Evidence Backs BRAF Inhibitor, Immunotherapy for Advanced Melanoma

Patrick Hwu, M.D., head of MD Anderson's Department of Melanoma Medical Oncology, presented evidence supporting the combination of BRAF inhibitors with immune therapy to treat advanced melanoma this morning at the 2012 American Association for Cancer Research annual meeting in Chicago.

Hwu chaired one of the meeting's three plenary sessions, titled "Immune Therapies: The Future Is Now." He presented results of research conducted with Gregory Liz_e, Ph.D., and Chengwen Liu, in his department.

Patients with advanced melanoma have a median survival of less than a year. Targeted therapy with BRAF inhibitors has shown promising response rates above 50 percent, but with less than 7-month median response duration, while immunotherapies such as interleukin-2 or anti-CTLA-4 can induce long-term survival in some, but have low response rates.

"Exciting new targeted and immunotherapy options for melanoma patients have emerged over the past year. Ultimately, the best potential patient outcomes may involve combinations of these two important approaches," says Hwu. "Such combinations may have the potential to result in higher, more durable clinical responses in patients with metastatic cancer."

The researchers found:

• Mutated BRAF induces an immunosuppressive tumor microenvironment which can be reversed by BRAF inhibitors.
• BRAF inhibitors enhance the migration of T-cells to tumor in a mouse tumor model.
• Therapy with BRAF inhibitors does not inhibit immune function in patients with metastatic melanoma.

"Kinase-targeted therapies for cancer have shown much promise for treating tumors. However, historically, many of these drugs have demonstrated off-target effects that can be harmful to normal cells of the immune system," Liz_e notes. "More recently developed kinase-targeted agents such as vemurafenib and GSK2118436, which target the mutated BRAF oncogene in melanoma, show far greater specificity for tumor cells and leave immune cells relatively unharmed."

Mutated BRAF suppresses immune system The researchers collected experimental evidence in both mouse models and humans showing that such treatments may actually act in a synergistic manner when combined.

"This is due to the fact that the BRAF oncogene appears to be an active inducer of immune suppression in cancer," Liz_e says. "Specific BRAF inhibitors were shown to reduce the production of immunosuppressive factors by tumor cells, leading ultimately to an increase in the infiltration of cytotoxic T-cells into tumor sites and improved antitumor responses.

"Furthermore, patients undergoing BRAF inhibitor treatment showed no detrimental effects on their immune system, providing a strong rationale to combine immunotherapy with specific kinase-targeted agents in future clinical trials for cancer patients," he says.

Because of their mutual interest in melanoma immunotherapy, Hwu and Liz_e became interested in exploring the possible connection between oncogene activation in cancer and immune suppression. "If inhibition of oncogenes reduced immune suppression in patients, it would make our immune therapies that much more effective," Liz_e says.

"Dr. Hwu and I decided to combine forces to do this study because we discovered we were working on different aspects of the same thing, only using different models; my lab's studies using human cells were in agreement with his findings using mouse models. The fact that BRAF inhibitors do not appear to harm the immune system makes us very excited to start combination trials in our melanoma patients," he notes.