Challenging T-ALL to IL-7Rp dual inhibition

In this issue of Blood, Courtois et al identify interleukin-7 receptor (IL-7R) expression as a potential biomarker for predicting sensitivity to JAK pathway inhibition in T-cell acute lymphoblastic leukemia (T-ALL).¹ 

To develop better directed treatment of T-ALL, Courtois et al divided patients into 3 main groups: those who express IL-7R (“expressers”), those who do not express IL-7R (“nonexpressers”), and those harboring IL-7R pathway–associated mutations (“mutants”). Using a panel of 46 patient-derived xenografts (PDX), the authors demonstrate ex vivo sensitivity to the JAK inhibitor ruxolitinib in IL-7R-expressing and -mutant patient groups, a finding which extends the potential clinical utility of ruxolitinib to the 70% of adult and pediatric patients with IL-7R-expressing T-ALL. As expected, ruxolitinib had no impact on IL-7R “nonexpresser” T-ALL cells. Using a multiomic approach, they show that “nonexpressers” have minimal IL-7R transcription owing to increased DNA methylation and minimal H3K4me3 signal (reflecting epigenetic downregulation of gene expression). In contrast, IL-7R-expressing T-ALL showed minimal methylation, high H3K4me3 signal, and high IL-7R transcription. They observed an inverse relationship between the ruxolitinib half maximal inhibitory concentration and H3K4me3 signal, suggesting that epigenetic modulation contributes to the greater vulnerability to ruxolitinib observed among IL-7R-expressing T-ALL. The authors also show that IL-7R-mutant T-ALL demonstrates strong functional dependency on BCL2 and, thus, ex vivo venetoclax sensitivity, whereas IL-7R-expressing T-ALL can be “primed” by ruxolitinib to enhance functional BCL2 dependency and, in turn, responsiveness to venetoclax. To demonstrate the therapeutic feasibility of JAK1/BCL2 dual inhibition, Courtois et al present 2 patients with relapsed/refractory T-ALL who both achieved transient responses with cotargeted therapy.

The supporting role of IL-7R signaling in T-ALL is well established. In 2011, Silva et al demonstrated that IL-7, a cytokine and hematopoietic growth factor critical for T lymphoid development, can promote T-ALL progression,² and Zenatti et al identified somatic gain-of-function mutations associated with the IL-7R pathway (IL-7Rp) in 9% of patients.³ Because of the inherent relationship between IL-7/IL-7R signaling activation and multiple downstream pathways, namely, JAK1/2, BCL2, and PI3K/AKT/mTOR, these foundational data cultivated an interest in targetable IL-7/IL-7R–associated pathways as potential therapeutic vulnerabilities in T-ALL (see figure). The ensuing literature demonstrated the role of cooperating mutations with IL-7R mutations in promoting leukemogenesis⁴ and showed that high IL-7R expression corresponded to IL-7R-mutant gene expression signatures, begetting sensitivity to targeted inhibition of JAK, STAT, PIM, and PI3K/Akt signaling.⁵ These data, highlighting a central role for the IL-7R pathway, provided a new target for therapies in T-ALL. Preclinical models of JAK inhibition have since primarily focused on early T cell precursor (ETP) T-ALL, a particularly aggressive T-ALL subtype with unique immunophenotypic and genomic features thought to be dependent on JAK/STAT signaling. Maude et al demonstrated aberrant JAK/STAT activation and IL-7 responsiveness in ETP T-ALL and showed preclinical efficacy of ruxolitinib in producing an in vivo leukemia response in a PDX model.⁶ 

Courtois et al add substantially to this literature by demonstrating the potential utility of IL-7R expression as a biomarker to predict ruxolitinib sensitivity in up to 70% of patients with T-ALL. Although the value of dual JAK and BCL2 inhibition in the setting of JAK pathway–activating mutations has been previously suggested,⁷ Courtois et al expand upon this concept by demonstrating consistent synergy using 10 mutant T-ALL samples with a range of IL-7R-pathway mutations in a PDX model. The authors also found that ruxolitinib priming enhanced venetoclax responsiveness in nonmutant IL-7R-expressing T-ALL in a PDX model. These data reveal an opportunity to apply IL-7R-expression status to predicting which patients might most benefit from IL-7/IL-7R pathway–associated targeted inhibition in the clinical setting, either as an adjunct to up-front T-ALL therapy in the context of future trials or as a salvage modality for bridging to stem cell transplant.

An important future consideration will involve the optimal therapeutic time point in which to incorporate ruxolitinib and venetoclax. Delgado-Martin et al demonstrated that glucocorticoid resistance (GC) represents a particular vulnerability and predictor of relapse in ETP and some non-ETP T-ALL and that removal of IL-7 or JAK inhibition resensitized GC-resistant, IL-7–dependent T-ALL to GC.⁸ Mechanistically, GC exposure directly causes upregulation of IL-7R expression, leading to downstream BCL2 upregulation, which in turn promotes leukemia survival. However, targeted inhibition of the IL-7R/JAK/STAT5/BCL2 signaling axis could reverse this phenomenon, recover GC sensitivity, and synergistically provide therapeutic benefit in T-ALL.⁹ These data suggest that dual inhibition combined with GC-rich treatment phases could potentially abrogate GC resistance in select cohorts. However, as in any aggressive and heterogeneous cancer, single-cell data have already introduced the concern that select T-ALL cell populations with variable responsiveness to inhibition may persist at relapse.¹⁰ Thus, the field will certainly benefit from efforts to combine synergistic IL-7R pathway–targeted therapies in a multifaceted attempt to avoid therapeutic escape, as here introduced by Courtois et al.

Conflict-of-interest disclosure: The authors declare no competing financial interests.