PAX5-JAK2 fusion

The median age was 39 years (range, 21-82) and pts had received a median of 5 (range, 2-9) prior therapies [inotuzumab ozogamicin 12/21 (57%); blinatumomab 18/21 (86%); venetoclax 12/21 (57%)]. In this phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with one pt with DLT noted at the 50µg/kg weekly dose level. Notably, all 3 pts treated at this dose level had evidence of clinical activity with 2/3 pts achieving MRD negative CR. Due to 1 pt with DLT at this dose level, this cohort is being expanded to treat 3 additional pts.

HCAR19 cells would be infused to 6 patients at two dose-levels: Dose-1:1x106 /kg; Dose-2:3-5x106 /kg body-weight after Lymphodepletion (Fludarabine-Cyclophosphamide), and observed for toxicity, HCAR19 in-vivo dynamics, and effects on tumor burden...Product related toxicities were Grade-2 Cytokine release syndrome(CRS)-1(33%) Tocilizumab-responsive, and B cell aplasia-1(33%) managed with Intravenous-Immunoglobulin... Autologous-HCAR19 was safe at starting-level Dose-1:1x106 /kg with low-toxicities, robust in-vivo dynamics, correlating well with pre-clinical studies, and sufficient responses to proceed with dose escalation, establishing the feasibility and pathway for CAR T-cell therapy in India and developing countries.

While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5 B-ALL tumors, implying that nuclear Pax5-Jak2 phosphorylates STAT5. Together, these data reveal Pax5-Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus.

In combination with dexamethasone, we assessed a further decrease of viability between 10 to 95%...Importantly, combination of BIBF1120 and CHZ868 showed a synergistic effect (-45%, at IC50)...Indeed, active caspase 3 increased when ruxolitinib was given in combination with chloroquine, an autophagy inhibitor (+20% vs ruxolitinib alone, p<0.01)...CHZ868 is a promising candidate for treatment of BCP-ALL carrying JAK2 fusions, showing high efficacy and specificity, both ex vivo and in vivo . Further studies will include combination with standard chemotherapy drugs with the aim to maintain its efficacy by reducing the intensity and toxicity of chemotherapy.

Importantly, the phosphorylation and pro-proliferative effect was blocked by the JAK1/2 inhibitor Ruxolitinib...To validate our result, we used 2-deoxy-D-glucose (2DG), a competitor of glucose which is a main substrate utilized in bioenergetics pathways of cancer cells...The oncogenic potential of cells harboring this fusion is likely driven by signaling pathway alterations and intensive metabolic changes with dependencies on sufficient energy substrate supply, a mechanism that could potentially be exploited in future therapeutical strategies. Support: AZV NV18–07-00129