IL-15/IL-15R alpha/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice

Engineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor alpha (IL-15R alpha), or heterodimeric IL-15/IL-15R alpha together with CD80 and tested as irradiated cell vaccines. IL-15 is a gamma c-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8(+) memory T cells. Coexpression of IL-15 and IL-15R alpha markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15R alpha/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15R alpha vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15R alpha/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (< 5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15R alpha/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15R alpha and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.

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