Personalized Adoptive T-cell Therapy for AML

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Abstract/Project Summary The development of strategies to expand and activate AML specific T cells is of critical importance. We have developed a personalized cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs), presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population, including shared and neoantigens. We have completed a phase II clinical trial in which patients that achieve remission following chemotherapy undergo serial vaccination with DC/AML fusions. Remarkably, despite a median age of 63, 71% remained free of disease with a median follow up of 5 years. Vaccination was associated with the expansion of T cells targeting both autologous AML cells and leukemia associated antigens. The DC/AML vaccine can be used as a platform to generate activated leukemia-specific T cells ex- vivo for adoptive immunotherapy. In this way, effector cells may be generated that are leukemia specific, capture tumor heterogeneity, and are activated ex vivo to achieve a functionally competent phenotype. We have demonstrated that vaccine stimulation in the context of IL7/IL-15 results in enhanced levels of central memory cells critical for long term persistence of response. While the generation of vaccine stimulated leukemia specific T cells ex vivo represents a promising strategy to effectively target AML cells in vivo, the immunosuppressive nature of the tumor microenvironment remains a barrier to the development of a memory response and long-term protection. We performed transcriptome analysis in the remission bone marrow at time of vaccination to identify biomarkers that were predictive of durable response as compared to early relapse following vaccination with DC/AML fusions. Of note, decreased expression of TGF-β in the bone marrow microenvironment was associated with durable remission. These results are consistent with prior reports suggesting TGF-β as a negative regulator of tumor immunogenicity, T cell activation and infiltration into the tumor bed. As such there is strong rationale to target TGFβ to enhance vaccine efficacy. In the present study, we will create a novel strategy for adoptive T cell therapy generated by vaccine mediated stimulation, selection of antigen specific T cells and ex vivo expansion. Functional characteristics will be examined in an immunocompetent murine leukemia model. We will then examine the effect of TGF-β inhibition on vaccine response and TGF inhibition within vaccine stimulated T cells by silencing of the downstream effector SMAD2. In the second aim, the T cell product will be characterized with respect to targeting of shared and neo-antigen targets, oligoclonal expansion and diversity of the repertoire, expression of markers of activation, exhaustion, senescence, and chemokines needed for migration into the tumor bed. In the third aim, we will conduct a Phase I study in which patients with AML who achieve complete remission will undergo adoptive therapy with vaccine stimulated T cells.