holy melanoma!

The mantra of treating melanoma has been the same as many other malignancies (colon, lung, ovarian, etc.): catch it before it spreads. What has separated melanoma, other than the fact that it is readily detectable with excellent prognosis as an in situ malignancy, once metastasized (which occurs in 20-25% of all melanomas), the prognosis has been almost incomparably poor.The life expectancy of a patient with stage IV malignant melanoma is less than one year, with fewer than 15% of patients surviving three years.Until recently, exisiting therapies for metastatic melanoma offered little hope of disease-free survival. The most promising therapies as recent as five years ago revolved around broad-scale harnessing of the immune system:

IL2 (proleukin) is a well-known T cell survival and proliferation signal, and has been shown to induce partial responses in 10-20% of patients (though few patients go into complete remission). The method of activity is presumed to be expansion of antitumor T cells. However, this therapy is associated with sepsis-mimicking complications such as severe hypotension and vascular leak syndrome.

IFNg is produced by NK cells as well as activated CD4 and CD8 T cells and drives both anti-viral and anti-tumor immunity by driving a number of transcriptional changes, including enhanced MHC-I presentation on all cells and maturation of macrophages and dendritic cells. It is one of the prime effector cytokines of Th1 CD4+ T cells.

While both of these therapeutic options are quite limited in their efficacy, the fact that they both act by broadly stimulating T cell effector functions suggested that enhancing antigen-specific T cell responses might provide mortality benefits in metastatic melanoma. So, here are some of the interesting and diverse treatment modalities under exploration:

Immunomodulatory therapy

The new therapies being explored in this vein expand upon the possibilities raised by recombinant IL-2 and IFN-g therapy by potentiating endogenous T cell antitumor activity. Drug developers have tried many interesting ways to boost the endogenous response:

Block suppressive T cell signals: CTLA-4 is expressed on T cells and upregulated following activation. It has a higher affinity for its ligand, B7, than the co-stimulatory molecule CD28, whose ligation is required for full T cell activation. By outcompeting CD28, CTLA-4 limits the duration of T cell signaling and maintains homeostasis. Mice lacking CTLA-4 die rapidly of multi-system autoimmune disease, suggesting that this homeostasis is critical to preventing autoimmunity. However, in patients with unresectable metastatic melanoma, it was felt that removing this suppressive T cell signal might increase reactivity towards low-affinity tumor antigens. Indeed, evidence supporting this was provided in a recent study by Hodi and associates published in the New England Journal.

In it, ipilimumab, a blocking antibody to CTLA-4, nearly doubled median survival (10 months vs. 6.4 month), and increased 1 year survival from 25% to 45%. Interesting, the limiting side effect for these patients was skin fibrosis and inflammatory diarrhea similar in histopathology to graft-versus-host disease and likely representing unchecked autoimmune reactivity seen in

earlier mouse studies and controlled in these patients with either high-dose steroids or TNFa inhibitors.

Improve T cell priming: Immunogenic peptides derived from melanoma cells were shown to induce tumor-infiltrating lymphocytes which led to tumor regression over fifteen years ago.

Unfortunately, vaccination with gp100 or other highly immunogenic peptides has proven disappointing. Recent efforts have focused on improving peptide delivery to lymph nodes in order to maximally prime anti-tumor T cells.

A recent paper in the Journal of Clinical Investigation used a bacterial vector, Listeria monocytogenes,for this process with the rationale that bacteria would activate toll-like receptor signaling and enhance dendritic cell maturation, and that Listeria's natural tropism for the liver would improve T cell homing to the liver, a common site of melanoma metastasis.Researchers were able to effectively target Listeria to dendritic cells, engineer effective DC activation, drive CTL generation against the melanoma antigen MART-1 as well as CD4 T cells against the antigen ESO-1, which drove effective tumor rejection in a mouse model. Key to the utility of this mechanism is ensuring that the vector's virulence is completely neutralized.

Improve immune cell homing: Somebody really clever came up with this novel idea: of creating a lytic herpes simplex virus which also expresses granulocyte-macrophage colony stimulating factor (GM-CSF); they then directly inject this virus into accessible tumors. A phase II trial of this was published in the Journal of Clinical Oncology last December; unbelievably, it seems to work, improving 1 year survival to greater than 50%. While likely not curative, it provides a fascinating method of decreasing metastatic tumor burden.

Adoptive Transfer of tumor-specific T cells: generation of tumor-infiltrating CD8 T lymphocytes has long thought to be the main mechanism of inducing tumor killing. About 4 years ago, a study in the Journal of Clinical Oncology demonstrated that adoptive transfer of Melan-A-specific CTLs did induce partial or complete responses in 27% of patients; however, these responses were complicated by both eosinophilia and tumor progression in which surviving tumor cells lost their melan-A expression, suggesting that CTLs alone may not be sufficient to control tumor growth.

Given the critical role of CD4 T cells in enhancing CD8 T cell survival and priming, the role of tumor-specific CD4 T cells has been a recent subject of interest. In a study published in NEJM in 2008, a case report from the Fred Hutchinson Institute in Seattle described a patient with metastatic melanoma expressing the immunogenic antigens MART, MAGE-3, ESO-1, but not gp100. Peripheral T cells were isolated from the patient and stimulated with dendritic cells pulsed with ESO-1. After ESO-1-specific CD4 T cells grew out, they were restimulated and expanded multiple times in vitro before being transferred adoptively into the patient. Follow-up 2 months later showed complete resolution of pulmonary and nodal disease and suppression of new metastasis; the patient remained disease free 2 years later at the time of publication. 2 more points here are quite interesting:

1) tumor analysis demonstrated regression despite the fact that not all tumor cells expressed the ESO-1 antigen.

2) Consistent with this, harvesting of the patient's peripheral blood cells revealed expansion of T cells specific not only for ESO-1, but for MART and MAGE-3, but not gp100. This is consistent with the concept known as "antigen spreading" in which ESO-1 expressing cells were killed, taken up by antigen presenting cells, and then induced activation of T cells against other immunogenic tumor peptides.

Growth factor signal inhibitors

In a totally separate direction, massive gene chip analyses have been performed to try to identify novel aberrant signaling pathways activated in melanoma T cells. A few years ago, it was revealed that 40-60% of melanomas carry a mutation in B-Raf, a serine-threonine kinase in the MAP kinase pathway. 90% of these mutations result in a glutamic acid for valine substitution (V600E) which results in constitutive activation. Plexxikon, an orally bioavailable inhibitor of mutant-BRAF, was recently used in a phase I trial for patients with metastatic melanoma which had this mutation. The phase I study (not placebo-controlled) resulted in an 81% response rate and has significantly increased progression-free survival (total survival could not be assessed at the time of publication). Analysis of tumor cells showed that the drug repressed MAP kinase activation, cell cycle activation, and tumor cell proliferation. Notably, this mutation is also seen in anaplastic thyroid cancer; phase I trials assessing response rates is underway.

I wonder how many people actually made it to the end of this?