Anti‐CD47 immunotherapy in combination with BCL‐2 inhibitor to enhance anti‐tumor activity in B‐cell lymphoma

Abstract CD47 expressed on cancer cells enables macrophage immune evasion. Blocking CD47 using anti‐CD47 monoclonal antibodies (mAbs) is a promising strategy. The anti‐CD47 mAb TJC4 has anti‐tumor activity but lacks hematological toxicity. Venetoclax, a B‐cell lymphoma 2 (BCL‐2) inhibitor for B‐cell malignancy, induces phosphatidylserine (PS) extracellular exposure, representing an “eat‐me” signal for macrophages. The present study aimed to explore whether TJC4‐Venetoclax combined therapy exerts synergistic anti‐cancer properties in B‐cell lymphoma. In vitro, flow cytometry and microscopy assessed whether TJC4 monotherapy or combination treatment could promote macrophage‐mediated phagocytosis of tumor cells. Induced PS exposure on the cell membrane was measured using flow cytometry with Annexin V‐FITC staining. In vivo, Venetoclax and TJC4's synergistic anti‐tumor effects were evaluated. B cell lymphoma cell lines express high levels of CD47 and patients with diffuse large B cell lymphoma expressing CD47 have a worse clinical prognosis. TJC4 eliminates tumor cells via macrophage‐mediated phagocytosis. In vitro and in vivo, the TJC4‐Venetoclax combination increased phagocytosis significantly compared with either agent alone, showing synergistic phagocytosis, and displayed synergistic anti‐cancer properties in B‐cell lymphoma. Our results support the TJC4‐Venetoclax combination as a promising therapy, and suppressing BCL‐2 and CD47 simultaneously could represent a novel therapeutic paradigm for B‐cell lymphoma.