Journal
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
Volume 11, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40164-022-00279-w
Keywords
Cancer immunotherapy; CD47; Bispecific antibody; B-cell lymphoma; Tumor microenvironment; Macrophages; NK cells; Dendritic cells
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Funding
- Light Chain Bioscience/Novimmune SA
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This study provides detailed mechanisms of how the CD47xCD19 bispecific antibody NI-1701 controls tumor growth in a lymphoma mouse model, including transforming the tumor microenvironment, enhancing immune effector cell responses, and facilitating dendritic cell-mediated phagocytosis. These findings suggest the potential therapeutic value of NI-1701 in the treatment of B-cell lymphoma.
Background CD47/SIRP alpha axis is recognized as an innate immune checkpoint and emerging clinical data validate the interest of interrupting this pathway in cancer, particularly in hematological malignancies. In preclinical models, CD47/SIRP alpha blocking agents have been shown to mobilize phagocytic cells and trigger adaptive immune responses to eliminate tumors. Here, we describe the mechanisms afforded by a CD47xCD19 bispecific antibody (NI-1701) at controlling tumor growth in a mouse xenograft B-cell lymphoma model. Methods The contribution of immune effector cell subsets behind the antitumor activity of NI-1701 was investigated using flow cytometry, transcriptomic analysis, and in vivo immune-cell depletion experiments. Results We showed that NI-1701 treatment transformed the tumor microenvironment (TME) into a more anti-tumorigenic state with increased NK cells, monocytes, dendritic cells (DC) and MHCIIhi tumor-associated macrophages (TAMs) and decreased granulocytic myeloid-derived suppressor cells. Notably, molecular analysis of isolated tumor-infiltrating leukocytes following NI-1701 administration revealed an upregulation of genes linked to immune activation, including IFN gamma and IL-12b. Moreover, TAM-mediated phagocytosis of lymphoma tumor cells was enhanced in the TME in the presence of NI-1701, highlighting the role of macrophages in tumor control. In vivo cell depletion experiments demonstrated that both macrophages and NK cells contribute to the antitumor activity. In addition, NI-1701 enhanced dendritic cell-mediated phagocytosis of tumor cells in vitro, resulting in an increased cross-priming of tumor-specific CD8 T cells. Conclusions The study described the mechanisms afforded by the CD47xCD19 bispecific antibody, NI-1701, at controlling tumor growth in lymphoma mouse model. NI-1701 is currently being evaluated in a Phase I clinical trial for the treatment of refractory or relapsed B-cell lymphoma (NCT04806035).
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