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Ruben Dyall^*, Wilbur B. Bowne, Lawrence W. Weber, Joel LeMaoult^*, Paul Szabo, Yoichi Moroi, Gregory Piskun, Jonathan J. Lewis, Alan N. Houghton, and Janko Nikoli-ugi^*

From the ^* T Cell Development Laboratory and the Swim Across America Laboratory, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021; and the Division of Geriatrics and Gerontology, Cornell University Medical College, New York 10021

In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I–associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.

Key Words: cytotoxic T lymphocyte • tumors • peptide vaccines • heteroclitic peptides • major histocompatibility complex class I

Address correspondence to Janko Nikoli-ugi, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 98, New York, NY 10021. Phone: 212-639-2387; Fax: 212-794-4019; E-mail: nikolicj{at}mskcc.org; or A.N. Houghton, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: 212-639-7595; Fax: 212-794-4352; E-mail: a-houghton{at}ski.mskcc.org

Abbreviations used: ER, endoplasmic reticulum; ERIS, ER insertion sequence; pCTL, precursor CTL; SEI, peptide SEIEFARL, a variant of SSI; SSI, Herpes simplex virus glycoprotein B_498–505 peptide SSIEFARL; TAY, peptide TAYRYHLL, an engineered variant of TWH; TM, synthetic adjuvant TiterMax; TWH, melanoma gp75_222–229 peptide, TWHRYHLL.

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