Immunotherapy for Melanoma
Let's spread the word about Immunotherapy! Click to share this page with your community.
Copy Link
  • Science of Immunotherapy
  • Clinical Trials
  • CRI's Impact
  • Related News & Resources

How is Immunotherapy Changing the Outlook for Patients with Melanoma?

Reviewed By: Jedd D. Wolchok, M.D., Ph.D.
Memorial Sloan Kettering Cancer Center and Ludwig Cancer Research, New York, NY

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.

Featured Scientist
Cassian Yee, M.D.
The University of Texas MD Anderson Cancer Center
Grantee  |  2013
View Funding Directory
Melanoma Statistics
Deadliest form of skin cancer
Of all skin cancers are melanoma
Year FDA approved immune-based Yervoy treatment
Types of immunotherapy clinical trials
Urgent Need

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, eight new drugs have been FDA approved for the treatment of melanoma, including four immunotherapies and four targeted therapies. The immunotherapy drugs are ipilimumab (Yervoy®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), and talimogene laherparepvec (T-VEC, Imlygic™). The first 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 that stimulates stronger anti-tumor immune responses.

The targeted therapies are vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), trametinib (Mekinist®), and cobimetinib (Cotellic®). These drugs target common genetic mutations, such as the BRAFV600 mutation, found in a subset of melanoma patients. Three interferon and interleukin-based treatments—aldesleukin (proleukin®), interferon alfa-2b (INTRON®), and pegintereferon alfa-2b (Sylvatron®)—are also approved for 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.

Side Effects

The side effects of immunotherapy are different than chemotherapy. Whereas chemotherapy’s side effects—nausea, hair loss, vomiting—stem from its destruction of all rapidly-dividing cells, both healthy and cancerous alike, immunotherapy’s side effects are often immune-related, and commonly include inflammatory symptoms such as rash, diarrhea, pruritus, and colitis, amongst others. These immune-related adverse events can be quite serious and even fatal, but are typically reversible when effective treatment guidelines on side effect management are followed.

Clinical Trials 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 seven main categories: checkpoint inhibitors, oncolytic virus therapies, cancer vaccines, adjuvant immunotherapy, adoptive cell therapy, monoclonal antibodies, and cytokines.

  • Checkpoint Inhibitors
  • Oncolytic Virus Therapies
  • Therapeutic Vaccines
  • Adjuvant Immunotherapies
  • Adoptive Cell Therapy
  • Monoclonal Antibodies

In 2011, ipilimumab (Yervoy)—which targets the CTLA-4 pathway—was approved by the FDA to treat unresectable or metastatic melanoma. The approval came on the heels of the first phase III clinical trial ever shown to improve overall survival in patients with the disease, with median overall survival of 10.1 months, versus 6.4 months in the control group. Long-term follow-up of patients who received ipilimumab showed that a large percentage were still alive at the two- and five-year mark. Some of the earliest treated patients remain cancer-free more than 10 years out.

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.

Pembrolizumab (Keytruda) and nivolumab (Opdivo)—two checkpoint inhibitors that target the PD-1 pathway—received FDA approval in 2014 for melanoma that did not respond to prior treatment. In one trial, patients treated with pembrolizumab had an overall response rate of 33%, compared with 12% for ipilimumab. The approval of nivolumab was based on a randomized clinical trial where the overall response rate was 32% in nivolumab-treated patients.

In 2015 and 2016, the FDA expanded its approval of pembrolizumab and nivolumab as first-line treatments for unresectable or metastatic melanoma, regardless of mutational status. As a single agent, ipilimumab is approved as a second-line treatment, as well as adjuvant therapy for patients with completely resected melanoma.

Perhaps most promising are results from a combination treatment using both ipilimumab and nivolumab, which the FDA approved in 2015 for previously untreated (first-line) unresectable or metastatic melanoma for patients without a BRAF mutation. In 2016, the FDA expanded the approval to include treating melanoma regardless of mutational status. Patients receiving the combination had an objective response rate of 50%, compared to 40% for nivolumab and 14% for ipilimumab—an increase greater than either drug alone.

Several additional checkpoint inhibitors, and checkpoint inhibitor combinations, are currently in development.


  • A phase I/II trial testing durvalumab (MEDI4736), which targets the PD-L1 pathway, and tremelimumab, an anti-CTLA-4 antibody, plus Poly-ICLC for patients with advanced, biopsy-accessible cancers, including melanoma (NCT02643303). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute. There are also four phase I trials testing durvalumab for patients with:
    • unresectable stage 3 or 4 melanoma, in combination with the checkpoint inhibitor tremelimumab (NCT02141542)
    • select cancers, including metastatic melanoma, in combination with tremelimumab plus radiation (NCT02639026)
    • select cancers, including melanoma, in combination with selumetinib, an inhibitor of MEK 1 and 2 (NCT02586987)
  •  A phase I study of CPI-444, which targets the adenosine-A2A receptor that suppresses the anti-tumor activity of immune cells, +/- atezolizumab is for patients with advanced cancer, including melanoma (NCT02655822). 
  • A phase I trial testing avelumab, which targets the PD-L1 marker, and PF-05082566, which is a 4-1BB/CD137 antibody, for patients with advanced cancers (NCT02554812).
  • A phase I trial testing PF-06801591, which targets the PD-1 marker, for patients with select cancers, including melanoma (NCT02573259).
  • A phase I/II trial testing PDR001, which is a PD-1 antibody, and MBG453, which targets the TIM-3 marker, for patients with select cancers, including melanoma (NCT02608268).



  • A phase I/II trial testing INCAGN01876 for patients with select cancers, including melanoma (NCT02697591).
  • A phase I trial of TRX518 in patients with melanoma (NCT01239134). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.



  • A phase I trial testing MGA271, a B7-H3 antibody, and ipilimumab in patients with melanoma (NCT02381314), and a phase I study testing MGA217 and pembrolizumab in patients with refractory cancer, including melanoma (NCT02475213).
  • A phase I study to test MGD009, a B7-H3 x CD3 DART protein, in patients with unresectable or metastatic B7-H3-expressing cancer, including melanoma (NCT02628535).



  • A phase I/II trial testing LAG525, which targets the LAG-3 marker, +/- PDR001, which is a PD-1 antibody, for patients with advanced cancers, including melanoma (NCT02460224).
  • A phase I trial testing IMP321 and pembrolizumab for patients with melanoma (NCT02676869).



  • A phase I/II trial testing ISF35, which targets the CD40 marker, and pembrolizumab for patients with melanoma (NCT02719015).


  • A phase I trial of PF-05082566, a 4-1BB/CD137 antibody, and avelumab, which targets the PD-L1 marker, for patients with advanced cancers (NCT02554812).



  • A phase I/II trial testing MBG453, which targets the TIM-3 marker, and PDR001, which is a PD-1 antibody, for patients with select cancers, including melanoma (NCT02608268).


In 2015, another type of immunotherapy—oncolytic virus therapy—was approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that has recurred after initial surgery. Talimogene laherparepvec (T-VEC, trade name Imlygic) is a genetically engineered herpes simplex virus that preferentially targets cancer cells and then replicates within them while also causing the cells to produce the protein GM-CSF, which recruits immune cells and promotes their growth. Eventually the tumor cells burst, releasing tumor-derived antigens, GM-CSF, and viral particles, all of which elicits an anti-tumor immune response. A clinical trial testing T-VEC versus GM-CSF showed the durable response rate was 16% in patients who received at least one dose of T-VEC, and 2% in the GM-CSF arm.[vi]

Despite its ability to target tumor cells and promote an immune response, T-VEC has not been shown to improve overall survival or have an effect on visceral metastases. Ongoing research aims to enhance the effectiveness of oncolytic virus therapy and broaden its applicability.

  • A phase I trial of Cavatak™, a formulation of the common cold virus, and pembrolizumab for patients with advanced melanoma (NCT02565992).
  • A phase I trial of Toca 511, a retroviral replicating vector, for patients with select cancers, including melanoma (NCT02576665).
  • A phase I trial of GL-ONC1, a vaccinia virus, for patients with solid cancers undergoing surgery (NCT02714374).

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 to test a dendritic cell—a messenger cell that can activate an immune response up to 100 times more potent than any other cell in the immune repertoire—vaccine loaded with tumor RNA in the adjuvant setting for patients with uveal (eye) melanoma (NCT01983748).
  • A phase I/II trial testing six melanoma peptides, along with Montanide and Poly-ICLC, for patients with melanoma (NCT02425306). The Cancer Research Institute is a collaborator on this trial. There is also a phase I/II trial testing the same vaccine combined with pembrolizumab for patients with melanoma (NCT02515227).
  • A phase I/II trial testing IMCgp100, which targets the gp100 marker, +/- durvalumab and/or tremelimumab, for patients with melanoma (NCT02535078). There is also a phase I trial of IMCgp100 for patients with advanced uveal melanoma (NCT02570308).
  • A phase I/II trial of a dendritic cell vaccine for patients with stage 4 melanoma with stable or slowly progressing disease (NCT02678741).
  • A phase II 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 testing Vigil™, composed of a plasmid encoding GM-CSF and a short hairpin RNA that downregulates TGFB1 and TGFB2, and pembrolizumab for patients with melanoma (NCT02574533).
  • A phase I trial of GRN-1201, which targets four different peptides, for patients resected melanoma (NCT02696356).
  • A phase I trial of DSP-7888, which targets the WT1 marker, for patients with select cancers, including melanoma (NCT02498665).


Adjuvants are substances that are either used alone or combined with other immunotherapies to boost the immune response. Some adjuvant immunotherapies use ligands—molecules that bind to proteins such as receptors—to help control the immune response. These ligands can be either stimulating (agonists) or blocking (antagonists).

  • A phase II trial of Poly-ICLC (Hiltonol®), a Toll-like receptor 3 agonist, for patients with select cancers, including melanoma (NCT02423863).
  • A phase I/II trial of SD-101, a Toll-like receptor 9 agonist, and pembrolizumab for patients with metastatic melanoma (NCT02521870).
  • A phase I/II trial of IMO-2125, a Toll-like receptor 9 agonist, and ipilimumab for patients with metastatic melanoma (NCT02644967).
  • A phase I trial of CMP-001, a Toll-like receptor 9 agonist, and pembrolizumab for patients with metastatic melanoma (NCT02680184).
  • A phase I trial of MGN1703, a Toll-like receptor 9 agonist, and ipilimumab for patients with advanced cancers, including melanoma (NCT02668770).

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 cellular adoptive immunotherapy using autologous (“self”) CD8+ antigen-specific T cells and ipilimumab in melanoma (NCT02027935).
  • A phase II trial of tumor infiltrating lymphocytes and pembrolizumab for patients with melanoma (NCT02500576).
  • A phase I/II trial of T cells engineered with one of two receptors in melanoma (NCT01740557).
  • A phase I trial of chimeric antigen receptor (CAR) T cells, which target the GD2 antigen, for patients with relapsed or refractory melanoma (NCT02482532).
  • A pilot trial of tumor infiltrating lymphocytes and nivolumab for patients with melanoma (NCT02652455).


Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.

  • A phase I/II trial of rovalpituzumab tesirine, which targets delta-like 3 (DLL3), for patients with advanced solid tumors that express the delta-like 3 antigen (NCT02709889).
  • A phase I trial of FPA008, an antibody that inhibits colony stimulating factor-1 receptor (CSF1R), which targets immune cells, and nivolumab for patients with advanced cancer, including melanoma (NCT02526017).
  • A phase I trial of GR-MD-02, a galectin inhibitor, plus ipilimumab in patients with metastatic melanoma (NCT02117362).


CRI Contributions and Impact

Since 1982, CRI has dedicated nearly $38 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.

  • Padmanee Sharma, M.D., Ph.D., and colleagues 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.
  • 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.
  • 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.

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;; Melanoma Research Foundation; CRI grantee progress reports and other CRI grantee documents

Last updated April 2016

[i] Improved survival with ipilimumab in patients with metastatic melanoma. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. N Engl J Med. 2010 Aug 19; 363 (8): 711-23. (PMID: 20525992)

[ii] Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen TT, Berman DM, Wolchok JD. J Clin Oncol. 2015 Jun 10; 33 (17): 1889-94. (PMID: 25667295)

[iii] Pembrolizumab versus Ipilimumab in Advanced Melanoma. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. N Engl J Med. 2015 Jun 25; 372 (26): 2521-32. (PMID: 25891173)

[iv] Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Lancet Oncol. 2015 Apr; 16 (4): 375-84. (PMID: 25795410)

[v] Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: January 23, 2016. Princeton, NJ: Bristol-Myers Squibb Company.

[vi] Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. J Clin Oncol. 2015 Sep 1; 33 (25): 2780-8. (PMID: 26014293)

*Immunotherapy results may vary from patient to patient.