Abstract 4152: Development of an immune modulating and tumor inhibiting hyaluronic acid nanoparticle encapsulated with Avasimibe for the treatment of cancer patients with comorbid atherosclerosis
Authors: Zhu Lei , Qian Weiping , Chen Minglong , Liu Tongrui , Staley Charles A. , El-Rayes Bassel , Jo Hanjoong , Yang Lily 
Published: June 2022

Cancer and cardiovascular diseases are the leading causes of death globally. Given the high percentage of cancer patients with co-existing atherosclerosis due to many shared risk factors, the development of novel cancer therapeutic agents with strong anti-tumor efficacy and therapeutic benefit on atherosclerosis can significantly improve the outcome of cancer therapy. Immune checkpoint inhibition (ICI) therapy using therapeutic antibodies has shown promises in the treatment of several types of human cancers. However, many cancer patients showed a poor response due to low delivery efficiency, lack of effector T cells, an immunosuppressive tumor microenvironment, and intrinsic resistance in solid tumors. Increasing numbers of patients developed immunotherapy related adverse effects (irAEs). It is well known that macrophages and effector T cells drive the progression of atherosclerosis. Recent clinical studies revealed that cancer patients received ICI therapy have 3-fold higher risk of atherosclerosis and 3-fold increases in plaque progression detected by PET imaging. To enhance therapeutic efficacy of tumor immunotherapy and decrease irAEs, we have developed a hyaluronic acid nanoparticle (HANP) conjugated with PD1 mimetic peptides that target and block PD-L1 function, and encapsulated with Avasimibe (PD1Y-HANP/Ava). Avasimibe is a multifunctional agent that decreases cholesterol accumulation, inhibits tumor growth, and enhances immune response by activating cytotoxic T cells. We found that systemic administrations of PD1Y-HANP/Ava led to targeted delivery into tumors and atherosclerotic plaques in a dual colon cancer and atherosclerosis mouse model, established by injecting mouse colon tumor cells into Apoe knockout mice on a high fat diet. PD1Y-HANP/Ava treatments resulted in 78% of tumor growth inhibition. Following surgical resection of residual tumors, 80% of PD1Y-HANP/Ava treated mice had disease-free survival of &gt;120 days and were protected from tumor growth after tumor cell re-challenging. Histological analysis of the major arteries revealed that the volume of atherosclerotic plaques decreased 70% in the mice treated with PD1Y-HANP/Ava compared the no-treated mice. Our results showed that PD1Y-HANP/Ava treatment increased infiltration of CD8+ T effector and dendritic cells, and activated cytotoxic T cells in mouse colon tumors. Colon tumor specific antibodies were detected in the mouse serum following PD1Y-HANP/Ava treatment. However, the levels of CD8+ T cells, dendritic cells, and macrophages were decreased in the atherosclerotic plaques, which could prevent ICI-induced cardiovascular irAEs. Results of this study should provide us with preclinical evidence for translational development of targeted immunotherapy for colon cancer patients with comorbid atherosclerosis.

Citation Format: Lei Zhu, Weiping Qian, Minglong Chen, Tongrui Liu, Charles A. Staley, Bassel El-Rayes, Hanjoong Jo, Lily Yang. Development of an immune modulating and tumor inhibiting hyaluronic acid nanoparticle encapsulated with Avasimibe for the treatment of cancer patients with comorbid atherosclerosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4152.