Safety And Efficacy Of Multiantigen-Targeted T Cells For Multiple Myeloma
BLOOD(2018)
摘要
Despite an array of approved agents for the treatment of multiple myeloma (MM), most patients eventually relapse after conventional treatments. The adoptive transfer of tumor-targeted T cells has demonstrated efficacy in the treatment of patients with chemo-refractory hematological malignancies including MM. While the majority of T cell-based immunotherapeutic studies in the clinic explore genetically modified T cells that target a single tumor-expressed antigen, we have developed a strategy to generate non-engineered T cell lines that simultaneously target multiple MM-expressed antigens, thereby reducing the risk of tumor immune evasion. We manufacture multiTAA-specific T cells targeting the tumor antigens PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin by culturing patient-derived PBMCs with autologous DCs loaded with pepmixes (15mer overlapping peptides) spanning all 5 target antigens in the presence of a Th1-polarizing cytokine cocktail. We have successfully generated multi-antigen-targeted lines for 19 patients, comprising a polyclonal mixture of CD4+ (28.9±7.2%) and CD8+ (56.6±7.2%) T cells reactive against 2 to 5 of the target antigens (by IFNg ELIspot), with no activity against non-malignant autologous targets (2±3% specific lysis; E:T 20:1). We assessed the clonal diversity using TCR vβ deep sequencing analysis and found that the majority (mean 79%; range: 59 to 95%) represented rare T cell clones that were unique to the ex vivo expanded cell line, thereby enabling in vivo tracking studies. To date we have infused 18 patients who had received a median of 4 lines of prior therapy at cell doses ranging from 0.5-2 × 10 7 /m 2 without prior lymphodepletion. Ten patients were refractory to their latest therapy and had active MM, while 8 were in remission at the time of infusion. At the 6 week assessment, of the 10 patients infused to treat active disease, 1 had a CR, 1 had a PR and 8 had SD. Seven of these 10 patients were infused u003e1 year ago. Although 2 of the 7 subsequently had disease progression, the remaining 5 continue to respond, with sustained CR (1), PR (2) or SD (2). Of the 8 patients in CR at the time of T cell infusion, all remained in CCR at the week 6 disease assessment and of the 6 evaluable patients who are u003e1 year post T cells, only 1 has relapsed. Clinical responses correlated with the emergence and persistence (u003e6mths) of “line-exclusive” tumor-reactive T cells in patient peripheral blood and marrow, as assessed by TCR deep sequencing. The expansion of product-derived clones was higher among patients with active MM than those in remission. No patient had infusion-related systemic- or neuro-toxicity. Thus, autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin can be safely administered to patients with MM, in whom they can subsequently be detected long-term in peripheral blood and marrow and where they produce sustained tumor responses.
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关键词
multiple myeloma,multiantigen-targeted
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