Nobel Prize Award Leads to Increase in Immunotherapy Research for Cancer Treatment

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According to estimates by The National Cancer Institute, the federal government’s principal agency for cancer research and training, 609,640 people in the U.S. will die from cancer in 2018, and an astonishing 40% of all Americans will be diagnosed with cancer at some point in their lifetimes. Perhaps these alarming statics are an indication for why there seems to be a renewed sense of hope, not to mention significant financial investment, around the science of immunotherapy — a type of cancer treatment that helps the body’s immune system fight cancer.

Immunotherapy isn’t a new idea; it has been used as a means to treat diseases such as smallpox as far back as the 18th century. However, only during the last 40 years have scientists been able to unlock the incredible healing capability of the human body to combat cancer — which is fueling an advanced rate of research funding by public, private and government entities alike.

Most recently, immunotherapy researchers James Allison MD of the Anderson Cancer Center and Tasuku Honjo of Kyoto University were honored with the 2018 Nobel Prize in Physiology or Medicine for their groundbreaking work on uncovering ways to activate the immune system to attack cancer. Their work led to the development of several drugs which allow for the routine use of effective immunotherapy. This is the first time in the history of the award that the development of a cancer treatment has been recognized with a Nobel Prize.

Today, thanks in part to the work of Allison and Honjo, cancer immunotherapy is one of the most rapidly growing areas of research in medicine, and clinical trials have already shown its effectiveness in treating patients with advanced stages of many types of cancer.

Did You Know?
The earliest medical use of the word “immunity” was in 1881, which meant, “exempt from disease,” in reference to the use of inoculations.

What is Cancer Immunotherapy?
The human immune system is the body’s defense system to combat pathogens and abnormal cells that can lead to infections and disease. Scientific advances have allowed treatments for a wide variety of diseases, as well as the safe transplanting of organs and the development of antibodies. Undoubtedly, some of the most exciting advances are occurring in the realm of cancer treatment. Now, by understanding how the immune systems works, cancer immunotherapy can give the body enhanced powers to carry out the identification of and eradication of damaged and cancerous cells.

How Do Cancer Cells Grow?
Human beings, and the organs that make up our bodies, are never quite at rest. Scientists estimate that nearly two trillion cells divide every day, although not all parts of the body create new cells at the same rate. Sometimes new cells are necessary to replace dead cells, as in the case of our skin where 30,000 to 40,000 old skin cells die every day and the entire outer layer of skin is replaced about every two weeks. For other body parts, new cells are required to replace damaged or injured tissue.

Cancer can occur when these continually growing cells contain mutations from the parent cell. Mutations are understandable when one considers that every time a cell divides, more than 3 billion DNA ‘letters’ that make up the genetic code of the parent cell are copied. Mistakes will happen.

In many cases, the immune system is prepared for this eventuality and equips the body to fight back and destroy these cells before any damage can be done. Unfortunately, when certain conditions exist, such as exposure to a cancer-causing substance (carcinogen) or other factors such as aging, lifestyle choices or even genetics, basic elements of the immune system, such as antibodies or other checks and balances against mutation, may not be up to the challenge.

T-Cells to the Rescue
T-cells are a type of white blood cell that is a prime element of the immune system. T-cells perform many functions, but one of the most important is to hunt down bacteria, viruses, mutations, or otherwise dangerous cells and destroy them before further cell division can occur. They use special molecules called antigens to differentiate between healthy and unhealthy cells. Receptors on the surface of a T-cell can bind with antigens that exist on the surface of a regular cell. If that antigen is on an unhealthy cell, the T-cell “reads” the antigen and will bind to it in order to release cytotoxins into the cell to destroy it.

Did You Know?
Spencer Trask, and in particular our Chairman, Kevin Kimberlin, was an early proponent of immunotherapy when he co-founded The Immune Response Corporation with polio vaccine pioneer, Jonas Salk. The company was founded in an effort to develop a vaccine that used the human body’s immune system to treat AIDs/HIV in the early 1990s.

Allison and Honjo — Weaponizing T-Cells
An issue that perplexed scientists was why T-cells fail to perform the task for which they are created. Despite the presence of cancerous cells, for some reason, T-cells appeared to be holding back, as if something was preventing them from doing their job. The goal became to boost the effectiveness of T-cells.

In the 1990s, working independently, Allison and Honjo each identified separate proteins that existed on the surface of T-cells that appeared to be inhibiting T-cells from binding with the antigens on cancerous cells and releasing the cytotoxins to kill the cells.

While at the University of California, Berkeley, Allison was among several scientists who found what was deemed a “checkpoint” protein, CTLA-4. CTLA-4 acted as a ‘brake’ on T-cells and actually kept them from performing to full potential. It seems that certain cancer cells could actually activate these checkpoint proteins that help a T-cell recognize a good cell from a bad one in order to avoid being destroyed. This is, of course, one of the wonders of any living organism, the creation of methods to protect its destruction. After all, the cancerous cell didn’t see itself as a threat to the body. Instead, it sees the T-cell as a threat to its own existence.

In 1996, Allison and his team developed an antibody that actually clung to the CTLA-4 and released the inhibiting factors generated by the cancerous cell. They then conducted experiments on mice with cancer, and using the antibody they had developed were able to not only eliminate cancer in the mice, but also prevent new cancerous tumors from growing. However, the medical community was skeptical that the same results could be found in humans. It wasn’t until 2003, after further clinical studies, this time on humans with metastatic melanoma, that the effectiveness of the CTLA-4 antibody on humans, although limited, was demonstrated. It took further research and testing for their antibody to be approved by the Food and Drug Administration (FDA) as a treatment for late-stage melanoma under the drug name, Ipilimumab.

Meanwhile, in 1992, at Kyoto University in Japan, Honcho identified a separate protein, called PD-1 (or programmed death-1), which, much like CTLA-4, also acted to inhibit the function of T-cells, although in a different manner. His team developed treatments to prevent the PD-1 from blocking the T cell’s performance. Their discovery proved effective against melanoma, as well as lung and renal cancers and certain types of lymphoma.

The results of the efforts of these two scientists and their teams have led to the creation of drugs, known as ‘immune checkpoint therapy’, which often combine the effectiveness of both CTLA-4 and PD-1 to target inhibiting proteins on T-cells. In addition, scientists are seeking to locate other checkpoint proteins besides CTLA-4 and PD-1 to widen the effectiveness of the immune system.

Did You Know?
Immune checkpoint therapy is but one of several types of cancer immunotherapies being tested today. Others include the use of monoclonal antibodies, cancer vaccines, and TRC, TIL, and CAR T-cell therapies.

A Long Journey
As with any new therapies, there are potential obstacles to immune checkpoint therapies gaining approval by the FDA. One is effectiveness for its intended use. Another is that the side effects cannot be harmful to the patient. Many of these therapies have produced side effects such as nausea, fatigue, flu-like symptoms, weight gain, diarrhea, and heart palpitations. In addition, as more researchers get on the immune checkpoint therapy bandwagon, funding sources are stretched and there may be tendencies to funnel funding and back the leading horse at the expense of broadening the research opportunities in order to more fully explore cure possibilities.

The Future
Overall, however, the results have been encouraging. As researchers learn more about human cell structure and the way the human body’s immune systems works, the future in the fight against cancer looks bright.

Just last month, a study published in the New England Journal of Medicine (Oct. 20, 2018) reported that immunotherapies helped extend the lives of women diagnosed with aggressive breast cancer. Researchers ran a clinical trial involving more than 900 patients with metastatic triple negative breast cancer who did not receive earlier treatment for metastatic disease. Patients receiving a combination of standard chemotherapy and immunotherapies reduced the risk of the death or the disease getting worse by 20 percent.

One thing is certain: Immunotherapy is changing cancer care and offering new hope for cancer patients.

Would you like to learn more about the history of immunotherapy? The Cancer Research Institute has put together an interactive “timeline of progress” that tracks key milestones from 1890 to 2018.

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Spencer Trask

Spencer Trask & Co. transforms big ideas into world-leading ventures through the power of the Spencer Trask Network.

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