“...these studies resulted in molecular understanding of immune responses to tumor cells in patients, quantitative and qualitative evaluation of anti-tumor T-cell response in patients, and development of immunotherapy in a more scientific way.”

I have cloned genes encoding human melanoma antigens recognized by T cells whose adoptive transfer resulted in tumor regression in the patients. These original landmark studies were actually published as a couple of papers in 1994, which were not included in this 1995-2005 search. The highly cited papers searched in this 1995-2005 period are the extensions of the 1994 original works, including additional cloning of interesting melanoma antigens, characterization of immune responses to the isolated antigens, clinical immunotherapy trials using the isolated melanoma antigens, and so on. This series of studies may be highly cited because these studies resulted in molecular understanding of immune responses to tumor cells in patients, quantitative and qualitative evaluation of anti-tumor T-cell response in patients, and development of immunotherapy in a more scientific way.

Many people might have negative feelings regarding immunotherapy, since clinically detected tumors once evaded the immune system through various unknown mechanisms. However, in the 1980s, we were sure that T cells are able to reject melanoma cells in patients based on the results from clinical trials of IL2 administration and adoptive transfer of anti-melanoma T cells. So, one of our most important questions at that time was, what molecules (antigens) on melanoma cells do T cells recognize? The answer to this question should lead to molecular and cellular understanding of immune responses to human cancer cells, and consequently lead to development of more effective immunotherapy. I then began this melanoma antigen isolation project, which took me three years for the isolation of melanoma antigens MART-1 and gp100 and was finally published in 1994.

The results of complete identification of several human melanoma antigens and their T-cell epitopes revealed the molecular nature of immune recognition of human cancer cells, including unexpected and very interesting observations such as the recognition of peptides derived from introns and alternative open reading frames, etc. These results enabled us to measure anti-tumor T-cell responses quantitatively and qualitatively in patients, and to understand precise problems regarding immunological rejection of cancers (tumor escaping from immune system), including antigen loss, tolerance induction, dysfunction of tumor-infiltrating T cells, and so on. Based on these studies, we are now able to develop immunotherapy in very scientific ways, for example, use of more immunogenic-designed antigens such as amino acid modified peptides. Thus, our works appear to be significant in the sense that they have changed the view of human tumor immunology and immunotherapy.

After the original cloning of several melanoma antigens, we and others investigated fine mechanisms of T-cell recognition of tumor cells, analyzed immune responses to the identified antigens in patients, and developed new types of immunotherapy in murine models and clinical trials. These extended studies led to many interesting discoveries, including how T cells recognize tumor cells, how tumor cells evade T-cell attack, and so on. We and others demonstrated future directions of immunotherapy development. In addition, identification of melanoma antigens contributed a lot to the understanding of melanoma development, the biology of melanocytes, and pigment disorders including autoimmune vitiligo.

The series of studies on the understanding of immune response to melanoma, and the development of efficient immunotherapy, are still ongoing. I am sure that, in the next 10 years, more extended studies on these subjects (biology of melanoma and melanocytes, development of immunotherapy) will be performed, more details will be revealed, and hopefully more efficient immunotherapy will be established for melanoma patients.