Laurie Barclay, MD, October 2004

Melanoma is a cancer of melanocytes, the skin cells producing the pigment melanin. Most cases develop in the skin, some in the eye (intraocular melanoma) or mucosa, and rarely in internal organs or beneath a nail (subungual melanoma).

Skin cancer is the most common cancer in the U.S., and the incidence is rapidly increasing, especially for melanoma. In the last 30 years, the incidence of melanoma has more than doubled, from 5.7 to 14.31 per 100,000 people each year. According to the American Cancer Society (ACS), approximately 53,600 new melanomas were diagnosed in the U.S. during 2002, and there were about 7,400 deaths from melanoma. Of all skin cancers, melanomas are the least common, but they account for the greatest number of deaths because of their tendency to metastasize.

Symptoms of skin melanoma include a change in an existing mole or the development of a new, unusual skin growth. Asymmetry, irregular borders, uneven distribution of color, and diameter greater than 0.25 inch (6 mm) are cardinal features of melanoma. Other suspicious features are scaliness, itching, oozing, and bleeding.

About two-thirds of all melanomas are superficial spreading melanoma, which first spreads through the epidermis. Other types include nodular melanoma, which is the most aggressive, and acral-lentiginous melanoma, which is the most common skin cancer in people of color, usually developing on the palms, soles or nails. Lentigo maligna melanoma has the best prognosis of all the melanomas, and it typically develops on the nose or cheeks of older adults.

Ultraviolet radiation from sunlight or tanning lamps is the best known risk factor for melanoma, because it can damage DNA within melanocytes and induce the development of oncogenes. Other risk factors include family history, advancing age, male sex, fair skin, multiple moles (nevi) or dysplastic nevi, immunodeficiency, and exposure to carcinogens including coal, tar, pitch, creosote, arsenic and radium.

The ACS recommends annual skin examinations for everyone over 40 years of age, or more often for those at higher risk, and monthly self-examination for everyone over 18 years of age. Suspicious moles should be biopsied. Criteria for staging (from 0 to IV) include thickness, depth, and degree of local spread and metastasis.

Depending on staging, patient age, and overall health, treatment options may include surgery, chemotherapy, radiation therapy, biological therapy, experimental therapy or various combinations. To reduce systemic toxicity and increase delivery of chemotherapy to the tumor, the technique of limb perfusion is useful for melanomas on the arm or leg. Immunotherapy uses native biologic response modifiers including interleukin-2 and interferon.

CenterWatch has identified a pipeline of 27 drugs in various stages of development for melanoma. Most of these target the immune system with antibodies, viruses, or other stimulants of humoral or cellular responses.

In December 2003, Genta submitted a new drug application (NDA) for Genasense (G3139; oblimersen sodium), an antisense oligonucleotide complementary to bcl-2. Genasense reduces production of Bcl-2, a protein made by cancer cells that is thought to inhibit apoptosis, or programmed cell death, induced by chemotherapy. By reducing the amount of Bcl-2 in cancer cells, Genasense may enhance response to other treatments for advanced melanoma.

As of May 3, the Oncologic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) determined that evidence of efficacy for Genasense, as measured by response rate and progression-free survival, did not outweigh the increased toxicity.

This recommendation was based on a Phase 3 trial of Genasense injection in combination with dacarbazine (DTIC) versus dacarbazine alone in chemotherapy-naive patients with metastatic melanoma. Among 771 patients enrolled from 139 sites in nine countries, those who received Genasense in addition to dacarbazine had a 51% improvement in median progression-free survival (74 days vs. 49 days); an improvement in durable response rate of six months, (13 patients vs. 5 patients); and a 72% increase in overall anti-tumor response rate (11.7% vs. 6.8%). Additional follow-up revealed six additional patients who achieved complete responses with Genasense, but none in the dacarbazine alone group.

The most common serious adverse event with Genasense was fever (5.9% vs. 3.1%), and the most common Grade 3 or 4 adverse events were neutropenia (21.3% vs. 12.5%), thrombocytopenia (15.6% vs. 6.4%), leukopenia (7.5% vs. 3.9%), anemia (7.0% vs. 4.7%), and nausea (7.0% vs. 2.5%).

Antigenics is in Phase III development of Oncophage (HSPPC-96), a personalized cancer vaccine using heat shock protein technology developed by Antigenics. By targeting only unique antigens on each specific patient’s tumor cells, Oncophage is designed to improve clinical response and survival while minimizing serious adverse effects or disrupted quality of life. Outpatient treatment usually begins within four to eight weeks postoperatively, with injection of the personalized Oncophage vaccine once weekly for four weeks, then every other week. In clinical trials thus far, Oncophage has a good overall safety and tolerability profile with minimal side effects including pain, postoperative pain, nausea, fever, weakness and constipation.

Another vaccine is Canvaxin, in Phase III testing by CancerVax. This vaccine is made from whole cancer cells that have been irradiated to prevent replication. Unlike Oncophage, this vaccine is derived from allogeneic, non- patient-specific, tumor cell lines selected for their ability to elicit an immune response and to express a large number of tumor-associated antigens.

Because this polyvalent vaccine expresses at least twenty known tumor-associated antigens, it may stimulate a stronger immune response than other immunotherapeutic agents using only cell fragments, peptides or antigens. After injection, Canvaxin stimulates activated T-cells and antibodies directed against tumor cells expressing one or more Canvaxin antigens.

Progenics Pharmaceuticals is in Phase III testing of GMK, a vaccine incorporating an immune stimulant or adjuvant and the GM2 ganglioside, a cancer antigen expressed by approximately 95% of melanoma cells. Follow-up for survival and relapse is ongoing in a Phase III trial comparing GMK to high-dose alpha interferon in melanoma patients at high risk of relapse.

Using a proprietary SPHERE peptide from its antigen discovery program, Genzyme Molecular Oncology has completed Phase II testing of an antigen-specific melanoma vaccine tailored to the patient's antigen profile. In a Phase I-II trial, investigators from Massachusetts General Hospital isolated and expanded dendritic cells from the patient and combined them ex vivo with adenoviral vectors encoding the Melan-A/MART-1 and gp100 genes. Of 21 patients evaluated, 15 demonstrated either clinical or immunologic responses to these gene-modified dendritic cells administered to the patient intradermally as a vaccine. Subsequent testing showed that 27 of 38 patients evaluated had a measurable immune response at least once following vaccination.

Anosys is in Phase II development of another tumor- specific dendritic cell-based exosome vaccine, using MAGE antigens isolated from dendritic cells and loaded into Dexosomes, or exosomes produced by dendritic cells containing essential components to activate both adaptive and innate immune responses.

An alternate approach to immune system activation is QS-21, an immune adjuvant in Phase III development by Antigenics. This triterpene glycoside stimulates humoral immune response but activates cellular immunity, giving it the potential to increase total vaccine-specific antibody response and T-cell response. By improving immune response to very low doses of antigen, QS-21 significantly decreases the amount of antigen required for a given dose and makes production more economical. It appears to be generally well tolerated, based on more than 50 clinical trials in approximately 3,500 humans, but it may cause transient reactions at the injection site.

Promune (CpG 7909), in Phase II testing by Coley Pharmaceutical, also stimulates specific humoral and cellular immune responses to cancer cells. By stimulating Toll-like receptor 9 (TLR9), ProMune targets plasmacytoid dendritic cells and B cells to reverse immune tolerance to malignant cells and to facilitate specific, sustained anti-tumor responses by producing antigen specific cytotoxic T cells and antibodies. Theoretical advantages of ProMune, either alone or as adjuvant therapy, include applicability to a variety of tumor types and metastases, provision of immune memory against tumor recurrence, and synergy with existing treatments.

Allovectin-7, in Phase II development by Vical, is a DNA/lipid complex containing the genes encoding HLA-B7 and ß2 microglobulin. These two genes form a Class I Major Histocompatibility Complex, or MHC-I antigen. Intratumoral injection of Allovectin-7 may enhance the immune response by several mechanisms, including a pro-inflammatory anti- tumor response. In HLA-B7 negative patients, introduction of a foreign HLA may trigger a T-cell response. In HLA-B7 positive patients, enhanced HLA-B7 and b2 microglobulin surface expression by injected tumor cells may increase antigen presentation to tumor specific T-cells.

Point Therapeutics is in Phase II testing of talabostat (PT-100), which stimulates the growth of primitive hematopoietic progenitor cells. Phase I safety studies showed the drug to be well-tolerated in healthy volunteers. Based on increased cytokine and chemokine activity in a Phase I chemotherapy-induced neutropenia study, this drug could be used as both an antitumor agent and to treat neutropenia and anemia associated with chemotherapy.

In a new twist on traditional chemotherapy, BioNumerik Pharmaceuticals is in Phase II development of BNP-1350 (Karenitecin). This lipophilic camptothecin silicon- containing agent is a fourth generation compound from a novel class of camptothecins called karenitecins. Although camptothecins have broad antineoplastic activity, common and serious side effects limit their use. Karenitecins appear to have lower toxicity and very high potency and broad activity against human cancers. In preclinical animal studies, orally administered BNP-1350 has demonstrated substantial activity in human melanoma xenografts without toxicity.

Another novel chemotherapeutic agent is Synthadotin (ILX-651), in Phase II development by ILEX Oncology. This orally bioavailable, synthetic pentapeptide analog of dolastatin has a unique mechanism of action targeting tubulin, and it has shown to be active in preclinical models for a variety of taxane-resistant tumors.

Most drugs in the melanoma pipeline are vaccines or other immunostimulants enhancing the body’s innate antitumor responses. With future development, these may show promise against this often fatal cancer, either alone or in conjunction with more traditional chemotherapeutic agents.