. They directly modify CD8 cells, so they are not reliant on the immune system to mount an adequate response like a vaccine is, however they also do not mount an antibody response.

This is a type of adoptive T-cell therapy. In some patients there will be T-cells which have recognized and are effective against their cancer, but they still aren't mounting an effective immune response. Maybe the body isn't producing enough of them due to the patient's weakened immune system, or maybe they are being immunosupressed by the cancer, etc. Whatever the case, these t-cells are taken from the body and screened to determine which ones have the strongest response. These are then grown in large numbers, before being put back into the patient. The much greater amount of active tumor infiltrating t-cells is then hopefully enough to overpower the cancer.

A type of adoptive t-cell therapy. T-cell receptors are taken engineered to have a high affinity for cancer antigens. These receptors are then reattached to t-cells and injected into the patient, giving them t-cells that strongly recognize their cancer.

A type of adoptive t-cell therapy. T-cell are taken from the patient and fused with a synthetic chimeric antigen receptor (CAR). This receptor is able to bind directly with its antigen target on the surface of cells, allows the treated t-cells to bypass MHC I binding and still be effective against cancer cells which downregulate MHC I. Thus far this has not been effective against solid tumors, as it has not been able to penetrate through the tumor mass, however it cures the patients that it is effective in.