Abstract
Abstract CD40 agonist antibodies (αCD40) have proven great potential as an anti-cancer immunotherapeutic by showing promising anti-tumor response in both preclinical and early clinical studies. However, it has been observed that the systemic administration of αCD40, even at low dose, is associated with serious immune- and hepato- toxicities. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed an immunosome where αCD40 is conjugated on the surface and VJ23, a small molecule immune-modulator was encapsulated inside it . Immunosome showed higher tumor accumulation till 96 hr of administration and displayed sustained release of αCD40 in vivo. Immunosome significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma tumor by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+M1 macrophage in TME. In addition, Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the expression of PD-L1 to modulate immunosuppressive TME. Moreover, Immunosomes significantly enhanced the level of pro-inflammatory cytokines (IFN-γ, IL-6, IL-2) and lowered anti-inflammatory cytokines (IL-4 and IL-10) level which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. Our results suggested that this novel formulation can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while reducing the associated toxicities. Citation Format: Vidit Gaur, Witty Tyagi, Sanjeev Das, Surajit Ganguly, Jayanta Bhattacharyya. Agonist CD40 engineered smart immunosomes induced anti-tumor immunity, reduced associated toxicities and showed tumor free survival in murine glioblastoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5312.
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