Cancer Immunotherapy

Melanoma

Melanoma is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on melanoma and immunotherapy clinical trials 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 only 5% of skin cancer cases, melanoma accounts for 77% of skin cancer-related deaths. Over the past few years, immunotherapy has dramatically changed the landscape of melanoma treatment. The immune-based treatment ipilimumab (Yervoy™) was the first drug shown to extend survival among patients with advanced melanoma. A number of exciting new immune-based treatments in development promise to save more lives. 

 

Urgent Need

One of the world’s fastest-growing types of cancer, melanoma claims one life every hour. 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 15% in cases where cancer has metastasized to distant sites or organs.

 

Treatment

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, or clinical trial participation. Radiation therapy is sometimes used as well, depending upon properties of the tissue removed at surgery.

Two drugs approved in 2011, the immunotherapy ipilimumab (Yervoy™) and vemurafenib (Zelboraf®), a therapy targeting a BRAF mutation found in approximately 50% to 60% of melanomas, are the only FDA-approved drugs shown to extend survival in cases of advanced melanoma.

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.

 

Melanoma Immunotherapy: History and Ongoing Clinical Trials

Melanoma has long been considered a promising target for immunotherapeutic approaches and has been a major focus of immunotherapy clinical development efforts. 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.

In 2011, the immunotherapy ipilimumab (Yervoy™) became the first drug ever shown to extend survival for patients with metastatic melanoma. Results from a large, phase III trial of ipilimumab demonstrated that it 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 lasting for years. Ipilimumab was first developed by CRI’s Scientific Advisory Council director James P. Allison, Ph.D., and tested in late-phase clinical trials by Jedd D. Wolchok, M.D., Ph.D., director of the CRI/Ludwig Cancer Vaccine Collaborative and head of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center.

To date, more than 300 clinical trials have been conducted testing immune-based therapies to treat melanoma, and more than 100 clinical trials are ongoing, including several that are in phase III testing. Some of the new approaches to immunotherapy for melanoma that have shown promise in early clinical trials and have advanced to late-phase development include:

  • T-Vec (aka talimogene laherparepvec, formerly known as OncoVEX) is currently being evaluated to treat inoperable melanoma in a randomized phase III clinical trial, which will be completed in September 2014 (NCT00769704). T-Vec is also being tested in a phase I/II trial in combination with ipilimumab for patients with stage IIIB-IV melanoma who are not eligible for surgical resection. The trial is expected to begin enrolling patients shortly (NCT01740297).
  • POL-103A is a cancer vaccine currently in a phase III trial sponsored by Polynoma LLC. The trial plans to enroll 1,059 patients with resected stage IIB, IIC, or III melanoma with a high risk of recurrence. The principal investigator on the trial is Craig Slingluff Jr., M.D., a CRI investigator award recipient from 1996 to 2000 and a current member of CRI/Ludwig Cancer Vaccine Collaborative (CVC). (NCT01546571)
  • GlaxoSmithKline is testing its MAGE-A3 antigen-specific cancer immunotherapeutic (ASCI) (GSK2132231A) in a phase III trial involving 1,349 patients with stage IIIB or IIIC melanoma. The trial is designed to see whether treatment can help prevent or prolong melanoma recurrence after surgery. The trial is scheduled to be completed in October 2016 (NCT00796445).
  • Nivolumab (BMS-936558) is an antibody targeting the PD-1 checkpoint molecule. Based on promising results from a phase I clinical trial completed in 2012[1], the drug’s manufacturer, Bristol-Myers Squibb, has launched several phase III trials of the agent, including two in melanoma. One of the trials is enrolling patients with unresectable or metastatic melanoma who have progressed following anti-CTLA-4 therapy (NCT01721746), and the second is for patients with previously untreated unresectable or metastatic melanoma (NCT01721772). Nivolumab is also being tested in two trials in combination with ipilimumab in patients with inoperable stage III or IV melanoma. The first is a phase I trial designed to identify the optimal doses of nivolumab and ipilimumab when administered concurrently (NCT01024231), and the second, a phase II trial that is scheduled to start in April 2013, is designed to test if giving the antibodies in a sequential fashion (ipilimumab before nivolumab, or vice versa) shows improved safety and/or efficacy (NCT01783938).

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for melanoma that are currently enrolling patients. For more information about melanoma immunotherapies in late-phase development, see our page on the Cancer Immunotherapy Pipeline.

 

CRI Impact on Melanoma

The Cancer Research Institute funds and coordinates a number of clinical and laboratory studies that are shedding light on immune-based treatment possibilities for melanoma, as well as on fundamental mechanisms of the disease. This research is leading directly to therapeutic advances that are helping patients with melanoma live longer and better lives.

Since 1982, CRI has dedicated more than $25 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, the Cancer Vaccine Collaborative (CVC), which have enrolled nearly 750 patients with melanoma. CVC clinical trials in melanoma are currently enrolling patients at New York University Langone Medical Center, Fred Hutchinson Cancer Research Center/University of Washington School of Medicine, Memorial Sloan-Kettering Cancer Center, University of Virginia, Mount Sinai School of Medicine, and the University of Pittsburgh.

See below for more information on current and past clinical trials conducted in the CVC network and other CRI-funded studies that are advancing the understanding and treatment of melanoma.

  • Currently, a minority (10% to 30%) of patients treated with ipilimumab 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 a major step toward this goal, CVC researchers Jianda Yuan, M.D., Ph.D., Sacha Gnjatic, Ph.D., Jedd D. Wolchok, M.D., Ph.D., and others at Memorial Sloan-Kettering Cancer Center (MSKCC), the Ludwig Center for Cancer Immunotherapy, and the Ludwig Institute for Cancer Research, in collaboration with investigators at Yale University, 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, which will begin accruing patients within the next few months, 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.
  • Through CRI’s venture philanthropy program, the Cancer Vaccine Acceleration Fund, a phase I trial in melanoma patients of an experimental antibody designed to target the GITR molecule to enhance the activity of T cells against cancer, was launched at Memorial Sloan-Kettering Cancer Center under the direction of Jedd D. Wolchok, M.D., Ph.D., in 2010. 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.
  • As demonstrated by studies with anti-CTLA-4 and anti-PD-1, the immune response to tumors can be enhanced by targeting costimulatory molecules on T cells. 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, CVC 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.

Other ongoing CRI-funded projects that are shedding light on melanoma include:

  • 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.
  • Corrie Ann Painter, Ph.D., a CRI postdoctoral fellow at the University of Massachusetts Medical Center, is investigating the adaptive immune response to melanoma in the zebrafish Danio rerio. In her project, she will determine the specific immune cells that are present in zebrafish melanomas and visualize their movement into and out of tumors, and then determine the functional role of each of these immune cells and define immunomodulatory factors that can provoke anti‐tumor responses. These studies will help identify genes that modulate the immune response to melanoma, toward the ultimate goal of augmenting current diagnostic and prognostic markers of melanoma and providing additional therapeutic strategies to combat the disease.
  • 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.

 

Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Facts & Figures 2012; GLOBOCAN 2008; NCI Surveillance Epidemiology and End Results (SEER); National Comprehensive Cancer Network (NCCN) Guidelines for Patients; ClinicalTrials.gov; Melanoma Research Foundation; Cancer Research UK; Bloomberg.com; CRI grantee progress reports and other CRI grantee documents



[1] 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

Reviewed By:

Jedd D. Wolchok, M.D., Ph.D.
Memorial Sloan-Kettering Cancer Center and Ludwig Cancer Research

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