TCR VACCINES FOR ACTIVE IMMUNOTHERAPY OF T-CELL MALIGNANCIES

We have developed a TCR-based vaccine approach for the treatment of T cell malignancies. TCR genes were isolated from C6VL, a T cell tumor o f C57BL/Ka origin. The transmembrane encoding domains of the TCR genes were replaced by sequences encoding for phosphatidylinositol-linked c ell surface expression. A high expressing cell line was produced by tr ansfection and amplification of the TCR genes. Large quantities of sol uble native C6VL TCR-alpha beta protein was obtained by treating the h igh-expressing cells with a specific phospholipase and purifying the r eleased TCR by affinity chromatography. Following vaccination with the TCR linked to keyhole limpet hemocyanin, specific anti-TCR humoral re sponses were induced. Both the carrier protein and an adjuvant were re quired for optimal responses. Hyperimmune serum from vaccinated mice r eacted specifically with C6VL cells, and the immunizations did not aff ect the TCR repertoire, which suggested that the immune response was I d specific. The TCR-vaccinated mice were specifically protected from a lethal number of C6VL tumor cells. B cell-deficient mice were not pro tected by TCR vaccinations. Similarly, TCR-immunized mice depleted of CD8(+) cells prior to tumor challenge were not protected. Thus, C6VL v accine effectively stimulated tumor protection, which depends on the p resence of both B cells and CD8(+) T cells.