Immunotherapy is a New Generation of Cancer Therapies that are Revolutionizing the Treatment of Melanoma and Many Other Malignancies.

These drugs are significantly different from conventional cancer treatments, which include chemotherapy, radiation and newer medications that target genetic mutations in tumors that spur unchecked cell growth. Instead of attacking the tumors themselves with the aim of killing them, immunotherapies rally the body’s natural defenses and unleash the immune system to vanquish the cancer. There are several molecules on the surface of immune cells that need to be activated to launch an immune response. But because cancer cells share traits with healthy cells, the immune system doesn’t recognize them as aberrant, and cancer cells avoid detection. The new drugs help the body circumvent this bit of subterfuge.

For over 40 years, the John Wayne Cancer Institute has investigated how tumors evolve in the context of the immune system.

Institute co-founder Donald L. Morton, MD, was an early advocate of finding ways to harness the immune system’s power to fight cancer. In the early 1970s, he pioneered a method of injecting Bacilli Calmette-Guérin (BCG), a weakened strain of the tuberculosis bacterium, directly into melanoma tumors, which was the first successful use of immunotherapy against metastatic human cancer. This research commenced in the melanoma research program under the late Dr. Donald L. Morton and continues today.

In 2011 the first of these drugs gained FDA approval. Ipilimumab is now used for metastatic melanoma. The drug is the first melanoma treatment that actually extended survival for people with late-stage disease. More than 20% of the patients were still alive three years later; most of them would have died otherwise. The drug thwarts the action of a protein known as CTLA-4.

This is a checkpoint molecule that acts as an “off switch” that cripples the T cells—the immune system’s foot soldiers—and stops them from harming healthy cells. But it can also block the T cells from attacking tumors.

Meanwhile, pembrolizumab and nivolumab target other proteins on the surface of cells—called PD-1 and PD-L1—that also act as immune system brakes. Pembrolizumab produces a response in a stunning one-third of patients.

“We have two new ways of approaching melanoma: directly attacking the melanoma cells with new molecular therapies, and immune therapies,” he says. “My passion has been to help develop these medical treatments for melanoma. The progress is tremendous. We now have patients with widespread melanoma who traditionally would have had about six months to live. Now almost half of these patients are being cured or have long-term survival.”

-Dr. O’Day

Clinical Trials

The John Wayne Cancer Institute has continued to be a leader in the field of immunotherapy and currently has a large number of clinical trials using immunotherapy combinations, immunotherapy with novel targeted therapy and immunotherapy with intratumoral injections. These trials are led by Dr. Steven J. O’Day.  In Dr. O’Day, the Institute has found a leading authority in the rapidly evolving field of cancer immunotherapy. Dr. O’Day played a leadership role in the development of the immune checkpoint inhibitor ipilimumab and presented the breakthrough ipilimumab clinical trial results at a 2010 meeting of the prestigious American Society of Clinical Oncology (ASCO). He was a clinical investigator in the development of the anti-PD1 antibodies pembrolizamab and nivolumab as well as the development of the MAPK inhibitors vemurafinib, dabrafinib and trametinib.

Doctor and nurse talking

Intra-Tumoral Immunotherapy

One of the most promising areas of clinical research in melanoma involves the administration of treatments directly into tumors.

The types of medications that are given that way vary, but that route enables physicians to not only deliver higher doses specifically to the tumor while sparing the rest of the body, it enables the use of targets within the tumors themselves. An example of this approach is intra-tumoral immunotherapy.

In intra-tumoral immunotherapy, agents that stimulate or help an immune response are placed directly within tumors. The goal of those responses is not only to kill the tumors into which they are injected, but also to generate a more far-reaching immune response, much like vaccination. Some of the therapies that have been investigated include what are called oncolytic viruses, which are viruses that have been modified to be able to grow preferentially in cancer cells. Others include gene therapies or more well established vaccine adjuvants.