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hand, most of these patients have progressive disease, and that suggests that these CTL precursors are not very effective. There is also concern for side effects—not vitiligo (due to destruction of normal melanocytes), which can occur without unacceptable consequences, but rather in the pigmented cells in the choroid layer of the retina, where the expression of fas ligand and TGJ-beta could contribute to inflammatory reactions. Nevertheless, several groups are going forward with plans for carefully devised clinical trials of immunotherapy against these antigens.

Antigens of Mutated Protein. Point mutations can also generate antigens on melanoma that are recognized by CTLs. One of the most interesting is a protein that normally binds to p16 in the regulation of the cell cycle. The mutation prevents this binding, thereby increasing entry into the S phase of the cell cycle. This mutation is both antigenic and oncogenic.

Another mutation antigen was isolated in renal carcinoma using CTL clones that recognize renal tumors but not autologous Epstein-Barr virus-transformed B-lymphocytes. The gene was identified by transfecting cos cells in combination with HLA-A21, because the lysis of this clone was inhibited by anti-HLA-A2 antibodies. Surprisingly, the cDNA alone could confer recognition, and the sequence was the sequence of HLA-A21 molecule that was mutated at position 117.

Experimental Results. Identification of tumor antigens has three advantages: (1) the patients are easily identified; (2) the antigens can be engineered for optimal immunization; and (3) there are several modes of immunization. Of those that have been tried thus far, one of the most impressive is adenoviral injection.

One experiment used mouse tumor antigen p815-A, a known epitope presented to CTL by LD molecules. Researchers inserted the sequence encoding for this peptide into the genome of an E3, E1-deletion mutant of adenovirus serotype 5. The location of the insertion was just after the promoter, which is a strong promoter active in a wide range of mammalian cells. Varying amounts of the plaque-forming units of adeno. P1A were injected intradermally in the ears of experimental mice, while other animals received equal numbers of control adenovirus. After 14 days, researchers removed spleen cells and stimulated them in vitro in the presence of L1210 cells transfected with either P1 A or P1 A and B7.1. Experimental animals that received higher concentrations produced a strong CTL response, especially if the stimulated cells were also transfected with B7.1. Results were similar when IL-2 was used in place of B7.1. Otherwise, however, results were less impressive: there was a CTL response, but never enough to protect against challenge with living p815 tumor cells, and prior infection with MD adeno virus prevented CTL responses to p815.

Prospects for Human Immunotherapy. Given the frequency of expression of different tumor antigen genes and the frequency of different HLA alleles in the human population, up to 82 percent of melanoma patients might



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