Abstract
AbstractEngineered 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 α (IL-15Rα), or heterodimeric IL-15/IL-15Rα together with CD80 and tested as irradiated cell vaccines. IL-15 is a γc-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-15Rα markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15Rα/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15Rα vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15Rα/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-15Rα/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-15Rα and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.
Highlights
Older individuals with acute myelogenous leukemia (AML) have poor outcomes because of more frequent high-risk features and comorbidities.[1]
We developed a novel model of postremission minimal residual disease (MRD) in leukemic mice that in part recapitulates the clinical setting in which AML cell vaccines would be administered
Because leukemia-associated stimulation of inhibitory immune responses poses challenges in the clinical setting,[9] we assessed whether 32Dp210 leukemia has immunosuppressive effects comparable to those observed in patients
Summary
Older individuals with acute myelogenous leukemia (AML) have poor outcomes because of more frequent high-risk features and comorbidities.[1]. Immunotherapies for AML have been explored, to date none have reliably reduced relapse rates.[2,3,4,5] In this context, autologous cell vaccines may have advantages for stimulating antileukemic immunity because responses are directed to multiple leukemiaassociated antigens, some of which are patient specific. Previous trials with autologous cell vaccines have induced antileukemic immunity, but responses were variable.[6] This is in part because AML blasts are ineffective in T-cell stimulation, because of their downregulation or absent expression of specific costimulators such as CD80,7,8 and because of their immune evasive effects including upregulation of checkpoint molecules and stimulation of inhibitory immune effectors (reviewed by Teague and Kline[9]). Immunotherapeutic efficacy may be further limited by a decline in T-cell responsiveness.[10,11,12,13]
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