IL7R mutation

Patients with IL7R mutations have higher NRM, shorter OS, and EFS than patients without IL7R mutations, even patients who have undergone HSCT. Future larger and multicentric prospective studies will be explored.

We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.

P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026

Overall, our studies demonstrate that SKs are key players in oncogenic, but not in physiological, IL-7/IL-7R-mediated signaling. We uncover the importance of the SK-IL7R signaling crosstalk in ALL and pinpoint the therapeutic potential of SK inhibitors for IL-7R-dependent ALL.

Background: 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. Altogether, this study provides valuable information to optimize translation of JAKi and venetoclax to clinics for T-ALL patients with relapse who need therapeutics to bridge to transplant. This treatment protocol may benefit to a larger group of patients who may be selected with an easily applicable flow-cytometry-based companion test. IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T- ALL patients eligible to JAKi up to nearly ~70% of T-ALL.

P1, N=15, Recruiting, University of Chicago | Trial primary completion date: Sep 2022 --> Sep 2023

Conversely, mutants were more sensitive to venetoclax than expressers. 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.

In fact, ADCP levels induced by OSE-127 treatment in vitro correlated with its capacity to reduce ALL blasts in the blood of PDX mice in vivo. Altogether, through its dual mode of action, OSE-127 may represent a powerful novel immunotherapy option for ALL patients, including cases with dysregulated IL7R signaling, particularly in combination with standard of care polychemotherapy.

P1/2, N=26, Not yet recruiting, Princess Maxima Center for Pediatric Oncology