Safety and Efficacy of Multiantigen-Targeted T Cells for Multiple Myeloma

Abstract

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 × 107/m2 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 >1 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 >1 year post T cells, only 1 has relapsed. Clinical responses correlated with the emergence and persistence (>6mths) 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.