ENHANCED IMMUNOGENICITY OF B-CELL LYMPHOMA GENETICALLY-ENGINEERED TO EXPRESS BOTH B7-1 AND INTERLEUKIN-12

The A20 murine B cell lymphoma was transfected with B7-1 and subsequen tly these variants and vector control variants were retrovirally infec ted to express murine interleukin-12 (mIL-12), In vitro data showed th at the B7-1 variants enhanced secretion of IL-2 and IL-4 by allogeneic T cells in mixed lymphocyte tumor cultures, While IL-12 variants stim ulated IFN-gamma, variants expressing both B7-1 and IL-12 stimulated I FN-gamma, IL-2, and IL-4 secretion, Tumorigenicity experiments showed that whereas B7-1 delayed tumor onset, only the mIL-12 variants with o r without B7-1 were completely rejected in syngeneic hosts, In additio n, tumor-free mice were protected against subsequent challenge with th e parental unmodified cells and had enhanced cytotoxic T lymphocyte (C TL) lysis activity, Results from minimal disease mixing experiments de monstrated that only the A20/B7-1/mIL-12 variant was able to reject A2 0 unmodified cells inoculated at the same site, whereas prolonged surv ival was observed when the A20 parental cells were inoculated at diffe rent sites, Depletion studies and injections into nu(-)/nu(-)mice demo nstrated that both CD4(+) and CD8(+) T cells may mediate immunity, The se data suggest that vaccinations with tumor cells genetically modifie d to express both B7-1 and IL-12 may alter cytokine profiles and gener ate CTL activity and, thus, the mechanisms of enhanced antitumor immun ity may be multifactorial.