外源性IL-2给药可提升循环T细胞水平、持久性及异体UCART20x22在B细胞淋巴瘤小鼠模型中的治疗疗效

Background: Non-Hodgkin's lymphoma (NHL) ranks as the sixth most common cancer among women and the seventh among men in the United States, with B-cell lymphomas constituting 80-85% of cases. Diffuse large B-cell lymphoma (DLBCL) is the predominant subtype. Despite significant advances in the treatment of B-NHL, significant unmet need remains for patients who are chemorefractory, relapse following autologous CD19 CAR-T or are unable to access autologous CD19 CAR-T because of supply, cost or other constraints. Off the shelf engineered allogeneic CAR-T offers a potential additional therapeutic option for patients. Advanced editing technology such as TALEN allows TRAC knockout to mitigate the risks of GvHD and also allows for the investigation of multiple alternative targets such as CD20 and CD22, to treat patients who may have antigen escape following previous treatment. While engineering technology can overcome the challenges of allogeneic therapy, efforts must still be made to further enhance expansion and persistence to allow for deep and durable responses. Clinical evidence suggests that the IL-2 cytokine, a potent T-cell growth factor essential for the proliferation of activated T cells, when combined in low-dose with CAR T-cell therapies improves pharmacokinetics and anti-tumor efficacy without compromising safety. Method: NSG mice were engrafted with Daudi-luc-GFP cells on D-7. UCART20x22 (bi-specific TALEN ® -engineered allogeneic T-cells targeting both CD20 and CD22), or vehicle were infused on D0. IL-2 was infused intraperitoneally after UCART20x22 administration as per different test regimens. Bioluminescence imaging was performed at regular intervals during the study to assess tumor control. UCART20x22 expansion and persistence was also measured at different timepoints. Results: IL-2 administration significantly increased circulating T-cell levels and prolonged T-cell persistence. Increased tumor control was observed when low-dose UCART20x22 was combined with exogenous interleukin 2 (IL-2). No relapse was observed up to day 50 in the concomitant IL-2 treated mice. These responses were observed even when the IL-2 treatment regimens were delayed respect to UCART20x22 infusion, although the intensity of T cell responses were less strong than upon concomitant treatment. No adverse effect were observed, as measured by body weight assessment over time. Additionally, there were no clinical signs of treatment-related morbidities in any of the treatment groups. Conclusion: The results of the in vivo studies support the use of IL-2 to improve the therapeutic outcomes of UCART20x22 in terms of depth and durability of disease response. This is currently being investigated in the NatHaLi-01 clinical study for R/R B-cell lymphomas, aiming to optimize response rates and durability of response in this patient population.