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Melanoma is one of the major cancer types for which new immune-based cancer treatments are currently available, with more in development. This page features information on melanoma and immunotherapy for melanoma patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with melanoma.
Melanoma is the deadliest form of skin cancer. Although it comprises less than 5% of skin cancer cases, melanoma accounts for the great majority of skin cancer-related deaths. Over the past few years, immunotherapy has dramatically changed the landscape of melanoma treatment. The immune-based treatment Yervoy (ipilimumab) was the first drug shown to extend survival among patients with advanced melanoma and was approved by the FDA in 2011. A number of exciting new immune-based treatments in development promise to save more lives.
In 2016, in the U.S., approximately 76,380 new melanomas will be diagnosed, and about 10,130 people will die from this disease. That is more than one life claimed every hour in the U.S. Moreover, the incidence of melanoma is on the rise in the U.S. and around the globe.
The main risk factor for melanoma, as for all skin cancer, is exposure to natural and artificial ultraviolet (UV) light. According to the American Academy of Dermatology, more people develop skin cancer from tanning than develop lung cancer from smoking.
Although melanoma is often easier to detect in its earlier stages than most cancers, it is also more likely to spread (metastasize) to other parts of the body. Metastasis represents the most significant cause of death from the disease. The 5-year survival rate for localized (stage I and II) melanoma is 98%; however, this drops to 17% in cases where cancer has metastasized to distant sites or organs. (These numbers are based on historical data collected up to 2011, and may change as immunotherapy is more widely used.)
Treatment for melanoma depends on the properties of the tumor and the stage at which the cancer is detected. If discovered early, the tumor may be removed surgically. In the case of advanced disease, the tumor is removed along with surrounding normal tissue and a sentinel lymph node. If a biopsy reveals that the cancer has spread to lymph nodes, treatments may include more extensive surgery, immunotherapy, targeted therapy, or clinical trial participation. Radiation therapy is sometimes used as well, depending upon properties of the tissue removed at surgery.
Since 2011, seven new drugs have been FDA approved for the treatment of melanoma, including four immunotherapies and three targeted therapies. The immunotherapy drugs are ipilimumab (Yervoy®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), and talimogene laherparepvec (T-VEC, Imlygic™). The frist three drugs are checkpoint inhibitors that “take the brakes off” the immune system and enable it to fight cancer; the last is an oncolytic virus therapy.
The targeted therapies are Zelboraf (vemurafenib), Tafinlar (dabrafenib), and Mekinist (trametinib). These drugs target common genetic mutations, such as the BRAF V600 mutation, found in a subset of melanoma patients.
Despite the recent FDA approvals of these drugs, some patients with advanced metastatic melanoma still have a significant risk of mortality. A substantial unmet need remains for new successful therapies in patients with this disease.
Immunotherapy for Melanoma
Melanoma has long been considered a promising target for immunotherapy and has been a major focus of immunotherapy clinical development efforts. Several immunotherapies are currently approved by the FDA and many more are in clinical development. Current immunotherapy approaches for melanoma fall into six main categories: checkpoint inhibitors, oncolytic virus therapies, cancer vaccines, adoptive T cell therapy, monoclonal antibodies, and cytokines.
In 2010, ipilimumab became the first drug ever shown to extend survival for patients with metastatic melanoma in a large phase III trial. Ipilimumab reduced the risk of death by 32% and nearly doubled the likelihood of patients surviving to 1 and 2 years, with some patients experiencing complete and durable clinical regressions. Based on these results, ipilimumab was approved by the FDA as first-line therapy for advanced melanoma in 2011. In October 2015, the FDA approved ipilimumab as adjuvant therapy to help prevent relapse after surgery for operable stage III melanoma.
Ipilimumab is a type of immune drug known as a checkpoint inhibitor. These treatments work by targeting molecules that serve as checks and balances in the regulation of immune responses. By blocking inhibitory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses.
This approach was pioneered by CRI’s Scientific Advisory Council director James P. Allison, Ph.D., who was the first to show that an antibody that blocked a molecule called CTLA-4 on T cells could lead to cancer regressions in mice. Ipilimumab was tested in late-phase clinical trials by Jedd D. Wolchok, M.D., Ph.D., director of the CRI/Ludwig clinical trials network and associate director of CRI’s Scientific Advisory Council.
Since ipilimumab was first approved, several other checkpoint inhibitors have been developed and two are FDA approved. In September 2014, pembrolizumab (Keytruda), made by Merck, was FDA approved for the treatment of advanced or unresectable melanoma. In December 2014, nivolumab (Opdivo), made by Bristol-Myers Squibb, was approved for this same indication. Both of these drugs block a molecule on T cells called PD-1.
The combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) has been tested in patients with advanced melanoma in several trials, with impressive results. A phase I trial of the combination showed that the 2-year survival rate for all dose cohorts was 79%. At the best-responding dose level (nivolumab 1 mg/kg and ipilimumab 3 mg/kg), the 2-year survival rate was even more impressive—88%. This is compared to a 2-year survival rate of about 15% for patients treated with conventional chemotherapy.
A phase II trial directly comparing this combination to ipi alone showed that the combination had an objective response rate (ORR) of 61% compared to 11% for ipi alone in patients without a BRAF mutation. For patients with a BRAF mutation, the ORR was 52% for the combo vs. 10% for ipi alone. For both patient groups, the rate of complete responses was 22% for the combo, but 0% for ipi alone. Importantly, both PD-L1-positive and PD-L1-negative patients had similar objective response rates (58% vs. 55%). Based on these results, the FDA approved the ipi + nivo combination in October 2015 for the treatment of advanced melanoma.
Several additional checkpoint inhibitors, and checkpoint inhibitor combinations, are currently in development.
MEDI4736, an anti-PD-L1 checkpoint inhibitor, is being tested in a phase I/II trial for melanoma (NCT02027961). MEDI4736 is also being tested in two phase I trials: one in combination with another checkpoint inhibitor, tremelimumab (anti-CTLA-4), for patients with melanoma (NCT02141542), and one by itself for patients with solid tumors (NCT01693562).
A phase I/II trial to test varlilumab (anti-CD27) and ipilimumab, or the combination of varlilumab, ipilimumab, CDX-1401 (DEC-205/NY-ESO-1 fusion protein), and Poly-ICLC in patients with unresectable stage 3 or 4 melanoma (NCT02413827).
MPDL3280A, an anti-PD-L1 antibody, is being tested in numerous cancers in a phase I trial (NCT01375842) and a phase I trial in melanoma (NCT01656642).
A phase I trial testing MGA271, a B7-H3 antibody that is an immune response regulator, and ipilimumab in patients with melanoma (NCT02381314).
A phase I trial to test a GITR antibody in patients with melanoma (NCT01239134). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.
Oncolytic Virus Therapies
Oncolytic virus therapy uses a modified virus that can cause tumor cells to destruct and generate a greater immune response against the cancer.
In October 2015, the FDA approved the oncolytic virus therapy talimogene laherparepvec (T-VEC, trade name Imlygic™), made by Amgen, for the treatment of stage III or IV melanoma that has relapsed after surgery. The approval was based on the results of a large phase III trial that showed that 16% of patients treated with T-VEC had durable shrinkage of their tumors compared to 2% of those getting a control drug called GM-CSF.
Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Several trials of vaccines, given alone or with other therapies, are currently enrolling patients:
A phase III trial for eltrapuldencel-T (NBS20), a dendritic cell vaccine given with GM-CSF, for melanoma (NCT01875653).
A phase III trial to test POL-103A in melanoma patients who have had surgery but have a high risk of recurrence (NCT01546571).
A phase II trial to test a multi-peptide vaccine and an IDO1 inhibitor, INCB024360, for patients with melanoma (NCT01961115). IDO is expressed by cancer cells in a range of tumor types and high IDO expression appears to correlate with poor outcomes in a number of cancers, including melanoma.
A phase II trial to test the DEC-205/NY-ESO-1 fusion protein CDX-1401 and Poly-ICLC vaccine, which is being given with or without CDX-301, a recombinant Flt3 ligand, in patients with melanoma (NCT02129075).
A phase IIb trial to test the HyperAcute-Melanoma vaccine (dorgenmeltucel-L) and ipilimumab in patients with melanoma (NCT02054520).
A phase I trial to test the personalized NeoAntigen cancer vaccine in patients with melanoma (NCT01970358).
A phase I trial to test a NY-ESO-1 vaccine and ipilimumab in patients with unresectable or metastatic melanoma whose tumors express NY-ESO-1 or LAGE-1 (a cancer-testis antigen that closely resembles NY-ESO-1) (NCT01810016). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.
Adoptive Cell Therapy
Another major avenue of immunotherapy for melanoma is adoptive cell therapy. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity or numbers, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.
A phase II trial of genetically modified T cells that express the receptor for the NY-ESO-1 molecule, being led by Steven Rosenberg, M.D., Ph.D., at the National Cancer Institute (NCT02062359).
A phase II trial of 4-1BB tumor infiltrating cells in melanoma, also being led by Steven Rosenberg, M.D., Ph.D., at the National Cancer Institute (NCT02111863). 4-1BB, also known as CD137, has costimulatory activity for activated T cells and can enhance immune activity to eliminate tumors in mice.
A phase II trial of cellular adoptive immunotherapy using autologous (“self”) CD8+ antigen-specific T cells and ipilimumab in melanoma, led by Cassian Yee, M.D., at The University of Texas MD Anderson Cancer Center (NCT02027935).
A phase I/II trial of T cells engineered with one of two receptors in melanoma, being led by Patrick Hwu, M.D., at The University of Texas MD Anderson Cancer Center (NCT01740557).
A trial of ipilimumab and adoptive cell transfer plus high dose interleukin-2 in melanoma at the H. Lee Moffitt Cancer Center and Research Institute (NCT01659151).
Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.
A phase Ib trial of GR-MD-02, a galectin inhibitor, plus ipilimumab in patients with metastatic melanoma (NCT02117362).
A phase Ib trial of bavituximab, an antibody that targets an immune-suppressing molecule in tumors, plus ipilimumab in patients with advanced melanoma (NCT01984255).
In 1998, the FDA approved the use of the immune molecule interleukin-2 (IL-2) to treat advanced melanoma. This provided the first proof-of-principle that an immune-based treatment could provide durable control of the disease. The immune molecule interferon alpha (IFNα) has also been used alone after surgery or in combination with other agents to treat advanced melanoma.
A phase I study of IL-15 in patients with melanoma (NCT01727076).
Go to our Clinical Trial Finder to find clinical trials of immunotherapies for melanoma that are currently enrolling patients.
CRI Contributions and Impact
Since 1982, CRI has dedicated nearly $30 million to fund laboratory and clinical research aimed at unlocking the power of the immune system to fight melanoma. This includes 36 clinical trials conducted through our global clinical trials network, which have enrolled nearly 750 patients with melanoma. See below for other CRI-funded studies that are advancing the understanding and treatment of melanoma.
Currently, a minority (~20%) of patients treated with ipilimumab (Yervoy) experience clinical benefit. Identifying biomarkers that can help predict which cancer patients are most likely to benefit, as well as gathering further insights into ipilimumab’s mechanism of action, will be key to enhancing the efficacy of this treatment. In 2015, Jedd D. Wolchok, M.D., Ph.D., and colleagues from Memorial Sloan Kettering published and important paper in The New England Journal of Medicine that helps to predict who will respond to anti-CTLA-4 therapy and who will not. It has been speculated for some time that one of the reasons that melanoma is often responsive to immunotherapy is because these cancers contain many genetic mutations (caused by UV radiation from sunlight). Wolchok and colleagues wanted to know if it was the total number of mutations that made the difference, or whether a small number of particularly powerful mutations were most important to success of therapy. Using DNA sequencing methods, they found that mutational load was correlated with clinical benefit, but that this alone was not sufficient to predict being a ‘responder’ to CTLA-4 blockade. Wolchok and colleagues were able to identify a common “molecular signature” of neoantigens that were found in anti-CTLA-4 responders versus non-responders. Intriguingly, the neoantigens they identified were very similar to sequences found in common infectious diseases, such as tuberculosis, Streptococcus pyogenes, and yellow fever virus. Their results raise the intriguing possibility that melanoma can elicit an immune response by activating the immune memory that we have generated to infectious diseases.
Padmanee Sharma, M.D., Ph.D., and colleagues have discovered a cellular pathway whose activation seems be important for having a good response to ipilimumab. Called ICOS, this pathway is activated on T cells in response to ipilimumab treatment, and the sustained activation of this pathway may explain why some patients respond better to therapy than others. This discovery has inspired the development of approaches to target this pathway in patients being treated with ipilimumab.
CRI researchers Jianda Yuan, M.D., Ph.D., Sacha Gnjatic, Ph.D., Jedd D. Wolchok, M.D., Ph.D., and others found that cancer patients who have pre-existing immunity to NY-ESO-1 are more likely to respond to ipilimumab than those who do not. At 24 weeks after ipilimumab treatment, NY-ESO-1-positive patients were nearly twice as likely to experience clinical benefit than NY-ESO-1-negative patients. In addition to helping to facilitate the identification of patients who may have greater benefit from the drug than others, these findings also hint at ways to improve the efficacy of treatment even in patients who initially may lack pre-existing immunity to NY-ESO-1, for example by combining ipilimumab treatment with vaccines to induce anti-NY-ESO-1 immune responses. Based on these findings, CRI and Ludwig have designed a trial to test two vaccine formulations based on the NY-ESO-1 antigen in combination with ipilimumab to see if the combination yields additional clinical activity and results in increased clinical benefit among a larger percentage of patients treated. The trial will enroll up to 18 patients with unresectable or metastatic melanoma whose tumors express NY-ESO-1 or LAGE-1 (a cancer-testis antigen that closely resembles NY-ESO-1) and for whom treatment with ipilimumab is indicated (NCT01810016).
Through CRI’s venture philanthropy program, a phase I trial in melanoma and other cancers will test the experimental antibody GITR to enhance the activity of T cells against cancer (NCT01239134). This was launched at Memorial Sloan Kettering Cancer Center under the direction of Jedd D. Wolchok, M.D., Ph.D. The antibody is the first treatment of its kind to be tested in human cancer patients, and is part of a new class of highly promising therapies like anti-CTLA-4 and anti-PD-1 that work by counteracting immune suppression.
CRI investigator Timothy N.J. Bullock, Ph.D., at the University of Virginia Health System, showed that a monoclonal antibody designed to activate the CD27 costimulatory molecule, which plays an important role in the activation, survival, and differentiation of T cells, significantly reduced the progression of metastases and primary tumors in a mouse model of melanoma. Further analysis showed that the antibody treatment supports the maintenance of tumor-specific killer T cells within the tumor, reduces the frequency of regulatory T cells within tumors, and enhances the ability of tumor-infiltrating natural killer cells and killer T cells to produce interferon-gamma, a critical anti-tumor immune molecule, suggesting that targeting the CD27 costimulatory pathway may be a promising approach to enhance tumor immunity.
Reporting in The Journal of Experimental Medicine, clinical trials investigator Hassane Zarour, M.D., and colleagues at the University of Pittsburgh Cancer Institute found that cells that express both the Tim-3 and PD-1 molecules constituted a highly dysfunctional subset of tumor-specific killer T cells in patients with advanced melanoma, supporting the combination of Tim-3 and PD-1 blockade to reverse tumor-induced T cell dysfunction in therapeutic interventions for patients with this disease.
Margaret Callahan, M.D., Ph.D., the Lloyd J. Old Postdoctoral Fellow at Memorial Sloan Kettering Cancer Center, is working to understand how targeted therapies like vemurafenib, which is directed against the BRAFV600E mutation in melanoma, may impact the immune system generally, as well as how it may impact anti-PD-1 checkpoint blockade immunotherapy specifically. The insights gained from these studies may guide the rational development of combinations of targeted inhibitors and immunotherapies to take into the clinic. This project is directly applicable to the development of new treatment strategies for melanoma, and may also be extended to help in the treatment of other cancers.
Jenna Elizabeth Geddes, the recipient of a Student Training and Research in Tumor Immunology (STaRT) grant at Harvard Medical School, is studying galectin-1 (Gal-1), a binding protein that is produced by melanoma cells and that may promote tumor immune escape by suppressing melanoma-specific killer T cells. She is investigating whether or not blocking the ligand for Gal-1 on killer T cells prior to adoptive T cell therapy makes T cells less susceptible to Gal-1 inhibition and can translate into enhanced melanoma control. If successful, these studies will greatly impact efforts to improve adoptive T cell therapy for melanoma.
One drawback of some immunotherapies is that they can have body-wide toxicities related to activating the immune system in a non-specific manner. CRI postdoctoral fellow Li Tang, Ph.D., of MIT, Cambridge, MA, has developed a novel technique to surmount this hurdle. The technique involves using nanotechnology in melanoma and other cancers to deliver immune-stimulating chemicals called cytokines directly to the site of tumors. In effect, the cytokines are smuggled in “on the backs” of T cells. This approach, which Dr. Tang recently patented, has the potential to greatly reduce systemic toxicities of immunotherapies.
Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2016; GLOBOCAN 2012; NCI Surveillance Epidemiology and End Results (SEER); National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; Melanoma Research Foundation; CRI grantee progress reports and other CRI grantee documents
Last reviewed May 2015; updated with new approvals October 2015.
 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012 Jun 28;366(26):2443-54. PMID: 22658127 (www.ncbi.nlm.nih.gov/pubmed/22658127)
Melanoma News & Stories
One-day, multi-distance ride through the Lower Hudson Valley’s breathtaking landscape to raise funds for CRI and increase awareness of the potential of immunotherapy to cure all cancers.
May 12, 2016
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Sage Berting, age 7, doesn’t have any family members or friends who are suffering from cancer. But she wanted to raise money for the disease that claims so many lives.
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