Immunotherapy: Using the Immune System to Treat Cancer
The immune system’s natural capacity to detect and destroy abnormal cells may prevent the development of many cancers. However, cancer cells are sometimes able to avoid detection and destruction by the immune system. Cancer cells may:
- reduce the expression of tumor antigens on their surface, making it harder for the immune system to detect them
- express proteins on their surface that induce immune cell inactivation
- induce cells in the surrounding environment (microenvironment) to release substances that suppress immune responses and promote tumor cell proliferation and survival
In the past few years, the rapidly advancing field of cancer immunology has produced several new methods of treating cancer, called immunotherapies, that increase the strength of immune responses against tumors. Immunotherapies either stimulate the activities of specific components of the immune system or counteract signals produced by cancer cells that suppress immune responses.
These advances in cancer immunotherapy are the result of long-term investments in basic research on the immune system—research that continues today. Additional research is currently under way to:
- understand why immunotherapy is effective in some patients but not in others who have the same cancer
- expand the use of immunotherapy to more types of cancer
- increase the effectiveness of immunotherapy by combining it with other types of cancer treatment, such as targeted therapy, chemotherapy, and radiation therapy
Immune Checkpoint Modulators
One immunotherapy approach is to block the ability of certain proteins, called immune checkpoint proteins, to limit the strength and duration of immune responses. These proteins normally keep immune responses in check by preventing overly intense responses that might damage normal cells as well as abnormal cells. But, researchers have learned that tumors can commandeer these proteins and use them to suppress immune responses.
Blocking the activity of immune checkpoint proteins releases the "brakes" on the immune system, increasing its ability to destroy cancer cells. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration (FDA). The first such drug to receive approval, ipilimumab (Yervoy®), for the treatment of advanced melanoma, blocks the activity of a checkpoint protein known as CTLA4, which is expressed on the surface of activated immune cells called cytotoxic T lymphocytes. CTLA4 acts as a "switch" to inactivate these T cells, thereby reducing the strength of immune responses; ipilimumab binds to CTLA4 and prevents it from sending its inhibitory signal.
Two other FDA-approved checkpoint inhibitors, nivolumab (Opdivo®) and pembrolizumab (Keytruda®), work in a similar way, but they target a different checkpoint protein on activated T cells known as PD-1. Nivolumab is approved to treat some patients with advanced melanoma or advanced lung cancer, and pembrolizumab is approved to treat some patients with advanced melanoma.
Researchers have also developed checkpoint inhibitors that disrupt the interaction of PD-1 and proteins on the surface of tumor cells known as PD-L1 and PD-L2. Agents that target other checkpoint proteins are also being developed, and additional research is aimed at understanding why checkpoint inhibitors are effective in some patients but not in others and identifying ways to expand the use of checkpoint inhibitors to other cancer types.
Immune Cell Therapy
Progress is also being made with an experimental form of immunotherapy called adoptive cell transfer (ACT). In several small clinical trials testing ACT, some patients with very advanced cancer—primarily blood cancers—have had their disease completely eradicated. In some cases, these treatment responses have lasted for years.
In one form of ACT, T cells that have infiltrated a patient’s tumor, called tumor-infiltrating lymphocytes (TILs), are collected from samples of the tumor. TILs that show the greatest recognition of the patient's tumor cells in laboratory tests are selected, and large populations of these cells are grown in the laboratory. The cells are then activated by treatment with immune system signaling proteins called cytokines and infused into the patient’s bloodstream.
The idea behind this approach is that the TILs have already shown the ability to target tumor cells, but there may not be enough of them within the tumor microenvironment to eradicate the tumor or overcome the immune suppressive signals that are being released there. Introducing massive amounts of activated TILs can help to overcome these barriers and shrink or destroy tumors.
Another form of ACT that is being actively studied is CAR T-cell therapy. In this treatment approach, a patient’s T cells are collected from the blood and genetically modified to express a protein known as a chimeric antigen receptor, or CAR. Next, the modified cells are grown in the laboratory to produce large populations of the cells, which are then infused into the patient.
CARs are modified forms of a protein called a T-cell receptor, which is expressed on the surface of T cells. These receptors allow the modified T cells to attach to specific proteins on the surface of cancer cells. Once bound to the cancer cells, the modified T cells become activated and attack the cancer cells.
Therapeutic antibodies are antibodies made in the laboratory that are designed to cause the destruction of cancer cells.
One class of therapeutic antibodies, called antibody–drug conjugates (ADCs), has proven to be particularly effective, with several ADCs having been approved by the FDA for the treatment of different cancers.
ADCs are created by chemically linking antibodies, or fragments of antibodies, to a toxic substance. The antibody portion of the ADC allows it to bind to a target molecule that is expressed on the surface of cancer cells. The toxic substance can be a poison, such as a bacterial toxin; a small-molecule drug; or a radioactive compound. Once an ADC binds to a cancer cell, it is taken up by the cell and the toxic substance kills the cell.
The FDA has approved several ADCs for the treatment of patients with cancer, including:
- ado-trastuzumab emtansine (Kadcyla®) for the treatment of some types of breast cancer
- brentuximab vedotin (Adcetris®) for Hodgkin lymphoma and a type of non-Hodgkin T-cell lymphoma
- ibritumomab tiuxetan (Zevalin®) for a type of non-Hodgkin B-cell lymphoma
Other therapeutic antibodies do not carry toxic payloads. Some of these antibodies cause cancer cells to commit suicide (apoptosis) when they bind to them. In other cases, antibody binding to cancer cells is recognized by certain immune cells or proteins known collectively as "complement," which are produced by immune cells, and these cells and proteins mediate cancer cell death (via antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity, respectively). Sometimes all three mechanisms of inducing cancer cell death can be involved.
One example of this type of therapeutic antibody is rituximab (Rituxan®), which targets a protein on the surface of B lymphocytes called CD20. Rituximab has become a mainstay in the treatment of some B-cell lymphomas and B-cell chronic lymphocytic leukemia. When CD20-expressing cells become coated with rituximab, the drug kills the cells by inducing apoptosis, as well as by antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.
Other therapies combine non-antibody immune system molecules and cancer-killing agents. For example, denileukin diftitox (ONTAK®), which is approved for the treatment of cutaneous T-cell lymphoma, consists of the cytokine interleukin-2 (IL-2) attached to a toxin produced by the bacterium Corynebacterium diphtheria, which causes diphtheria. Some leukemia and lymphoma cells express receptors for IL-2 on their surface. Denileukin diftitox uses its IL-2 portion to target these cancer cells and the diphtheria toxin to kill them.
Cancer Treatment Vaccines
The use of cancer treatment (or therapeutic) vaccines is another approach to immunotherapy. These vaccines are usually made from a patient’s own tumor cells or from substances produced by tumor cells. They are designed to treat cancers that have already developed by strengthening the body’s natural defenses against the cancer.
In 2010, the FDA approved the first cancer treatment vaccine, sipuleucel-T (Provenge®), for use in some men with metastatic prostate cancer. Other therapeutic vaccines are being tested in clinical trials to treat a range of cancers, including brain, breast, and lung cancer.
Immune System Modulators
Yet another type of immunotherapy uses proteins that normally help regulate, or modulate, immune system activity to enhance the body’s immune response against cancer. These proteins include cytokines and certain growth factors. Two types of cytokines are used to treat patients with cancer: interleukins and interferons.
Immune-modulating agents may work through different mechanisms. One type of interferon, for example, enhances a patient’s immune response to cancer cells by activating certain white blood cells, such as natural killer cells and dendritic cells. Recent advances in understanding how cytokines stimulate immune cells could enable the development of more effective immunotherapies and combinations of these agents.
Research at NCI
Immunotherapy research at NCI is done across the institute and spans the continuum from basic scientific research to clinical research applications.
The Center of Excellence in Immunology (CEI) brings together researchers from across NCI and other NIH institutes to foster the discovery, development, and delivery of immunotherapy approaches to prevent and treat cancer and cancer-associated viral diseases.