Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes.

Abstract

SummaryFour melanoma proteins, MART-l, gpl00, tyrosinase, and tyrosinase-related protein-1 (gp75) were evaluated for recognition by HLA-A2-restricted melanoma-specific cytotoxic T lymphocytes (CTLs) derived from the tumor-infiltrating lymphocytes (TIL) of 10 different patients. 9 of 10 TIL recognized MART-l, 4 recognized gpl00 (including 3 that also recognized MART-l), but none of the TIL recognized tyrosinase or gp75. Based on the known HLA-A2.1 peptide binding motifs, 23 peptides from MART-1 were synthesized in an attempt to identify the epitopes recognized by TIL. Three peptides were recognized by TIL when pulsed on T2 target cells. One of the 9-met peptides, AAGIGILTV, was most effective in sensitizing the T2 cells for TIL lysis. This peptide was recognized by 9 of 10 HLA-A2-restricted melanoma-specific CTLs. Therefore, this peptide appears to be a very common immunogenic epitope for HLA-A2-restricted melanomaspecific TIL and may be useful for the development of immunotherapeutic strategies.

Novel antibodies as anticancer agents

“…Among this group, many specific antigens were identified, such as NY-ESO-1 and the MAGE-1 antigens, which belong to cancer-testis family, gp100, which belongs to the differentiation antigens group, and many more (Visseren et al, 1997;Chen et al, 1998a, b;Jager et al, 1998;Pascolo et al, 2001). It is well-established that human melanoma cells express antigens that are recognized by cytotoxic T-lymphocyte (CTL) derived from cancer patients (Brichard et al, 1993;Kawakami et al, 1994;Wolfel et al, 1994;Fleischhauer et al, 1996;Pittet et al, 1999;Kawakami et al, 2000;Engelhard et al, 2002;Romero et al, 2002;Schaed et al, 2002). These are mainly differentiation antigens such as gp100, MART1 and tyrosinase, which represent a very attractive target because their expression is limited to a well-defined cell lineage (melanocytes).…”

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

“…Both antigens are highly characterized from an immunological standpoint and encompass major histocompatibility complex (MHC) class-I (A*0201)-restricted epitopes. 7,8 In several recent clinical studies there have been encouraging reports of success after adoptive T-cell therapy with MART-1/ Melan-A-specific T cells that resulted in objective tumor responses of varying durability, supporting the applicability of this antigen to cancer immunotherapy. 9,10 Nevertheless, attempts to effectively immunize and elicit objective clinical responses against these two antigens using 'vaccines' have successfully shown immunity but not yet yielded strong evidence of clinical benefit.…”

Melanoma antigen expression in serial fine-needle aspiration samples in patients with metastatic malignant melanoma participating in immunotherapy clinical trials

“…It is recognized by cytotoxic T lymphocytes in the context of HLA-A*0201. 9,13,14,21 Anti-MART-1 murine monoclonal antibody, M2-7C10, was developed at the NCI 2 and shown to be superior to HMB-45 for the diagnosis of MMM in FNA samples. 10 In a recent large scale study performed in our institution, 84% of MMM lesions (80% of patients) were immunoreactive with anti-HMB-45 whereas 92% of MMM lesions (90% of patients) were immunoreactive with anti-MART-1.…”