1068 Evaluation of the innate and adaptive immune modulatory properties and anti-tumor activity of CD38-targeted interferon alpha

• Published in: Journal for immunotherapy of cancer Vol. 11; no. Suppl 1; p. A1175
• Main Authors: Sampson, James F, Zhang, Hong, Hara, Tomoya, Zhang, Dong Mei, Hinthorne, Adam J, Collins, Sabrina C, Curley, Michael D
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Immunocompetence; Immunotherapy; Regular and Young Investigator Award Abstracts
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.1068

BackgroundModakafusp alfa is a novel immunocytokine therapy comprising two attenuated interferon alpha (IFNα) moieties fused to a humanized anti-CD38 IgG4 monoclonal antibody. Modakafusp alfa is currently being evaluated in Phase I and II clinical trials in multiple myeloma and in solid tumors.MethodsTo better understand the impact of modakafusp alfa on different immune cell subsets in immunocompetent mouse models, we generated a murine surrogate of modakafusp alfa comprising an anti-mouse CD38 murine IgG1 antibody genetically fused to two molecules of mouse attenuated IFNα (hereafter referred to as mCD38-mAtt).ResultsIntraperitoneal administration of mCD38-mAtt demonstrated anti-tumor activity in a variety of syngeneic tumor models comprising different tumor immune microenvironments, levels of tumor CD38 expression, and intrinsic sensitivities to IFNα. Follow-on mechanistic studies, which targeted the depletion of specific immune cell subsets, revealed that loss of T cells and natural killer (NK) cells blunted tumor growth inhibition by mCD38-mAtt, indicating that these cells may be key effectors mediating the anti-tumor activity of mCD38-mAtt. In syngeneic tumor models, mCD38-mAtt enhanced NK cell activation in the tumor and selectively reduced the macrophage population, thereby modifying the tumor microenvironment. Treatment with mCD38-mAtt increased the presence and activation of tumor antigen-specific CD8 T cells, which correlated with a reduction in tumor mass.ConclusionsTaken together, these data indicate that mCD38-mAtt acts as an enhancer of both innate and adaptive immunity in immunocompetent mouse models that drives an anti-tumor immune response, independently of tumor CD38 expression.