Strategies that unleash the immune system to attack cancer cells are being developed at a rapid pace. Maintaining an up-to-date understanding of the immune system and an awareness of new immunotherapies and changing indications for existing ones is essential to providing effective cancer care. This article aims to increase oncology nurses’ knowledge of immunotherapies.
Cancer immunotherapy involves using the body’s own immune system to fight cancer. Cancer cells avoid detection and elimination by the immune system, and so engaging the immune system against cancer is difficult. Foreign cells such as bacteria have proteins on their surface not normally found in the human body; however, cancer cells are more similar to normal cells and have fewer clear differences from normal cells. This makes it difficult for the immune system to recognize cancer cells as foreign. Immunotherapy treatments often seek to make cancerous cells more obvious to the immune system.
The immune system has two parts, known as the innate and adaptive immune systems. These systems differentiate between pathogens and self. They create an immune response against antigens, which are any substance that raises an immune response.
The innate immune system is diverse. Its components include physical barriers such as skin and mucosal membranes; effector cells that include macrophages, natural killer (NK) cells, innate lymphoid cells, dendritic cells, mast cells, neutrophils, and eosinophils; pattern recognition mechanisms such as Toll-like receptors; and humoral mechanisms that include complement proteins and cytokines.1 Cytokines are a complex group of proteins that are produced when the immune system is activated.2 They allow immune cells to communicate and coordinate their attack on antigens. Cytokines include interleukins, interferons, and colony-stimulating factors, among others.
The innate immune system works rapidly and is usually characterized by tissue inflammation. It uses repeated patterns to recognize pathogens and employs a variety of effector mechanisms to respond quickly. One of its roles is to initiate the adaptive immune system.
The adaptive immune system consists of T and B cells. In contrast to the innate immune system, the adaptive system responds more slowly but is more specific. The adaptive immune system includes B cells, which produce thousands of highly targeted antibodies once activated; regulatory T cells, which provide checks on the activity of the immune system so it does not damage healthy cells; CD4+ helper T cells, which direct and support specialized cells such as B cells and CD8+ killer T cells; CD8+ killer T cells, which can each kill thousands of harmful cells; and antibodies, which seek and bind to antigen proteins. The innate immune system also creates memory of an antigen, which is important for cancer immunotherapy because it can decrease metastasis and limit the occurrence of a second malignancy.3
The innate immune system is linked to the adaptive immune system through dendritic cells.3 When the innate immune system is activated, the dendritic cells travel to nearby lymph nodes and present antigen to T cells, activating them. When the dendritic cell presents an antigen, the response to that antigen depends on the microenvironment where the dendritic cell found the antigen. Ultimately, T cells are responsible for cell-mediated immune responses, which are considered the most important mechanism used by the immune system to kill solid tumors.3
Knowledge of how dendritic cells work has led to sipuleucel-T, which is based on ex vivo (cultured outside the body) activated dendritic cells. A patient’s monocytes, a precursor of dendritic cells, are incubated with a fusion protein that links the target antigen, Prostatic Acid Phosphatase, to a cytokine known as granulocyte-macrophage colony-stimulating factor (GM-CSF). This fusion protein drives the monocytes to mature into dendritic cells. The target antigen causes the activated dendritic cells to produce an immune response against the prostate cancer. Sipuleucel-T was approved by the US Food and Drug Administration (FDA) to treat patients with metastatic prostate cancer. In a randomized, controlled trial, sipuleucel-T improved median survival by 4.1 months, compared with placebo.4
Monoclonal antibodies are now standard of care for a number of tumor types. Antibodies are proteins that bind to a specific antigen. Monoclonal antibodies are designed to recognize very specific antigens on certain types of tumor cells. Monoclonals circulate in the body until they find and attach to the antigen. Once attached, some monoclonal antibodies work by attracting other immune system cells that destroy the cells containing the antigen; others block tumor antigens or molecules that promote the survival of tumors.3,5
Commonly used monoclonal antibodies include trastuzumab (Herceptin), which targets HER2 and is FDA-approved for the treatment of breast cancer and metastatic gastric cancer; and rituximab, which targets CD20 and is FDA-approved for non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). Trastuzumab’s target, the HER2 protein receptor, can be expressed in large amounts on the surface of some cancer cells, where it helps the cells to grow. When trastuzumab binds to the HER2 receptor, it inactivates the receptor. Antibodies such as trastuzumab and rituximab are known as naked monoclonal antibodies, meaning they do not have a drug or radioactive material attached to them. Most naked monoclonal antibodies work through antibody-dependent cell-mediated cytotoxicity (ADCC), in which natural killer cells recognize those cells coated with antibodies and kill them.
Monoclonal antibodies can have a chemotherapy drug, toxic agent, or radioactive material attached to them. Ado-trastuzumab emtansine (TDM-1; Kadcyla) received FDA approval in 2013 for the treatment of metastatic HER2-positive breast cancer in patients who failed prior therapy with trastuzumab and a taxane.1 This antibody-drug conjugate adds the potent microtubule-disrupting drug DM1 to trastuzumab—in other words, a targeted delivery of chemotherapy to cells that overexpress HER2.6 Also in 2013, brentuximab vedotin (anti-CD30-MMAE [monomethyl auristatin E]; Adcetris) was approved by the FDA for the treatment of relapsed or refractory Hodgkin lymphoma or anaplastic large cell lymphoma.1 This drug uses the brentuximab antibody to target CD30, which has limited expression in healthy tissue but is expressed by Hodgkin lymphoma and anaplastic large cell lymphoma. Brentuximab vedotin delivers MMAE, a cytotoxic agent that causes cell death by apoptosis.7
An example of a monoclonal antibody with a radioactive particle attached is ibritumomab tiuxetan (Zevalin). Ibritumomab tiuxetan is an antibody against CD20 with yttrium-90 attached. It is FDA-approved for the treatment of refractory non-Hodgkin lymphoma.1 CD20 is expressed on the surface of lymphocytes, including the cancer cells of patients with non-Hodgkin lymphoma. The radiation enhances the killing effect of the antibody.