We report here the adoptive transfer, to patients with metastatic melanoma, of highly selected tumorreactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. This approach resulted in the persistent clonal repopulation of T cells in those cancer patients, with the transferred cells proliferating in vivo, displaying functional activity, and trafficking to tumor sites. This led to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction. This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus-related acquired immunodeficiency syndrome and other infectious diseases.Immunotherapy of patients with cancer requires the in vivo generation of large numbers of highly reactive antitumor lymphocytes that are not restrained by normal tolerance mechanisms and are capable of sustaining immunity against solid tumors. Immunization of melanoma patients with cancer antigens can increase the number of circulating CD8 + cytotoxic T lymphocyte precursor cells (pCTLs), but to date this has not correlated with clinical tumor regression, suggesting a defect in function or activation of the pCTLs (1).Adoptive cell transfer therapies provide the opportunity to overcome tolerogenic mechanisms by enabling the selection and activation of highly reactive T cell subpopulations and by manipulation of the host environment into which the T cells are introduced. However, prior clinical trials, including the transfer of highly active antitumor T cell clones, failed to demonstrate engraftment and persistence of the transferred cells (2-5). Lymphodepletion can have a marked effect on the efficacy of T cell transfer therapy in murine models (6-9) and may depend on the destruction of regulatory cells, disruption of homeostatic T cell regulation, or abrogation of other normal tolerogenic mechanisms.To determine whether prior lymphodepletion might improve the persistence and function of adoptively transferred cells, 13 HLA-A2 + patients with metastatic melanoma received immunodepleting chemotherapy with cyclophosphamide and fludarabine for 7 days before the

Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer.

The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies.

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