Lisa Raedler, PhD

According to data collected between 2004 and 2010, only 16% of Americans with metastatic melanoma, including people of all ages and races, and both genders, survive for 5 years or more after diagnosis.

Table 1. Systemic Treatment Options for Metastatic Melanoma

Preferred Regimens for Metastatic Melanoma

Dacarbazine- or temozolomide-based combinations &plusmn; chemotherapy, IL-2, interferon (IFN) alfa

[Adapted from National Comprehensive Cancer Network (NCCN) Guidelines Melanoma: Clinical Practice Guidelines in Oncology. Version 2.2015.

Until recently, management of patients with metastatic melanoma was highly challenging. Today, however, the development and introduction of novel agents have significantly altered the treatment landscape. The current options of systemic treatments for metastatic melanoma features immuno-oncology agents and medications that target specific genetic mutations, as well as chemotherapy agents (

Because melanoma cells have a unique relationship with the human immune system, immunotherapy agents have played a major role in disease management. Historically, IL-2, and IFN were used as standard treatments for both early-stage and advanced-stage melanoma.

It is now clear that the body&rsquo;s attempts to remove melanoma cells are thwarted by naturally occurring immune checkpoints and other regulatory pathways. Immune checkpoints are pathways hardwired into the immune system that allow self-tolerance. The immune system is able to recognize parts of foreign proteins as abnormal (antigens) and increase inflammation to destroy them but continue to protect &lsquo;self&rsquo; tissue. By blocking these pathways, ipilimumab, nivolumab, pembrolizumab and other checkpoint inhibitors strengthen the ability of tumor-infiltrating T lymphocytes (T cells) to &lsquo;see&rsquo; these cancer cells for the danger that they represent, and remove them.6 In patients with melanoma, clinical trials of checkpoint inhibitors have demonstrated impressive objective response rates and, in some cases, extended survival, despite advanced stages of disease and significant tumor burden.

When functioning properly, the body&rsquo;s immune system detects foreign material, known as antigens, and protects healthy tissue. Using innate immunity, the body mounts nonspecific defense mechanisms when it detects antigens. Phagocytic lymphocytes, dendritic cells (DCs), and other antigen-presenting cells (APCs) in the circulation identify and remove foreign material.

The more complex adaptive immune response is initiated by repeated processing and recognition of antigens. Antibodies that target specific antigens are then created. Adaptive immunity also features a memory; future responses against the same antigen are more efficient.

There are 2 types of adaptive immune responses: humoral immunity, which is mediated by antibodies produced by B lymphocytes, and cell-mediated immunity, which is facilitated by T cells. In cell-mediated immunity, APCs present antigen fragments to T cells for removal using a major histocompatibility complex (MHC).

Adapted from Chen DS, Mellman I. Immunity. 2013;39:1-8.

As shown in Figure 1, cell-mediated immunity to cancer can be a self-propagating cycle. Ideally, T-cell responses amplify as cancer cells are killed, resulting in continued elimination of the tumor.

Repeated presentation of antigens, whether they are bacteria or tumor cells, is the first critical step to inducing an adaptive immune response.

Because cancer cells have undergone many genetic changes, they shouldin theory&ndash;offer many tumor-associated antigens for T cells to recognize and destroy.

To survive, melanoma and other cancer cells have devised multiple ways to &lsquo;hide.&rsquo;. Researchers have learned that most tumor antigens are self-proteins. The immune system tolerates these antigen fragments as self, and the tumor escapes surveillance.

T-cell activation is suppressed and adaptive immune memory does not occur.

Novel Strategies to Boost Immune Response in Melanoma

According to Sasha E. Stanton, MD, PhD, of the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, &ldquo;Our body&rsquo;s response to foreign antigens is inflammation. But, to protect from autoimmunity, its response to self-antigens is dampened. Tumors are very smart. They figure out ways to subvert antitumor responses by taking advantage of this dampening effect.&rdquo;

Although melanoma and other cancer cells have a wide variety of ways to avoid immune detection, an equally large array of therapeutic strategies exist to boost T-cell, DC, and immune mediator functioning. Table 2 lists novel immunotherapy agents in development for melanoma. The ultimate goal of these therapies is to ensure that fully functional tumor-specific T cells eliminate melanoma cells and establish active, ongoing, and long-term immune surveillance against new cancer cells.

Table 2. Investigational Immunotherapy Agents for Melanoma

Melanoma vaccines (oncolytic viruses, oncolytic immunotherapy)

enhances the immune capacity of natural killer cells and T cells, up-regulating IFN-Æ´, and antigen presentation and processing. A phase II trial of intratumoral electroporation of plasmid IL-12 showed that, among 85 treated lesions, the complete response (CR) rate was 45%, partial response (PR) rate was 8%, and stable disease rate was 31%. Untreated distant lesions regressed in 13 of 22 evaluable patients.

, given as an intralesional injection, is a nonpyrogenic saline solution that induces chemical tumor ablation and has &lsquo;bystander&rsquo; effects in uninjected lesions. A phase II trial among 80 patients with measurable advanced-stage melanoma showed a 52-week overall response rate (ORR) of 51%, including 26% CR.

is directly injected into melanoma lesions. It is engineered from herpes simplex virus 1 (HSV-1) to replicate inside tumor cells and cause immunogenic cell death (ICD). Lysis of cancer cells in this fashion releases tumor-derived antigens, as well as granulocyte-macrophage colony-stimulating factor (GM-CSF), to stimulate an adaptive immune response. A phase III trial demonstrated durable responses in 16% of T-VEC patients versus 2% receiving subcutaneous GM-CSF. Median overall survival was 23.3 months for T-VEC and 18.9 months for GM-CSF (P = 0.051).

involve extracting T cells from a patient&rsquo;s tumor, expanding them in a laboratory, and then infusing them back into the patient to mount an effective immune response. A phase II trial of TILs in advanced melanoma demonstrated an ORR of 44% (2 CRs, 22 PRs) in 54 patients. Responses were seen in patients who had previously been treated with checkpoint inihibitors.

activation alerts the immune system to pathogens and initiates both innate and adaptive immune responses. Intralesional Bacille Calmette-Gu&eacute;rin combined with topical imiquimod, a TLR7 agonist, resulted in CRs for 5 of 9 patients. The other 4 patients in this trial had a PR (1) or &lsquo;surgical CR&rsquo; (3) after resection of solitary resistant lesions.

Stanton explained, &ldquo;Melanoma is leading the way in immunotherapy. It is an immunogenic tumor. While targeting programmed death 1 (PD-1) is a great start, it is not a home run. There are a lot of ways to modify tumors and make PD-1 more effective. T-VEC [talimogene laherparepvec] and other vaccines that use multiple tumor-associated antigens are particularly exciting.&rdquo;

Just as oncologists have learned that cytotoxic chemotherapy agents can synergize in the management of cancer, combining immunotherapies may be the best way to exploit their clinical value. Multiple clinical trials of checkpoint inhibitors together with therapeutic vaccines and other immunotherapeutic strategies are under way to learn whether or not they can counteract immune system tolerance, improve antitumor immunity, and extend survival for patients with melanoma.

Repeated presentation of tumor-associated antigens is the first critical step to inducing an adaptive immune or T-cell response.

Cancer cells have evolved to evade the body&rsquo;s adaptive immune system, including both B-celland T-cell responses.

Melanoma is an immunogenic tumor. In addition to checkpoint inhibitors, oncolytic vaccines and other developmental immunotherapies offer the possibility of durable remission.

Stanton looks forward to moving these combination strategies into patients with earlier stages of cancer. &ldquo;We know that tumor antigens evolve over time. Ideally, we would use earlier tumor antigens to create vaccines that prevent progression of early-stage disease,&rdquo; she said.

Skin Cancer Foundation. What is melanoma? www.skincancer.org/skin-cancer-information/melanoma. Accessed March 10, 2015.

National Cancer Institute web site. SEER Stat Fact Sheets: Melanoma of the Skin. http://seer.cancer.gov/statfacts/html/melan.html. Accessed March 10, 2015.

American Cancer Society. Treatment of melanoma skin cancer by stage. Last Revised: December 23, 2014. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-treating-by-stage. Accessed March 10, 2015.

National Comprehensive Cancer Network. Melanoma: Clinical Practice Guidelines in Oncology. Version 2.2015. Updated April 22, 2014. http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Accessed March 10, 2015.

Srivastava N, McDermott D. Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape.

Tseng WW, Malu S, Zhang M, et al. Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.

Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle.

Klebanoff CA, Gattinoni L, Restifo NP. CD8+ T-cell memory in tumor immunology and immunotherapy.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.

Kaufman HL, Disis ML. Immune system versus tumor: shifting the balance in favor of DCs and effective immunity.

Howard JH, Thompson JF, Mozzillo N, et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

Gujar SA, Lee PWK. Oncolytic virus-mediated reversal of impaired tumor antigen presentation.

Daud A, Algazi P, Ashworth MT, et al. Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. http://meetinglibrary.asco.org/content/134277-144.

Agarwala SS, Thompson JF, Smithers BM, et al. Mature data on PV-10 as chemoablation for unresectable stage III melanoma and plans for a randomized trial. ASCO 2014; abstract 9027. http://meetinglibrary.asco.org/content/132320-144.

Kaufman HL, Andtbacka RHI, Collichio FA, et al. Primary overall survival from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous GM-CSF for the treatment of unresected stage IIIB/C and IV melanoma. ASCO 2014; abstract 9008a. http://meetinglibrary.asco.org/content/133898-144.

Glitza IC, Bernatchez C, Bassett RL, et al. Treatment with tumor-infiltrating lymphocytes (TIL) in metastatic melanoma and clinical benefit regardless of site of origin, mutation status, or prior checkpoint blockade. ASCO 2014; abstract 9079. http://meetinglibrary.asco.org/content/132922-144.

Kidner TB, Morton DL, Lee DJ, et al. Combined intralesional Bacille Calmette-Guerin (BCG) and topical imiquimod for in-transit melanoma.

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Melanoma is the most deadly skin cancer. According to data collected between 2004 and 2010, only 16% of Americans with metastatic melanoma, including people of all ages and races, and both genders, survive for 5 years or more after diagnosis.

Lisa Raedler, PhD | Authors

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Tumor Antigens and Their Role in Immune Response in Melanoma