Polymer chimera of stapled oncolytic peptide coupled with anti-PD-L1 peptide boosts immunotherapy of colorectal cancer.

Abstract

Rationale: Scarce tumor mutation burden and neoantigens create tremendous obstacles for an effective immunotherapy of colorectal cancer (CRC). Oncolytic peptides rise as a promising therapeutic approach that boosts tumor-specific immune responses by inducing antigenic substances. However, the clinical application of oncolytic peptides has been hindered because of structural instability, proteolytic degradation, and undesired toxicity when administered systemically. Methods: Based on wasp venom peptide, an optimized stapled oncolytic peptide MP9 was developed with rigid α-helix, protease-resistance, and CRC cell cytotoxicity. By incorporating four functional motifs that include D-peptidomimetic inhibitor of PD-L1, matrix metalloproteinase-2 (MMP-2) cleavable spacer, and MP9 with 4-arm PEG, a novel peptide-polymer conjugate (PEG-MP9-aPDL1) was obtained and identified as the most promising systemic delivery vehicle with PD-L1 targeting specificity and favorable pharmacokinetic properties. Results: We demonstrated that PEG-MP9-aPDL1-driven oncolysis induces a panel of immunogenic cell death (ICD)-relevant damage-associated molecular patterns (DAMPs) both in vitro and in vivo, which are key elements for immunotherapy with PD-L1 inhibitor. Further, PEG-MP9-aPDL1 exhibited prominent immunotherapeutic efficacy in a CRC mouse model characterized by tumor infiltration of CD8+ T cells and induction of cytotoxic lymphocytes (CTLs) in the spleens. Conclusion: Our findings suggest that PEG-MP9-aPDL1 is an all-in-one platform for oncolytic immunotherapy and immune checkpoint blockade (ICB).

• Authors: Lu Lu, He Zhang, Yudong Zhou, Jiayi Lin, Weidong Gao, Ting Yang, Jinmei Jin, Lijun Zhang, Dale G Nagle, Weidong Zhang, Ye Wu, Hongzhuan Chen, Xin Luan
• Journal: Theranostics (Theranostics) Vol. 12 Issue 7 Pg. 3456-3473 ( 2022) ISSN: 1838-7640 [Electronic] Australia
• PMID: 35547769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• B7-H1 Antigen
• Immune Checkpoint Inhibitors
• Immunologic Factors
• Matrix Metalloproteinase 2
• Peptides
• Polymers

Topics

• Animals
• Mice
• B7-H1 Antigen (metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (therapy)
• Immune Checkpoint Inhibitors
• Immunologic Factors
• Immunotherapy
• Matrix Metalloproteinase 2
• Peptides
• Polymers