Melanoma Peptides

Definition
Melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin. Metastatic melanoma is known to be one of the most resistant cancers. Peptides derived from melanoma cells can be used for treatment of Melanoma.

Discovery
One of the first clinical trials to use peptides derived from melanoma cells was performed by Rosenberg et al., who vaccinated stage IV melanoma patients with a modified immunodominant peptide of the gp100 antigen, g209-2M. They found that 10 out of 11 (91%) of patients showed a consistently high level of immunization against the native g209-217 peptide, but not against the control peptide g280-288. Although many developed an immunologic response to the peptide vaccine, all patients went on to develop progressive disease. However, this study provided a central proof-of-principle that patients with advanced melanoma were readily able to mount an immune response against their own self-antigens1.

Structural Characteristics
When designing a peptide-based approach, it is important to recognize that most tumor nodules are comprised of a heterogeneous population of tumor cells with different levels of tumor antigen expression. It has previously been shown that synchronous lesions of patients with metastatic melanoma are heterogeneous in their tumor antigen expression2, with data suggesting that daughter cell lines derived from patients with metastatic melanoma exhibit an overall heterogeneous expression of the common tumor antigens, such as gp100, NY-ESO 1 and the melanoma antigen gene antigens 3.Analysis of the isolated peptides immunogens that are isolated by panning phage display peptide libraries has shown that the large majority of them do not display a significant homology in their sequence with the published amino acid sequence of the HMW-MAA (high molecular weight-melanoma associated antigen). Furthermore the isolated peptides have distinct sequences. Most of the peptides react only with the antibody used for their isolation and do not cross react even with antibodies which display a high degree of homology in the amino acid sequence of the variable regions of their heavy and light chains with those of the antibodies used for their isolation4.

Mode of Action
The identification and molecular characterization of human tumor associated antigens (TAA) have provided well defined moieties to implement active specific immunotherapy in patients with malignant diseases. The large majority of TAA identified in melanoma cells with T cells or with antibodies have been found to be self-antigens which are expressed in larger amounts in malignant cells than in their normal counterparts, most likely because of abnormalities in gene regulation associated with the transformation process. Malignant melanoma utilizing mouse anti-idiotypic monoclonal antibodies which mimic the high molecular weight-melanoma associated antigen (HMW-MAA). Anti-idiotypic antibodies elicited anti- HMW-MAA antibodies in more than 50% of the immunized patients. During the establishment of self-identity, of B cell clones that recognize the HMW-MAA with high affinity. In contrast the immunogenicity of the corresponding antiidiotypic antibodies is likely to reflect their ability to stimulate clones which have not been deleted during the establishment of self-identity, since they secrete antibodies reacting with the corresponding antigen with an affinity below the threshold required for their deletion. Expression of HMW-MAA by pericytes suggests that the effect of anti-HMW-MAA immunity on melanoma lesions may be mediated not only by a direct interaction with melanoma cells, but also by disturbing the blood supply 4.

Functions
Immunologic response to the peptide vaccine- all patients went on to develop progressive disease 5. The isolated peptides have distinct sequences. Most of the peptides react only with the antibody used for their isolation and do not cross react even with antibodies which display a high degree of homology in the amino acid sequence of the variable regions of their heavy and light chains with those of the antibodies used for their isolation. The discovery that immune T-cells recognize intracellularly processed peptides associated with major histocompatibility locus molecules has revolutionized the cancer vaccine field by providing new reagents for the generation of immune responses against cancer. The cloning of tumor antigen genes has proceded most rapidly in melanoma because of the ease with which melanoma-specific T-cells can be propagated in vitro. HMW-MAA as a target of immunotherapy because of its high frequency of expression in patients with melanoma, its high expression by melanoma cells with limited intra- and inter lesional heterogeneity, its restricted distribution in normal tissues and its suggested role in the metastatic potential of melanoma cells4.

References
1.Rosenberg SA, Yang JC,Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE.(1998). Immunologic and therapeutic evaluation of a synthetic tumor associated peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med., 4(3):321-327.
2.Riker AI, Kammula US, Panelli MC, Wang E, Ohnmacht GA, Steinberg SM, Rosenberg SA, Marincola FM. (2000). Threshold levels of gene expression of the melanoma antigen, gp100, correlates with tumor cell recognition by cytotoxic T-lymphocytes. Int. J. Cancer., 86(6):818-826.
3.Riker AI, Panelli M, kammula US, Wang E, Wunderlich J, Abati A, Fetsch P, Rosenberg SA, Marincola FM. (1999). Development and characterization of melanoma cell lines established by fine needle aspiration biopsy: advances in the monitoring of patients with metastatic melanoma. Cancer Detect. Prev., 23(5):387-396.
4.Wang X, Luo W, Ferrone S (2000).Inmunotherapy of melanoma: Peptide mimics of human high molecular weight-melanoma associated. Medicina (B Aires)., 60(2):48-50.
5.Riker AI, Radfar S, Liu S, Wang Y, Khong HT (2007). Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin. Biol. Ther., 7(3):345-358.

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