Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts

TL;DR

The drug asciminib does not interfere with antibody therapy in a type of leukemia, suggesting it could be a good treatment option.

Contribution

Asciminib, unlike other tyrosine kinase inhibitors, does not impair antibody-dependent cellular cytotoxicity in B-ALL.

Findings

Asciminib does not interfere with antibody-dependent cellular cytotoxicity (ADCC) in B-ALL cell lines.

In contrast to dasatinib and ponatinib, asciminib preserves NK cell activation and tumor cell lysis.

The results suggest asciminib should be tested in clinical trials for B-ALL patients.

Abstract

Acute lymphoblastic leukemia is a malignant disease which is commonly treated with various chemotherapeutic drugs. Novel therapeutic options are gaining interest, most of them involving therapeutic antibodies. In a high-risk genetic subset called BCR-ABL1 positive acute lymphoblastic leukemia, tyrosine kinase inhibitors are successfully used. Tyrosine kinase inhibitors combine well with chemotherapy but might interfere with antibody therapy. The effects of tyrosine kinase inhibitors on antibody dependent cellular cytotoxicity are not fully understood. We therefore tested a novel inhibitor called asciminib that is tested in acute lymphoblastic leukemia and assessed its influence on immune cell activation by antibodies. We found that asciminib, in contrast to other agents such as dasatinib, does not interfere with antibody therapy and should therefore be tested in clinical trials for patients with acute lymphoblastic leukemia.

B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

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