This class of immunotherapies work by targeting the differences within cancer cells compared to normal, healthy cells. As these types of therapies do not normally affect healthy cells, the side effects are often quite different from that of non-targeted and chemotherapy treatments. These therapies work by triggering the immune system to specifically focus in on cancer cells or from inside the cell to result in cell death.
Immunotherapy agents can affect the stages of the adaptive cancer-immunity cycle. Checkpoint inhibitors, CAR T-cell therapy and cancer vaccines target different stages of the cancer cell cycle.
One of the body’s own defense strategies is the production of antibodies, proteins that bind to specific antigens on the surface of the cancer cells, thereby marking them for destruction by immune cells. Researchers are designing antibodies that target specific antigens on cancers cells to boost the immune response, called monoclonal antibodies.
Monoclonal antibodies are an example of active immunity and are being used to treat cancer (breast, lymphoma, and colorectal) in addition to a variety of other diseases. Monoclonal antibodies can be used to block the production of abnormal proteins found in cancer cells, attach to proteins on the surface of cancer cells and flag the cells for destruction, or by inhibiting or slowing down the pathways that cancer cells use for growth.
They can also be conjugated to therapeutic drugs that have cytotoxic effects on cancer cells. However, one caveat that must be considered is for monoclonal antibodies to be effective, researchers must identify the exact antigen for specific cancer cells present in patient’s body. This means this treatment option is only effective in certain cancer types.
Example of FDA Approved Therapy
Nivolumab (Opdivo, Bristol-Myers Squibb) is a human monoclonal antibody against programmed death-1 (PD-1) inhibitory receptor expressed on a variety of immune cells. Binding of PD-1 to one of its two ligands, PD-L1 or PD-L2, results in suppression of the immune response. Nivolumab has a high specificity and affinity for the PD-1 receptor and its blockage of the PD-1/PD-L1 or PD-L2 inhibitory pathway, which leads to increased immune system regulation.
Nivolumab is approved both as a monotherapy and in use with other therapeutic agents in a variety of cancer types; however, the use of PD-L1 as a biomarker is still heavily debated.
Checkpoint Inhibitors - Pathway Specific
As discussed in module 3, the different pathways elicited by the immune system are regulated by various checkpoint proteins and/or factors that can stimulate or inhibit the immune response to stimuli. Targeted immunotherapies primarily focus on checkpoint inhibitors as a way of passive immunity and are a variant of monoclonal antibodies discussed above.
Immune checkpoint inhibitors, as you may recall, work by slowing down or stopping an overly active immune response with the potential to damage healthy cells in addition to the cancer cells that initiated the response. These inhibitors work by preventing T cells from interacting and thereby mounting an immune response against other cells.
Tumor cells exploit this mechanism and deactivate tumor-infiltrating lymphocytes (TILs) thus preventing them from targeting tumor cells. One of the most well-known pathways exploited by tumor cells is PD-1/PD-L1. PD-1 receptor is expressed on the surface of activated T cells upon binding with PD-L1 on the surface of healthy cells, a signal is sent to prevent T cells from attacking normal cells. Some tumor cells overexpress PD-L1 to bind to activated T cells and render them inactive and ineffective.
Therapies that target immune checkpoint inhibitors are not interacting directly with tumor cells, they are targeting either PD-1 or PD-L1 to inhibit the binding, thereby enhancing the immune response against cancer cells.
Example of FDA Approved Therapy
Pembrolizumab (Keytruda, Merck) operates in a similar manner to nivolumab; it is a highly selective human monoclonal antibody that targets the PD-1 receptor on the cell surface. Pembrolizumab enhances the activation of T-cell mediated immune response against cancer cells by inhibiting the binding of PD-1 produced by the tumor cell from binding to its receptor. Pembrolizumab has been used across a variety of cancer types both as a monotherapy and in combination with other anti-cancer pharmacotherapy as well as in all lines of therapy.
Therapeutic vaccines contain whole or fragments of cancer cells or antigens associated with a specific type of cancer. They are designed to expose the immune system to a specific antigen to stimulate an immune response to recognize and destroy cancer cells containing that antigen. A patient’s immune cells can be removed and used to create the vaccine that will then be injected back into the body to enhance the immune response to inhibit cancer growth, shrink tumor, prevent recurrence, and potentially eliminate cancer cells all together. These vaccines can often be combined with other therapeutic agents to aid in boosting the immune system.
Some cancers are also caused by viruses, for instance human papillomavirus (HPV) strains have been linked to cervical, anal, throat, vaginal, vulvar and penile cancers. Thus, vaccinating patient populations at high risk for developing certain cancers helps protect against infection and the potential development of the associated cancers. Vaccines for HPV have been shown to significantly reduce the likelihood of developing cervical cancer. These types of preventive vaccines do not target cancer cells directly as they have not formed yet. While immunotherapeutic vaccines work by signaling the immune system to mount a direct attack on specific cancer cells currently in the body.
Example of FDA Approved Therapy
Sipuleucel-T (Provenge, Dendreon Pharmaceuticals LLC) is FDA approved for the treatment of advanced prostate cancer. Provenge is made by harvesting antigen presenting cells and dendritic cells from a patient and then modifying them in the laboratory to immune vaccine to be re-introduced in the patient. The vaccine then stimulates the T-cell immune response in the body to target the prostatic acid phosphatase antigen highly expressed on most prostate cells.
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