Targeting Ibrutinib to Tumor-Infiltrating T Cells with a Sialic Acid Conjugate-Modified Phospholipid Complex for Improved Tumor Immunotherapy.

Abstract

Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses. SA-GA-OCT@PC-mediated combination therapy with PD-L1 blockade agents dramatically suppressed tumor growth and inhibited tumor relapse in B16F10 melanoma mouse models. Overall, the combination of the SA-modified nanocomplex platform and PD-L1 blockade offers a treatment opportunity for IBR in solid tumors, providing novel insights for tumor immunotherapy.

• Authors: Cong Li, Chuizhong Fan, Shuang Lu, Qiujun Qiu, Xin Gao, Xinyang Yan, Shuo Wang, Bing Zhao, Xinrong Liu, Yanzhi Song, Yihui Deng
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 20 Issue 1 Pg. 438-450 (01 02 2023) ISSN: 1543-8392 [Electronic] United States
• PMID: 36382950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ibrutinib
• N-Acetylneuraminic Acid
• B7-H1 Antigen
• Phospholipids

Topics

• Mice
• Animals
• N-Acetylneuraminic Acid
• B7-H1 Antigen
• Phospholipids
• Neoplasm Recurrence, Local
• Immunotherapy
• Tumor Microenvironment