Advanced melanomas that recur after surgery are difficult to treat with radiation and chemotherapy. New treatments, such as immunotherapies, offer benefits for these more advanced cancers. Immunotherapies stimulate the body’s immune system to attack cancer cells in various ways. Some forms of immunotherapy are already approved and routinely used to treat some melanomas, while others are still experimental.
In 2011, the U.S. Food and Drug Administration (FDA) approved ipilimumab (Yervoy) to treat metastatic melanoma. It was the first new drug approved to treat this disease in over 14 years. Seattle Cancer Care Alliance (SCCA) was involved in the earliest clinical trials of ipilimumab, which yielded promising results.
Ipilimumab is a monoclonal antibody that sticks to an important protein on blood cells called T-lymphocytes, or T-cells, the most important immune-system cells in controlling tumor growth. Ipilimumab blocks a signal on T-cells that suppresses their activation after a normal, vigorous response to infection or inflammation. This suppression protects our tissues from being attacked by our own overactivated T-cells. But it can also prevent our T-cells from attacking tumor cells. Blocking the signal with ipilimumab allows T-cells to recover their activity and kill tumor cells. While ipilimumab can provide long-term remission for a fraction of patients, it occasionally causes dangerous side effects resulting from an autoimmune reaction in which the patient’s overstimulated immune system attacks not only cancer cells but the patient’s healthy tissues.
After surgery to remove melanoma, interferon is sometimes recommended to reduce the chance of melanoma returning. Another form of immune-stimulating treatment, but less powerful than ipilimumab, interferon is being tested in patients after surgery. While interferon has been a standard FDA-approved treatment for nonmetastatic melanoma following surgery, its ability to prevent relapse is very weak, and it causes many side effects. Many investigators and companies are working to develop better and safer therapies for patients at risk of relapse following melanoma surgery.
A synthetic version of interleukin-2 (IL-2), a natural cytokine (protein that can boost the immune system), may be used to control advanced melanomas. Sometimes IL-2 is given along with chemotherapy. It has been used for several decades and is sometimes used to treat patients whose melanoma has spread. The potential benefit is that some patients on this therapy may achieve long-term complete remission (no sign of cancer). But due to the potential for severe side effects IL-2 use is limited. Patients and doctors should discuss and carefully weigh the potential benefits and risks before starting this treatment. Studies are underway to find out if some patients have specific features that make them more likely to benefit and if testing can identify these patients. This would help doctors to determine whether the potential benefit for a particular individual outweighs the risks associated with the treatment’s toxicity.
Many types of investigational immunotherapies are being offered at SCCA to patients with melanoma. They include drugs that block PD-L1 or PD-1 and tumor-infiltrating lymphocyte therapies.
Drugs that Block PD-L1 or PD-1
Melanoma cells often have a protein on their surface called PD-L1 that helps them evade the immune system. The PD-L1 on tumor cells sticks to a substance called PD-1 on T-cells, causing the T-cells to undergo programmed cell death. This lethal phenomenon can be prevented by blocking the interaction between PD-L1-expressing tumor cells and PD-1-expressing T-cells. Blocking either PD-L1 or PD-1 can allow the T-cells to attack the tumor effectively. New antibody drugs that block either of these elements have shown great promise against melanoma and several other tumors and are under investigation at SCCA and other centers. Recently completed as well as ongoing studies are expected to lead to FDA approval of one or more of these antibody drugs in the not-too-distant future.
Antibodies that block PD-L1 or PD-1 may have higher antitumor activities than ipilimumab. They also appear to be associated with milder and less frequent autoimmune complications. Combinations of ipilimumab and PD-1-blocking antibodies are being studied because their effects are slightly different, so together they may stimulate the immune system even more effectively than either drug alone.
Tumor-infiltrating lymphocyte (TIL) therapy is another promising form of immunotherapy being investigated in people with stage IV melanoma. TILs are unique because they are immune system cells that naturally exist in people and that infiltrate melanoma tumors.
TILs can recognize and attack melanoma cells, but melanoma responds by suppressing TILs and placing them in a sleeping state. Doctors can remove some suppressed TILs from the patient, reactivate them in the laboratory, grow them into the billions, and then reinfuse them into the patient. The idea is that the high number of activated TILs will be able to attack the melanoma more effectively. This therapy is still investigational but has achieved long-term disease control and some complete responses in melanoma patients.
For this treatment, doctors surgically remove a melanoma tumor from the patient’s body. A portion of the tumor is delivered to a laboratory at Fred Hutchinson Cancer Research Center. In the lab, TILs are generated from the melanoma tissue over five to seven weeks. Then they are ready for infusion back into the patient. They can also be frozen (cryopreserved) for future use, if the patient is not ready for treatment.
Prior to the infusion of TILs, patients receive one week of lymphodepleting chemotherapy, which prepares their body by clearing out immune cells suppressed by their cancer and making space for the incoming TILs. After the TIL infusion, patients receive high-dose IL-2, which “feeds” the freshly infused TILs so they survive longer and attack cancer cells more effectively. The hospital stay for chemotherapy, TIL infusion, and high-dose IL-2 is around 10 to14 days.
Molecularly targeted drugs are not immunotherapies, but some of them can enhance the immune system’s control of a tumor. However, because of potentially severe side effects, it is essential to test combinations of targeted drugs and immunotherapies carefully in clinical trials to find the best and safest doses and schedules, which may also depend on certain patient characteristics. Learn more about targeted therapies for melanoma.
To learn more about clinical studies for melanoma at SCCA, be sure to ask your doctor about melanoma studies that are recruiting patients.
“The Power Within,” an article on the Hutch website, provides an excellent overview of immunotherapy and its potential for fighting cancer.