Cancer cells are immortal by nature, and thus impervious to the body's immune system that can successfully fight off other diseases. Recent research has focused on ways that the immune system can be strengthened, and thus enlisted in the fight against cancer.
Antibodies are a critical component of a body's defenses. These Y-shaped proteins are produced by the immune system in response to the presence of a foreign invader such as bacteria, viruses, or other cells or proteins that the immune system recognizes to be different from "self." Thousands of white blood cells called B lymphocytes can each make a specific kind of antibody that binds to that antigen. When such immune recognition occurs, the lymphocyte triggers a massive clonal production of the antibody, capable of binding to foreign antigens all over the body.
Tumor proteins are not classically immunogenic to an individual; they are not innately recognized as foreign, so researchers cleverly devised ways to manufacture antibodies that are now targeted to what have become, for all intents and purposes, "target antigens," on tumor cells.
Cancer medicine has replicated the process of antibody production to go after molecules that are expressed on the surface of a tumor cell–an advance predicted by 1908 Nobel Prize winner Paul Ehrlich, who referred to antibodies as potential "magic bullets" in the treatment of disease.
Drug research has focused on monoclonal antibodies, which provide a form of passive immunity by artificially acquired immunization that lasts several weeks and is made possible by injection of engineered antibodies that are targeted to abnormal cancer cells.
The process of producing monoclonal antibodies won its inventors, Georges Kohler and Cesar Milstein, a Nobel Prize in 1984. Researchers do this by injecting human cancer cells into mice so that their immune systems will make antibodies against these foreign cells. They then remove B-cells from the spleen of the mice, and these B cells are then fused with a laboratory grown immortal cell, such as a cancer cell, to create a "hybrid" cell called hybridoma. Hybridomas are factories that can indefinitely produce large quantities of the same type of engineered antibodies - hence the term monoclonal antibodies.
The idea is that these monoclonal antibodies will act like natural antibodies, stimulating a process known as "antibody-dependent cellular toxicity," which employs natural killer cells in the body to remove or neutralize cancer cells expressing the target antigens.
Rituxan and Beyond
Rituxan was the first monoclonal antibody approved by the Food and Drug Administration for treatment of cancer. It was initially approved in 1997 to treat certain types of lymphoma that had not responded to chemotherapy, but it is now standard therapy for the initial treatment of all B-cell non-Hodgkin's lymphoma. Rituxan's chimeric antibody latches on to the CD20 antigen on the surface of these B cell cancers, flagging the immune system to destroy them.
One year later, the monoclonal antibody Herceptin was approved for the treatment of metastatic breast cancer defined by the over-expression of the HER2/neu growth receptor antigen, which characterizes 30 percent of all breast cancer cases. Although it was initially approved for advanced breast cancer, recent studies have found that it cuts the chance of relapse among patients with early breast cancer by 50 percent.
Other approved monoclonal antibodies include Mylotarg, for acute myelogenous leukemia; Campath, for chronic lymphocytic leukemia and T-cell lymphoma; Zevalin, for non-Hodgkin's lymphoma; and Erbitux for metastatic colon cancer.
Avastin, also known as bevacizumab, was initially approved for colorectal cancer and has since been approved for non-small cell lung cancer. It is being studied in a number of other cancers as well. Avastin is unique from other monoclonal antibodies because it does not target an antigen on cancer cells, but goes after a signaling protein, called vascular endothelial growth factor, that stimulates production of new blood vessels that feed the tumor. This process, which scientists call anti-angiogenesis, seeks to kill tumors by choking off their blood supply, which they need to live.
As recently as 2008, scientists released data on Avastin at the AACR's Annual Meeting. Researchers found that adding Avastin to standard chemotherapy and radiation in patients with rectal cancer fully prevented tumor spread and "normalized" tumor blood vessels enough to enable effective therapy. At four years, local control was observed in 100 percent of patients and disease free survival was observed in 88 percent.
In phase I research, the AME-133v, a monoclonal antibody, showed either complete our partial response in one out of four patients with follicular lymphoma. These patients had all been treated with rituximab, a monoclonal antibody, but did not have a response. AME-133v is considered the next generation of therapy.
Inducing Apoptosis
Beyond monoclonal antibodies, researchers are looking at ways to induce apoptosis, or cell death, in a tumor cell. Unlike all other antibodies, which bind to receptors to either turn them off or signal an immune response, this tactic activates so-called "death receptors" on the outside of cancer cells, resulting in tumor cell death.
This strategy focuses on death receptors known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors. TRAIL is part of the Tumor Necrosis Factor (TNF)-super family of receptors and ligands that regulate normal cell death; researchers have tried to use TNF itself as an agent to induce cancer cells to die, but it proved too toxic.
So now research is focused on pharmaceutical agents that can provoke TRAIL to do its work. Researchers in Germany studied bortezomib as a therapeutic option in patients with glioma and found a significant response at the cellular level. In prostate cancer, low-dose 12-O-tetradecanoylphorbol-13-acetate showed activity as well.
Most recent research is taking place at the cellular level, but scientists are also working in clinical trials to see the effect of this antibody therapy in patients. Researchers believe death receptors originated as a mechanism used by the early immune system to "learn" which cells should be destroyed, such as normal cells that are infected by viruses, or immune cells that are not functioning properly.