Despite ipilimumab’s therapeutic success, its overall response rate is 10% to 15% in patients with advanced melanoma.15,16 When disease progression occurs, localized radiotherapy is administered to relieve tumor pressure. In some instances, the addition of radiotherapy results in an abscopal effect. The abscopal effect refers to a rare phenomenon of tumor regression at a sight distant from the primary site of radiotherapy. Localized radiotherapy has been shown to induce the abscopal effect in some types of cancer, including melanoma.17 The biologic characteristics underlying this effect are not clearly understood but may be mediated by immunologic mechanisms.18 Ipilimumab has also been shown to enhance immunity to NY-ES-01 and patients with pre-existing NY-ESO-1 antibodies seem to benefit even more. NY-ESO-1 is an antigen expressed in 30% to 40% of patients with advanced melanoma. It is not present in normal adult tissue except in testicular germ cells and the placenta.19
Postow and colleagues reported on the success of the addition of radiotherapy to a woman undergoing treatment for metastatic melanoma with ipilimumab and its effect on NY-ES-01.17 Radiotherapy was administered in order to reduce tumor pressure on her spine. Four months later, her spinal tumor, as well as tumors distant to the primary site of radiotherapy, began to shrink as is seen with the abscopal phenomenon. One metastatic lesion was removed prior to ipilimumab treatment and the NY-ESO-1 expression was confirmed. Temporal associations were also noted and included tumor shrinkage with antibody responses to NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. This patient’s unexpected systematic response to radiotherapy in combination with ipilimumab provides new insights and may open the door for new therapeutic options for treating advanced melanoma.
Though these results appear promising, the vast majority of patients with metastatic melanoma do not respond to the anti-CTLA-4 antibody and still need effective treatment options. In 2002, researchers at the Sanger Institute discovered that mutations in the gene encoding the serine/threonine protein kinase B-RAF (BRAF) occurred in more than 60% of melanomas initially tested.20 Melanomas that carry the BRAF V600E mutation activate the mitogen-activated protein kinase (MAPK) pathway at a continuous rate, thereby promoting cell proliferation and preventing apoptosis.21 Vemurafenib (Zelboraf, Genentech, Inc.), a new agent approved in 2011 in the battle against melanoma, was developed as a potent kinase inhibitor with specificity for the BRAF V600E mutation within cancer cells.