TSLPR CAR T-cell therapy: A new hope for CRLF2+ ALL, but timing of JAK inhibition is crucial
Although chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough in the treatment of ALL, relapse remains a major problem. TSLPR CAR T-cell therapy specifically targets the thymic stromal lymphopoietin receptor (TSLPR), which is overexpressed in CRLF2-rearranged ALL cells, and has shown promising results in preclinical models. The current study investigates the combination of TSLPR CAR T-cell therapy with the JAK1/2 inhibitor ruxolitinib, with the aim of enhancing anti-leukemic activity while managing toxicity.
Synergistic approach with a catch
The researchers tested their hypothesis that simultaneous targeting of TSLPR with CAR T cells and inhibition of intracellular JAK/STAT signaling with ruxolitinib would yield synergistic anti-leukemic effects.1213 In vitro experiments confirmed the potent activity of TSLPR CAR T cells against CRLF2+ ALL cell lines and patient-derived xenograft (PDX) models.514 However, in vivo studies showed that co-administration of ruxolitinib reduced the proliferation, cytokine production and anti-leukemic activity of TSLPR CAR T cells, resulting in suboptimal leukemia clearance.615 These findings highlight the complexity of the immune system and the delicate balance required when combining immunotherapy with targeted therapies.
Ruxolitinib: Double-edged sword
Ruxolitinib, while effective in inhibiting JAK/STAT signaling in leukemia cells, was also shown to affect T cell expansion and activation.161718In vitro experiments showed a dose-dependent inhibition of T cell expansion and cytokine production by ruxolitinib, with a more pronounced effect on CD4+ T cells.1920 These findings are consistent with the known role of JAK/STAT signaling in T cell development and function.21Importantly, ruxolitinib reduced the expression of activation markers (CD25, CD71) and polyfunctionality of TSLPR CAR T cells.2022 However, these effects appeared to be reversible after discontinuation of ruxolitinib, suggesting that strategic timing of JAK inhibition is crucial to maintain CAR T cell functionality.
Optimized sequential therapy
The researchers then investigated a sequential treatment strategy, in which ruxolitinib was administered after the peak of TSLPR CAR T-cell expansion. This approach was shown to significantly improve anti-leukemic activity in vivo compared to co-administration. In addition, delayed ruxolitinib administration reduced CAR T cell-induced toxicity, as demonstrated by improved survival in PDX models. Importantly, TSLPR CAR T cell functionality was restored following discontinuation of ruxolitinib, enabling these cells to fight a renewed leukemia challenge. These findings support the development of a “maintenance therapy” strategy with ruxolitinib after TSLPR CAR T-cell therapy to prevent relapse and prolong remission.
Applicability in DS-ALL
The study findings were confirmed in preclinical models of CRLF2+ DS-ALL, demonstrating the broad applicability of this strategy.Both ruxolitinib monotherapy and TSLPR CAR T-cell therapy demonstrated significant anti-leukemic activity in DS-ALL PDX models. Also in this context, delayed ruxolitinib administration appeared to optimize TSLPR CAR T-cell activity and improve leukemia clearance.
Clinical implications and future research
This study provides important insights for the development of optimized treatment strategies for CRLF2+ ALL. The findings highlight the need to carefully consider the timing of JAK inhibition in combination with TSLPR CAR T-cell therapy. A sequential approach, in which ruxolitinib is administered after the initial CAR T-cell expansion, maximizes anti-leukemic activity and minimizes immunosuppressive effects. Clinical studies are needed to validate these findings and assess the safety and efficacy of this promising strategy in pediatric patients.Future research will focus on identifying biomarkers that can predict which patients will benefit most from this combined therapy.
(writing credit to Uri Ilan, MD - Prinses Máxima Centrum voor kinderoncologie)
Follow the Topic
-
Leukemia
This journal publishes high quality, peer reviewed research that covers all aspects of the research and treatment of leukemia and allied diseases. Topics of interest include oncogenes, growth factors, stem cells, leukemia genomics, cell cycle, signal transduction and molecular targets for therapy.
Please sign in or register for FREE
If you are a registered user on Research Communities by Springer Nature, please sign in