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.”
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.