IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

The IL-7R antagonist lusvertikimab reduces leukemic burden in xenograft ALL via antibody-dependent cellular phagocytosis

“… 34 Numerous recent studies show the IL-7R pathway to be critical for ALL development 5 , 6 , 10 , 35 , 36 and its exploitability for ALL treatment. 12 , 13 , 14 , 37 , 38 Preclinical data suggest that direct targeting of IL-7R in ALL cells using research-grade CD12 mAbs outperforms inhibitors of IL-7R downstream effectors such as ruxolitinib (targeting JAK/STAT signaling). 12 …”

“… 48 Additionally, a recent report showed comparable expression levels of CD127 in pediatric and adult patients, suggesting that both groups may benefit from IL-7R immunotherapy. 38 …”

Advances in IL-7 Research on Tumour Therapy

“…One study found that IL-7 was able to increase the number of CD4+ and CD8+ T cells and improve the function of these cells in lymphoma patients. The combination of IL-7 with chemotherapy or immunotherapy has been suggested as a potential therapeutic strategy for improving the treatment response and survival in lymphoma patients [ 91 ]. IL-7 has also shown potential in the treatment of colorectal cancer.…”

CD7 Nanobody-Based Immuno-Nanotoxin for Targeted Treatment of T-Cell Acute Lymphoblastic Leukemia

“…T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive and heterogeneous hematological malignancy of T-cell progenitors that is associated with a high relapse rate and mortality. , Intensive chemotherapy, as the standard and first-line treatment, has substantially improved the survival outcomes of T-ALL patients who can tolerate it. − However, the clinical prognosis of frail patients intolerant to chemotherapeutics and relapsed patients resistant to chemotherapy remains poor as a result of the severe lack of therapeutic options. − Nelarabine, the only drug approved for treating relapsed and refractory T-ALL patients, only achieved a one-year overall survival of ca. 24% and carried a boxed warning for severe neurotoxicity. − Therefore, there is a desperate need to develop effective and safe therapeutic options.…”

“…T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive and heterogeneous hematological malignancy of Tcell progenitors that is associated with a high relapse rate and mortality. 1,2 Intensive chemotherapy, as the standard and firstline treatment, has substantially improved the survival outcomes of T-ALL patients who can tolerate it. 3−5 However, the clinical prognosis of frail patients intolerant to chemotherapeutics and relapsed patients resistant to chemotherapy remains poor as a result of the severe lack of therapeutic options.…”