Immunotherapy

Types of Cancer Immunotherapies

Immunotherapy is a strategy doctors use to treat many different types of cancer using the body’s own immune system. Immunotherapy helps the immune system recognize and attack cancer cells that have been hiding and target them for destruction, which is very different from the following types of cancer treatments.

  • Chemotherapy uses drugs to kill rapidly multiplying cells, including cancer cells and sometimes healthy cells.
  • Radiation therapy targets a specific region of the body with high-energy X-rays to destroy cancer cells.
  • Targeted therapy drugs target specific genes or proteins in cancer cells or in cells related to cancer growth, such as the blood vessels that supply oxygen and nutrients to the cancer cell.
  • Surgery to remove a tumor can be invasive and may leave behind cancer cells that have the potential to develop into new tumors.

Treating cancer with immunotherapy offers multiple benefits. It is less likely to affect healthy tissues and cells, which may reduce the likelihood and severity of side effects. Although side effects to immunotherapies may be more tolerable, in general, serious reactions called adverse events are possible. Your doctor will let you know what to watch for. If you begin to have any adverse effects or side effects, call your doctor at once (see Side Effects).

Immunotherapy offers the ability to be effective long after the treatment has ended. This is a feature of the immune system called “memory.” When your immune system encounters a virus like chicken pox, it automatically remembers it if it is exposed to it again and offers you immunity from that virus. With immunotherapy, your immune system may be able to recognize a specific type of cancer cells easier, which can lead to long-term, cancer-free remission of that type and increased overall survival.

To be a candidate for immunotherapy, you must have a functioning immune system, not have an autoimmune disorder and not be taking immunosuppressive medications. Biomarker testing may also be needed. Some immunotherapies are approved to treat cancers in people with specific biomarkers present. If immunotherapy is an option for you, monitoring your health and any possible side effects are key once treatment begins.

 

 

Adoptive Cellular Therapy

Adoptive cellular therapy is a treatment that enhances or changes the body’s own immune cells to be able to fight cancer. There are two main strategies. In one strategy, the doctor isolates T-cells that have attached to a patient’s tumor (tumor-infiltrating lymphocytes, or TILs), helps them multiply, and then administers them back to the patient. In the second strategy, a patient’s own T-cells are collected and new receptors are added which enable the T-cells to recognize specific antigens (foreign substances such as bacteria, viruses or parasites) on the surface of cancer cells. These engineered T-cells are called chimeric antigen receptor T-cells, or CAR-T. They are then infused back into the patient. In both cases, the goal is for the T-cells to multiply, seek and destroy the cancer cells that carry those specific antigens. Although this strategy is approved by the FDA for limited use, research focused on expanding its availability continues through clinical trials.

Immune Checkpoint Inhibitors

The body’s immune system is so strong that it has the potential to attack normal, healthy cells along with foreign cells. To avoid doing so, the immune system regulates itself so that it only produces enough white blood cells to fight the non-self antigens (foreign cells) that are present in the body. When the white blood cells have completed their attack, the immune system slows down. It does this by using checkpoints.

Checkpoints keep the immune system “in check,” preventing an attack on normal cells through the use of regulatory T-cells (see Explaining the Immune System). A series of signals that occur when the correct proteins and receptors on cell surfaces connect and tell the regulatory T-cells to slow down the immune system after an immune response is finished.

To better understand how this happens, think of the proteins on the cell surface and their receptors on a different cell's surface as puzzle pieces. Proteins have “tabs” that protrude (stick out), and receptors have “spaces” that curve inward. When the puzzle pieces fit together, chemicals and information are exchanged between them, triggering signals to the immune system to slow down. Three pieces of the puzzle work together to slow the immune system.

  1. CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a receptor that binds with certain molecules to tell the immune system to slow down.
  2. PD-1 (programmed cell death protein 1) is a receptor involved with telling T-cells to die and to reduce the death of regulatory T-cells (suppressor T-cells). Both have an effect to slow down an immune response. PD-1 can only tell the immune system to slow down if it connects with PD-L1.
  3. PD-L1 (programmed death-ligand 1) is a protein that, when combined with PD-1, sends a signal to reduce the production of T-cells and enable more T-cells to die.

When PD-1 (the receptor) and PD-L1 (the protein) combine, the reaction signals the immune system that it is time to slow down. CTLA-4, however, can connect with more than one protein, which is a more complex reaction than the PD-1 and PD-L1 interaction. When CTLA-4 combines with any of the various proteins, it also tells the immune system to slow down.

One of the ways cancer can outsmart the immune system is by producing PD-L1 (the protein) on the surface of its cells and using it to camouflage its appearance so that T-cells will think they are normal cells. T-cells only expect normal cells to produce PD-L1, so when a T-cell encounters PD-L1 on a cancer cell, it is tricked into sending the signal for the immune system to slow down. This is how cancer can hide from the immune system.

Immune checkpoint inhibitors are drugs that prevent the proteins and receptors (puzzle pieces) from fitting together and triggering the slowdown of the immune system.

When an immune checkpoint inhibitor is given, the immune system is not so easily fooled by the cancer’s disguise. By not slowing down, it’s like the immune system develops X-ray vision and can see through the camouflage the cancer cell is wearing. This keeps the immune response on and also helps the immune system recognize cancer cells as foreign cells.

The following immune checkpoint inhibitors currently approved for use in immunotherapy block connections between specific proteins.

  • Anti-CTLA-4 antibodies allow the T-cells to continue fighting cancer cells instead of shutting down.
  • Anti-PD-1 drugs allow for the continued or increased production of T-cells and enable them to continue fighting cancer.
  • Anti-PD-L1 molecules allow the T-cells to see through the disguises of some tumor cells, recognize them as the enemy and attack them.

Monoclonal Antibodies

Antibodies (a type of protein) are the body’s way of tagging an antigen (foreign substance). They are produced from plasma cells, which are mature forms of B-cells. Antibodies are produced for specific antigens. They bind to the antigen and allow the rest of the immune system to recognize the antigen as foreign and target it for destruction.

Monoclonal antibodies (mAbs) are antibodies made in a laboratory that are designed to target specific tumor antigens. They can work in different ways, such as flagging targeted cancer cells for destruction, blocking growth signals and receptors, and delivering other therapeutic agents directly to targeted cancer cells. They can also be created to carry cancer drugs, radiation particles or laboratory-made cytokines (proteins that enable cells to send messages to each other) directly to cancer cells. When a mAb is combined with a toxin, such as a chemotherapy drug, it travels through the system until it reaches the targeted cancer cell, where it attaches to the surface, gets swallowed by the tumor cell and breaks down inside the cell, releasing the toxin and causing cell death. Combining mAbs with radiation particles, a treatment known as radioimmunotherapy, allows for radiation to be delivered in lower doses over a longer period of time directly to specific cancer cells. This direct form of radiation delivery typically damages only the targeted cells.

Three different types of mAbs are used in cancer treatment.

  1. Naked mAbs work by themselves. No drugs or radioactive particles are attached to them.
  2. Conjugated mAbs have a chemotherapy drug or a radioactive particle attached to them. They are used to deliver treatment to the cancer cells. These also are referred to as tagged, labeled or loaded antibodies.
  3. Bispecific mAbs are made up of two different mAbs and can attach to two different proteins at the same time.

Nonspecific Immune Stimulation

The goal of this strategy is to boost the whole immune system instead of just specific parts. It can be used alone or in combination with other treatments to produce increased and longer-lasting immune responses. Different types of nonspecific immune stimulation include the following.

  • Cytokine immunotherapy aids in communication among immune cells and plays a big role in the full activation of an immune response. This type of immunotherapy works by introducing large amounts of the following laboratory-made cytokines to the immune system to promote specific immune responses:
    • Interleukins are cytokines that help regulate the activation of certain immune cells.
    • Interferons are cytokines that boost the ability of certain immune cells to attack cancer cells.
    • Granulocyte-macrophage colony stimulating factors (GM-CSFs) are cytokines that stimulate the bone marrow, promoting the growth of immune and blood cells and the development of dendritic cells, which become antigen-presenting cells (cells that show the antigens to T-cells).
  • Modified bacteria are used to treat certain cancers. Some bacteria have been changed to ensure they will not cause the disease to spread while stimulating an immune response.
  • Toll-like receptor agonists recognize patterns in bacteria or viruses and produce a signal that activates the immune cell to attack. The immune system often detects germs through a series of receptors (called toll-like receptors) found on the surface of most immune cells. Several of these specialized receptors have been evaluated for use in cancer treatment.

Oncolytic Virus Immunotherapy

An oncolytic virus only attacks and kills cancer cells. Oncolytic virus immunotherapy uses viruses that directly infect tumor cells and induce an immune response against the infected cells. One of the most-studied approaches uses a weakened version of the herpes simplex virus that has been changed from the original and contains the cytokine GM-CSF. The virus targets specific cancer cells, infects them and duplicates itself continuously within the cell until it ruptures. This rupture kills the cell and releases the GM-CSF cytokine produced by the virus to promote an overall immune boost against the cancer. This process increases the chance that the attack can also begin killing cancer cells that have not been infected with the virus.

Vaccinations

Two types of vaccines are used against cancer: preventive vaccines and treatment vaccines. Preventive vaccines are given before a person develops cancer with the goal of stopping it from forming. Currently, preventive vaccinations are available for human papillomavirus (HPV), the cause of many cervical, anal, and head and neck cancers, and for hepatitis B virus (HBV), a known risk factor for liver cancer.

Treatment vaccines may be given to treat existing cancers. These vaccines are created from either viruses or tumor cells that have been changed in a laboratory. Their goal is to direct immune cells to the cancer cells. Some of these vaccines are custom-made for the patient’s specific tumor type while others are “off-the-shelf” vaccines that contain one to more than 100 antigens that are common to the patient’s type of cancer.

Available types of treatment cancer vaccinations include the following.

  • Tumor cell vaccines are made from tumor cells that are similar to a patient’s cancer type. (In rare cases, these vaccines are made from a patient’s own tumor.) In some cases, the tumor cells are changed in the laboratory to express a new property or are treated with drugs that make the tumor cells or their components easier for the immune system to recognize. The vaccines are treated with radiation to prevent spreading and are then injected back into the body to help the immune system recognize remaining cancer cells.
  • Antigen vaccines are typically made from one to five of the antigens that are either unique to or overexpressed (more than needed) by tumor cells. They may be specific to a certain type of cancer but are not patient-specific.
  • Dendritic cell vaccines (or antigen-presenting cell [APC] vaccines) are made from white blood cells removed from the patient. The cells are sent to a lab, changed into dendritic cells, and then exposed to tumor antigens so that they’ll transform into mature APCs. When they’re injected back into the patient, they share the antigen information with the T-cells so the cells releasing that specific antigen are targeted and destroyed.
  • Vector-based vaccines are made from altered viruses, bacteria, yeast or other structures that can be used to get antigens into the body. Often, these germs have been altered so that they no longer cause disease. Some vaccines can be used to deliver more than one cancer antigen at a time. Vector-based vaccines are injected into the body to create an immune response, both specific and overall. Tumor-specific vectors are changed to train the immune system to recognize, target and destroy cancer cells. One vector-based vaccine currently being studied to treat leukemia is an HIV virus (modified to no longer cause disease) that targets B-cells, the cells primarily affected by leukemia.

 

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