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Abstract
Multiple cancer-associated antigens recognized by human tumor infiltrating lymphocytes have been identified and characterized. The majority of these antigens are either non-mutated proteins overexpressed on cancers or are antigens expressed only on cancers and cells in the germ line. Substitution of anchor residues of the immunodominant peptides from these proteins results in increased peptide immunogenicity and following immunization with these modified peptides, high levels of circulating CD8+ antigen reactive T cells can be generated in patients with metastatic cancer. Tumor regressions in vivo are sporadic and unpredictable, however, and we have thus explored approaches to increase the anti-tumor potential of these immunologic approaches. In a clinical trial of patients with metastatic melanoma immunized with these melanoma peptides in conjunction with an antibody reactive against CTLA-4, objective cancer regressions were seen in patients associated with autoimmunity including autoimmune colitis and gastritis, autoimmune hepatitis, and autoimmune hypophysitis.
We have conducted a clinical trial in which patients received a non-myeloablative chemotherapy followed by the adoptive transfer of tumor reactive cells plus high dose IL-2. Forty percent of patients, who were previously refractory to treatment with high dose IL-2 and many with chemotherapy, had objective regressions of metastatic cancer. Lymphocytosis, in vivo persistence and proliferation of the transferred cells and clonal repopulation of the transferred lymphocytes were seen in some patients associated with cancer regression and the occasional onset of autoimmunity to normal melanocytes. These approaches demonstrate that the development of strong reactivity against normal melanocyte melanoma antigens overexpressed on melanomas can result in tumor destruction and autoimmunity.
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