#2 Anti-CTLA-4 Drug (ipilimumab), Targeted T-Cell Antibody for Metastatic Melanoma

Overview

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells located
in the skin. While anyone can develop melanoma, it is still not clear how all melanomas develop. Exposure to
ultraviolet (UV) radiation clearly plays a big role. A history of sunburns, especially severe sunburns at an early age, have been shown to increase the risk of developing melanoma. In addition, exposure to UV radiation from indoor tanning increases the danger.

Melanoma usually occurs in adults, but it is sometimes found in children and adolescents. About 20% of all
melanomas will spread. This cancer is not only resistant to most drug therapies, but when it moves to the brain,
there is little that can be done to arrest its onslaught. Patients with late-stage melanoma have a 15% survival rate.

Although melanoma accounts for barely 3% of skin cancer cases, it causes the most skin cancer deaths.
The incidence of metastatic melanoma has increased over the last 30 years, and the death rate has been increasing faster than that of most other cancers. There were approximately 68,000 new cases of melanoma in the United States in 2009, with 8,700 melanoma-related deaths.

A recent randomized study in the New England Journal of Medicine reported that about 23% of patients with
advanced stage III or IV metastatic melanoma in 125 cancer centers who took an experimental anti-CTLA-4 drug called ipilimumab were still alive two years later, compared to 14% of those who did not receive the drug. Onaverage, those taking ipilimumab survived 10 months, compared to the six months for those who received only a melanoma drug.

What ipilimumab does so well is specifically target the protein molecule, CTLA-4 (or cytoxic T-lymphocyte associated antigen 4), which is found on white blood cells and suppresses the immune system from fighting disease. When ipilimumab is taken, it acts as a T-cell potentiator, however, and blocks the action of CTLA-4, allowing the patient’s immune system to fight the cancer more vigorously. Even though ipilimumab does not cross the blood-brain barrier, the newly activated T-cells do. Small studies with ipilimumab have reported that patients with brain metastases caused by melanoma experienced a 15-month response from the drug, on average.

The long-held dream of researchers to find a way to harness the patient’s own natural defense system to destroy their cancer tumor cells is now getting closer to reality. The effectiveness of ipilimumab in melanoma therapy further confirms the role of immunotherapy as an effective therapeutic treatment, and there are now ongoing clinical trials with other promising immunotherapeutic drugs for patients with prostate cancer and neuroblastoma.

The FDA grants priority review status to medications that offer major advances in treatment, or that provide therapy where no adequate treatment exists. Based on its extraordinary response in improving the survival rates of patients with previously treated advanced melanoma, ipilimumab has received FDA priority review status and the approval of this life-saving drug is expected soon. If all goes as expected, ipilimumab will be the first new melanoma drug available in decades.

Where Are They Now

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells located in the skin. Although melanoma accounts for barely 3% of skin cancer cases, it causes the most skin cancer deaths. A new drug called ipilimumab specifically blocks the action of the protein molecule, CTLA, which is found on white blood cells and suppresses the immune system from fighting disease. Ipilimumab targets CTLA and allows the patient's immune system to fight the cancer more vigorously.

Ipilimumab was approved by the FDA in March 2011 and in recent phase III trials, the combination therapy of ipilimumab and nivolumab was found to significantly increase progression free survival of melanoma patients by as much as 60% when compared to treatment with ipilimumab alone. Professionals believe that this novel combination of two cancer therapies will become the new standard of care for treatment of melanoma. The therapy has been used in trials for both brain metastasis and systematic disease and has reported similar response rates according to earlier published studies. A 2016 published paper cites the therapy as having challenges with immune checkpoint inhibitors in the treatment of brain tumors more than Metastatic Melanoma. The outlook, however, remains hopeful as more years of research are necessary to test the effectiveness of the therapy as it pertains to brain tumors. As for the metastatic melanoma aspect of the therapy, a 2016 case where this therapy was adapted to a patient previously resistant to T- Cell transfers and impilimumab treatment and was considered a success as of May 2016 as the patient remains disease free. The outcome of combining CTLA4 blockade and the transfer of T cells enhanced the activity of T Cells and provides a broad promise for ipilimumab- resistant melanomas.
 

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