Immunotherapy may be patients’ biggest hope for transforming cancer treatment. This approach boosts a patient’s own immune system to fight cancer. More and more immunotherapy treatments are showing promise for more and more patients, and Science magazine named immunotherapies 2013’s Breakthrough of the Year.
Melanoma, which has always been at the leading edge of cancer immunotherapy, was again at the forefront in 2013. In particular, researchers saw successes for immunotherapy drugs known as immune checkpoint antibodies. These drugs boost the immune system by attacking certain immune system-blocking proteins, including PD-L1, PD-1, CTLA-4, and a combination of the last two. Some of these drugs were described in an earlier blog post.
So far, 2014 has seen progress in scientists’ understanding of why immune checkpoint antibodies (such as the anti-PD1 drugs nivolumab and MK-3475 and the anti-PD-L1 drug MPDL2380A) work—or don’t work. The need to understand why immunotherapies are very efficient in some but not all patients is obvious.
PD-L1 is a protein that is expressed on some melanoma tumor cells. When it encounters and binds to PD-1 on immune system cells called T cells, PD-L1 inhibits T cells’ tumor-killing abilities. It would seem that expression of PD-L1 on tumors would incapacitate immune T cells attempting to invade a tumor. Perhaps so, but recent insights have revealed that PD-L1 is actually associated with the presence of high numbers of T cells in tumors (a recognized ‘good sign’). Indeed, it has now been shown that T cells invading and trying to attack tumors actually trigger increased expression of PD-L1 on tumors (see this interesting study from Thomas Gajewski’s laboratory at The University of Chicago). Moreover, it is these high-PD-L1 tumors that are most responsive to anti-PD-1 immune checkpoint antibodies (nivolumab or MK-3475), as another study concluded.
These insights were upheld at the 2014 American Association for Cancer Research (AACR) Annual Meeting, held April 5–9 in San Diego, California. A clinical trial testing MK-3475 had previously found a melanoma-fighting effect in 41% of patients given different doses of the drug; 81% of patients survived for at least 1 year after the treatment. New results from this 135-patient trial were presented at AACR by Adil I. Daud, Ph.D., director of melanoma clinical research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. He reported that 46% of patients whose tumors expressed PD-L1 responded well to treatment, compared to only 17% of those whose tumors did not express PD-L1. One-year survival was also higher in PD-L1–positive patients: 86% were still alive after 1 year compared to 72% of patients with PD-L1–negative tumors.
It should be noted that similar results were found when MK-3475 was given to patients with lung cancer, even though notable differences exist between lung cancer and melanoma. However, a lot of work still needs to be done to transform these findings into standard-of-care practice for oncologists. For one, it is not trivial to quantify the expression of PD-L1 on tumors, and a reliable test needs to be developed and validated.
In a recent publication from the laboratory of Steven Rosenberg, Ph.D., at the National Cancer Institute, expression of PD-1 on T cells that had invaded melanoma tumors was found to be strongly predictive of the success of an immunotherapy treatment known as adaptive cell transfer (ACT). ACT is a hugely promising new treatment. Even though ACT is fairly complicated, this finding may help identify those patients for whom it could be most effective.
At AACR, preliminary results were also reported from a clinical trial that is testing a new drug called DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma. Each molecule of DEDN6526A has two parts: an ‘antibody’ protein that recognizes and binds to a protein called ETBR, and a drug that kills cells in the process of multiplying. ETBR is found at high levels in metastatic melanoma compared to normal skin, so the antibody delivers the drug directly to the cancer cells, sparing healthy cells.
Of the 12 patients who received 1.8 mg/kg of DEDN6526A in the trial, 4 (2 with cutaneous and 2 with mucosal melanoma) experienced tumor shrinkage. The other 8 patients had stable disease (tumors that neither grew nor shrank) for at least 6 months. Jeffrey R. Infante, Ph.D., lead author of the study and Director of the Drug Development Program at Sarah Cannon Research Institute in Nashville, Tennessee, noted that patients with any form of melanoma with high levels of ETBR seem more likely to benefit from treatment with DEDN6526A.
Another newsworthy item from the AACR meeting was a report of preliminary findings from a clinical trial testing a vaccine treatment for melanoma. The vaccine, known as IMCgp100, resulted in long-lasting tumor shrinkage or disappearance for some patients, leading to expansion of the trial to allow more patients to enroll.
On the other hand, some recent immunotherapy news has been disappointing. Talimogene Laherparepvec (T-VEC), a virus-based treatment for advanced and metastatic melanoma, showed promising results for patients as recently as in March 2014. In a reversal of this good news, the latest from this phase III trial revealed that the goal of improved overall patient survival was not achieved.
Finally, there are some hopeful developments for melanoma patients whose tumors have mutations in the BRAF protein (as detected by molecular testing). A recent study published in the scientific journal Nature determined that the mutant BRAF protein relies on copper for its cancer-promoting activity. The U.S. Food and Drug Administration (FDA) has already approved drugs that lower levels of copper in the body to treat a metabolic disorder known as Wilson disease. (Wilson disease is a genetically based inability to filter out and get rid of excess copper.) In a remarkable example of a quick transition from basic science to clinical investigation, Duke University (where the original research was performed) has opened a clinical trial that will test if lowering copper levels with an FDA-approved drug trientine may improve outcomes for patients taking the drug vemurafenib to treat their melanomas.