Melanoma: Can future therapies improve prognosis?

October 1, 2008

The natural history of melanoma has changed little over the years, despite advances in testing and treatment such as cytotoxics, DNA-damaging agents, antimicrotubule drugs, and immunomodulatory therapies. Only 15% of advanced-stage patients respond to the two FDA-approved agents, interleukin-2 and dacarbazine (DTIC or DTIC-Dome).

ABSTRACT: Advances in testing and treatment could alter melanoma’s reputation as the malignant histology that gives oncology a bad name.

The natural history of melanoma has changed little over the years, despite advances in testing and treatment such as cytotoxics, DNA-damaging agents, antimicrotubule drugs, and immunomodulatory therapies. Only 15% of advanced-stage patients respond to the two FDA-approved agents, interleukin-2 and dacarbazine (DTIC or DTIC-Dome).

The dismal prognosis for melanoma prompted one expert to call it “the malignant histology that gives oncology a bad name (Table 1).” But the picture may be changing, thanks to advances in understanding of melanoma biology, immune regulation, and tumor-induced immune suppression.

These factors must all be taken into consideration in designing a treatment approach, said Jeffrey S. Weber, MD, the originator of the “bad name” label. Dr. Weber is director of the Donald A. Adam Comprehensive Melanoma Research Center at H. Lee Moffitt Cancer Center and associate chair in the department of oncologic sciences at the University of South Florida, both in Tampa.

Dr. Weber, along with other experts, discussed novel pathways in drug developments for melanoma. Based on current research, Dr. Weber said he now sees “a significant glimmer of hope for new treatments on the horizon.”

Unblocking the road

Multiple agents will be needed to tackle the disease, not only to stimulate T cells (for instance, by targeting melanoma-associated antigens) but also to take on the mechanisms that interfere with response. The immune system must be disinhibited and T-cell suppression must be eliminated or regulated in a way that facilitates immunotherapy.

Such combinations might involve a vaccine (cellular, protein- or peptide-based, recombinant viral vector-based, anti-idiotype, or glycopid) coupled with a cytotoxic plus an agent that would deplete regulatory T cells and myeloid suppressor cells. The vaccine might be given with a new-generation adjuvant that will help T lymphocytes and natural killer T lymphocytes recognize melanoma cells and an immunomodulating agent that could be synergistic with the vaccine.

As a means of “unblocking” one of the roadblocks to effective immunotherapy, the anti-CTLA4 monoclonal antibodies are the source of much hope. The upregulation of the CTLA4 molecule on active T cells leads to down-modulation of the immune response. At ASCO 2008, investigators reported 1-year survival of approximately 50% with the anti-CTLA4 antibody ipilumumab (Figure 1) in refractory metastatic patients and over 60% in treatment-nave subjects (abstract 9022).

The news for tremelimumab, however, was not so good. The agent failed to show improvement in overall survival compared with standard therapy, and the study was stopped early due to treatment futility (abstract LBA9011).

Findings with the tyrosine kinase inhibitor axitinib were also impressive, with a median survival of 13 months in an unselected advanced disease population (abstract 9006).

Early findings have also been encouraging with anti-PD-1 (programmed death-1) and anti-CD137 monoclonal antibodies, as well as CD40 agonist antibodies, according to Dr. Weber, who spoke at ASCO 2008.

The ideal vaccine

Vaccines have long been considered a rational approach, said Dr. Weber. Melanoma is “both the classic immunogenic tumor and the tumor in which we are likely to see the greatest benefit from immunological manipulation,” he said.

There have been fits and starts in vaccine development, however. In a May 2008 review, Italian investigators noted that melanoma vaccines represented a “scientifically exciting but still clinically unrewarding field of investigation” (Expert Rev Dermatol 3:195-207, 2008).

For instance, the adjuvant ganglioside GM2-KLH21 vaccine once seemed promising. But the EORTC 18961 patients treated with GM2 actually had worse survival rates than patients assigned to observation (abstract 9004).

“GM2 vaccine is not only ineffective but may even be detrimental in stage II melanoma,” Dr. Weber commented. The negative findings mirror those seen with the similar Canvaxin vaccine in stage III melanoma, he noted.

“This raises significant concerns about vaccines. We may be increasing the level of suppressor cells by vaccinating patients in the absence of other immunomodulation,” Dr. Weber said.

There were more positive findings for the GM-CSF-encoding oncolytic virus OncoVEX, which produced a 32% response rate (even in distant metastases) and durable responses in a study presented at ASCO (abstract 9008), but Dr. Weber remains skeptical about a solo vaccine approach.

“I don’t think an individual vaccine will be useful in the absence of immunomodulators, and I don’t think we yet have an ideal vaccine or even one that is highly likely to be useful in melanoma,” said Dr. Weber, who has been heavily involved in vaccine research. “We are still trying to find the best antigen-specific vaccine, and the answer is not in.”

“Short of a combined approach, we will generally not see cures in melanoma,” he predicted. “The promise is in the immunomodulating agents and antibodies. With vaccines, it’s back to the drawing board.”

Signaling pathways

In terms of novel approaches, the focus of drug development in the last decade has been on the Ras/Raf/mitogen-activated protein (MAP) kinase cascade, but agents targeting this pathway have been disappointing in clinical trials. Attention has turned to the molecular alterations within melanoma cells, especially the metabolic enzymes expressed in the tumor microenvironment and the developmental signaling pathways that are active in aggressive tumors.

Strategies to interfere with these signals are poised for translation into the clinic, said Thomas F. Gajewski, MD, PhD, associate professor of pathology and medicine at the University of Chicago.

Several factors involved in the metabolic alterations in the microenvironment could serve as therapeutic targets: inducible nitric oxide synthase (iNOS), indoleamine-2,3-dioxygenase (IDO), and arginase.

High expression of iNOS protein seems to be a negative prognostic factor for survival as well as a biomarker; therefore, clinical benefits might be derived from interfering with nitric oxide. By “quenching” nitric oxide, researchers have been able to overcome the resistance of the melanoma cell to apoptosis, Dr. Gajewski reported at ASCO 2008.

In terms of the developmental processes at work in aggressive melanomas, the Notch, Wnt, and Nodal pathways may be the prime targets. “Inhibition of these pathways in preclinical models has shown important effects,” he said.

Undoubtedly, multiple classes of agents will be needed to make an impact on melanoma, he agreed, not just to facilitate an immune response but because of the nature of the beast.

“My sense is that melanoma is not one disease, but a disease with many molecular subtypes,” Dr. Gajewski told Oncology News International.

For example, c-KIT mutations, which are associated with gastrointestinal stromal tumors (GIST), are observed in 20% of the 10% of melanoma patients with acral lentiginous melanoma (involvement of the palms, soles, nails). There are anecdotal reports that imatinib (Gleevec), which is effective in GIST, can produce major responses in this molecular subtype.

“I believe our mission is to define these subtypes and determine which patients will respond to the individual therapeutic approaches,” he said.