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.
Melanoma is the most deadly skin cancer.1According 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.2
Preferred Regimens for Metastatic Melanoma
Other Active Regimens
[Adapted from National Comprehensive Cancer Network (NCCN) Guidelines Melanoma: Clinical Practice Guidelines in Oncology. Version 2.2015.4]
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 (Table 1).3,4
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.5
It is now clear that the body’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 ‘self’ tissue. By blocking these pathways, ipilimumab, nivolumab, pembrolizumab and other checkpoint inhibitors strengthen the ability of tumor-infiltrating T lymphocytes (T cells) to ‘see’ 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.7-10When functioning properly, the body’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;39:1-8.11
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.11Repeated presentation of antigens, whether they are bacteria or tumor cells, is the first critical step to inducing an adaptive immune response.12Because cancer cells have undergone many genetic changes, they shouldin theory–offer many tumor-associated antigens for T cells to recognize and destroy.13
To survive, melanoma and other cancer cells have devised multiple ways to ‘hide.’. Researchers have learned that most tumor antigens are self-proteins. The immune system tolerates these antigen fragments as self, and the tumor escapes surveillance.14T-cell activation is suppressed and adaptive immune memory does not occur.15
According to Sasha E. Stanton, MD, PhD, of the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, “Our body’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.”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.16
Melanoma vaccines (oncolytic viruses, oncolytic immunotherapy)
Plasmid IL-12enhances 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.17
Rose bengal disodium (PV-10), given as an intralesional injection, is a nonpyrogenic saline solution that induces chemical tumor ablation and has ‘bystander’ 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.18
Talimogene laherparepvec (T-VEC)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).19
Tumor-infiltrating lymphocytes (TILs)
TILsinvolve extracting T cells from a patient’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.20
Toll-like receptor (TLR) agonists
TLRactivation alerts the immune system to pathogens and initiates both innate and adaptive immune responses. Intralesional Bacille Calmette-Guérin 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 ‘surgical CR’ (3) after resection of solitary resistant lesions.
Stanton explained, “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.”
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.
Stanton looks forward to moving these combination strategies into patients with earlier stages of cancer. “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,” she said.