Immunotherapy

Immunotherapy Strategies

Immunotherapy is among one of the newest approaches to treating cancer. Immunotherapy is based on the understanding that cancer cells can hide from the immune system through multiple techniques. Different immunotherapies help restore the immune system’s ability to find and destroy tumors in various ways. Research into immunotherapy is rapidly expanding, and clinical trials with current and in-development drugs are underway.

Immunotherapy differs from these other cancer treatments.

  • Chemotherapy, which uses drugs to kill rapidly multiplying cells, including cancer cells and sometimes healthy cells, as well.
  • Radiation therapy, which targets a specific region of the body with high-energy X-rays to destroy cancer cells.
  • Targeted therapy, which may target the internal components and function of the cancer cell, the receptors on the outside of the cancer cell or the blood vessels that supply oxygen to the cancer cell.

Immunotherapy is a type of targeted therapy. The difference between targeted therapy and immunotherapy is that targeted therapies work directly on the tumor while immunotherapies work to boost the immune system to attack the cancer.

Immunotherapy depends on a functioning immune system, so it is important to make sure that you do not have an autoimmune disorder or are not taking any immunosuppressive medications. After taking into consideration these and other factors, such as your overall health, type and stage of your cancer and your treatment history, your doctor may recommend one or a combination of treatments.

Not everyone is a candidate for immunotherapy. If immunotherapy is not suggested for you, do not be disappointed; many other treatments are available. In addition, you may be a candidate for a clinical trial that offers access to a leading-edge treatment that is not yet available to all (see Clinical Trials). Ask your doctor about all your options, taking into consideration possible side effects, before making any treatment decisions.

Immunotherapy has the potential to remain effective for long intervals far beyond the end of treatment — a feature called “memory.” Memory is the same feature that allows a tetanus vaccine, for example, to remain effective for many years. This effect can lead to long-term, cancer-free remission and increased overall survival. Because it’s less likely that immunotherapy will affect healthy tissues and cells, side effects may be less common and either less severe or more easily treatable for some people. As with any treatment, however, there are still associated risks that should be discussed with your doctor.

Once treatment begins, monitoring is key. More monitoring and follow-up occur with immunotherapy than with most other forms of treatment. You will likely undergo testing to allow your doctor to evaluate how well treatment is working by measuring the size of the tumor as treatment progresses.

Several different immunotherapy strategies are currently being studied or used as cancer treatments, including the following.

Adoptive T-cell transfer (T-cell therapy)

Adoptive T-cell transfer involves enhancing the body’s own T-cells to fight cancer. There are two main types of adoptive cell transfer immunotherapy. One type involves the doctor isolating T-cells from a patient’s tumor (tumor-infiltrating lymphocytes, or TIL), expanding them to large numbers, and then administering them to patients. In the second strategy, T-cells collected from the patient are engineered with new receptors (chimeric antigen receptor T-cells, or CAR-T) to recognize specific antigens on the surface of cancer cells, and then infused back into the patient. In both cases, the T-cells multiply, seek and destroy the cancer cells that carry those specific antigens.

This type of immunotherapy is still investigational and available only through clinical trials. Studies have shown promise in the treatment of leukemia, lymphoma, metastatic melanoma, neuroblastoma and synovial cell sarcoma.

Immune checkpoint inhibitors

Immune checkpoint pathways are specific connections between molecules on the surfaces of immune cells — specifically between antigen-presenting cells and T-cells, or between T-cells and tumor cells — that help regulate the immune response. Some tumor cells have proteins on their surface that bind to activated immune cells and inhibit their function. This connection effectively puts the brakes on the attack (known as tumor-induced immunosuppression).

Immune checkpoint inhibitors are drugs that block the checkpoint from being engaged, which essentially turns the immune response back on. These immune checkpoint inhibitors currently are being used to treat cancer.

  • Anti-CTLA-4 antibodies block the connection necessary to engage the CTLA-4 protein, allowing the T-cells to continue fighting cancer cells instead of shutting down the immune response. CTLA-4 is a protein receptor found on the surface of T-cells. When activated, CTLA-4 is capable of suppressing the immune system response. Anti-CTLA-4 drugs prevent this from happening.
  • Anti-PD-1 drugs block the connection necessary to engage the PD-1 protein, allowing the T-cells to continue their response against cancer cells. The PD-1 checkpoint pathway is one of several pathways for putting the brakes on the T-cells. When the PD-1 receptors on the surface of T-cells connect with the PD-1 ligand (PD-L1) on the surface of cancer cells or other immune cells, signals are sent to the T-cells to slow down the response. Anti-PD-1 drugs prevent this from happening.
  • Anti-PD-L1 molecules bind to the PD-1 proteins on the T-cell and turn them off. Cancer cells have the ability to make certain molecules appear on the surface, including PD-L1 and PD-L2 of the PD-1 checkpoint pathway. Cancer cells may also cause immune cells near the cancer to express PD-L1. Anti-PD-L1 molecules allow T-cells to attack the cancer cells.

Monoclonal antibodies

One of the body’s natural immune responses to foreign substances is the creation of antibodies specific to the antigens found on the surface of invading germ cells. Some antibodies can recognize portions of proteins on the surface of cancer cells. Researchers can design antibodies that specifically target a certain antigen.

Monoclonal antibodies (mAbs) are antibodies made in a laboratory that are designed to target specific tumor antigens. Also, mAbs can work in different ways, such as flagging targeted cancer cells for destruction, blocking growth signals and receptors or delivering other therapeutic agents directly to targeted cancer cells. They also can 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 (see Figure below). 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.

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

Nonspecific immune stimulation

This immunotherapy strategy gives the immune system an overall boost and 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. Cytokine immunotherapies involve introducing large amounts of laboratory-made cytokines to the immune system to promote specific immune responses. Different types include the following:
    • 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 factor (GM-CSF) is a cytokine that stimulates the bone marrow, promoting the growth of immune and blood cells and the development of dendritic cells.
  • Modified bacteria are used to treat certain cancers. Some bacteria have been modified to ensure they will not cause the disease to spread while stimulating an immune response.
  • Toll-like receptor agonists “see” 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

One treatment strategy uses viruses to attack cancer. Oncolytic virus immunotherapy involves the use of viruses to directly infect tumor cells and induce an immune response against the infected cells. With one of the most-studied approaches, a modified, weakened version of the herpes simplex virus that also contains the cytokine GM-CSF is used. 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 protein induced 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

Although researchers have been trying to develop vaccines to fight cancer for many years, knowledge gained in recent years is improving this treatment approach. Vaccines against cancer are created from either modified viruses or tumor cells and are designed to direct immune cells to the cancer cells. In some cases, these vaccines are developed from a patient’s own tumor, but usually they are “off-the-shelf” and contain one to more than 100 antigens that are common to the patient’s type of cancer. There are two types of cancer vaccines: prophylactic vaccines, which prevent the viruses that cause cancers, and therapeutic vaccines, which treat existing cancers. Currently, prophylactic vaccinations are available for human papillomavirus (HPV), the cause of many cervical, anal, and head and neck cancers, and hepatitis B virus (HBV), a known risk factor for liver cancer.

Therapeutic cancer vaccinations include the following.

  • Tumor cell vaccines are made from tumor cells that are similar to a patient’s cancer type. (These vaccines are made from a patient’s own tumor only in rare cases.) In some cases, the tumor cells are genetically engineered 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 any remaining cancer cells.
  • Antigen vaccines are typically made from one to five of the antigens that are either unique to or overexpressed by tumor cells. They may be specific to a certain type of cancer but are not patient-specific.
  • Dendritic cell (or antigen-presenting cell [APC]) vaccines are made from white blood cells extracted from the patient. The cells are sent to a lab, exposed to chemicals that turn them 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, and any other cells that release 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 genetically modified 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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