Antengene Corporation Limited has announced that a preclinical research paper evaluating the combination of ATG-037 (CD73 small molecule inhibitor) and selinexor for the treatment of multiple myeloma (MM), conducted in collaboration with the Department of Hematology at Peking University Third Hospital, has been published in Cancer Gene Therapy.
The research team first analysed CD73 expression across multiple tumour cell lines following selinexor treatment, then tested the combination in vivo using a J558-inoculated BALB/c mouse model, with mice divided into a vehicle group, an ATG-037 monotherapy group, a selinexor monotherapy group and a combination-therapy group. Single-cell RNA sequencing was used to characterise immune cell subtypes and tumour-immune crosstalk, immunofluorescence staining was performed on tumour tissue, and a co-culture model of CD8+ T cells and multiple myeloma cell lines was established to confirm the mechanism behind the combination’s antitumour effect.
Selinexor treatment was found to upregulate CD73 expression in the majority of tumours, a resistance-associated mechanism that the combination approach was designed to counter. In the mouse model, the combination therapy suppressed tumour growth with an inhibition rate of 62%, compared with 31% for ATG-037 monotherapy and 43% for selinexor monotherapy. Single-cell RNA sequencing showed the combination synergistically potentiated CD8+ T cell activation by enhancing the interaction between CD8+ T cells and Enpp1+ cells via the CD80–CD28 signalling pathway, and the resulting increase in CD8+ T cell infiltration into tumour tissue was confirmed by immunofluorescence staining. In co-culture experiments, CD73 inhibition was shown to strengthen selinexor-mediated tumour cell killing by activating CD8+ T cells, with significantly elevated levels of Granzyme B and IFN-γ observed in the combination group.
The study highlights the synergistic potential of combining selinexor with a CD73 inhibitor for enhancing CD8+ T cell-mediated tumour cytotoxicity in MM. Selinexor therapy upregulates CD73 in the TME, driving adenosine accumulation and an immunosuppressive state. Combined use of ATG-037 blocks this immunosuppressive feedback loop via suppression of CD73-dependent adenosine synthesis, restoring CD8+ T cell activation and proliferation while enhancing T cell cytotoxicity through activation of the CD80-CD28 co-stimulatory axis. These findings establish a novel, clinically feasible therapeutic paradigm for addressing drug resistance and refractory MM.