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Liyan Li1, Qianwei Miao2, Fanqiang Meng1
1Department of Pharmacology, Molecular Cancer Research Center, School of Medicine, Sun Yat-Sen University, Guangzhou/Shenzhen, China.
Abstract:
Immune checkpoint blockade therapies, especially those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have achieved impressive clinical responses in multiple types of cancers. To optimize the therapeutic effect of the checkpoint antibodies, many strategies including targeting delivery, controlled release, and cellular synthesis have been developed. However, within these strategies, antibodies were attached to drug carriers by chemical bonding, which may affect the steric configuration and function of the antibodies. Herein, we prepared cluster of differentiation 64 (CD64), a natural catcher of the fragment crystalline (Fc) of monomeric immunoglobulin G (IgG), and over-expressed it on the cell membrane nanovesicles (NVs) as PD-L1 antibody delivery vehicle (CD64-NVs-aPD-L1), which was employed to disrupt the PD-1/PD-L1 immunosuppressive signal axis for boosting T cell dependent tumor elimination. Meanwhile, chemical immunomodulatory drug cyclophosphamide (CP) was also encapsulated in the vesicle (CD64-NVs-aPD-L1-CP), to simultaneously restrain the regulatory T cells (Tregs) and invigorate Ki67+CD8+ T cells, then further enhance their anti-tumor ability. Methods: The cell membrane NVs overexpressing CD64 were incubated with PD-L1 antibody and chemotherapeutic agent CP to prepare CD64-NVs-aPD-L1-CP. Results: The CD64-NVs-aPD-L1-CP could simultaneously interrupt the immunosuppressive effect of PD-L1 and decrease the inhibition of Tregs, leading to tumor growth suppression and survival time extension. Conclusion: CD64-NVs are charismatic carriers to achieve both checkpoint blockade and immunomodulatory drugs for combined cancer immunotherapy.
Insights
This study developed novel nanovesicles (NVs) using cluster of differentiation 64 (CD64) to deliver programmed death-ligand 1 (PD-L1) antibodies and cyclophosphamide (CP). This combination therapy effectively suppresses tumor growth by blocking immune checkpoints and regulatory T cells, enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- Immune checkpoint blockade (ICB) therapies targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) show promise in cancer treatment.
- Current strategies for optimizing ICB therapies often involve chemical conjugation, potentially impacting antibody function.
- Developing novel delivery systems is crucial for enhancing the efficacy of cancer immunotherapies.
Purpose of the Study:
- To develop a novel nanovesicle (NV) delivery system for combined cancer immunotherapy.
- To utilize cluster of differentiation 64 (CD64) expressed on NVs for enhanced antibody targeting and delivery.
- To investigate the synergistic effects of PD-L1 blockade and cyclophosphamide (CP) delivered via CD64-expressing NVs.
Main Methods:
- Engineered cell membrane nanovesicles (NVs) overexpressing cluster of differentiation 64 (CD64).
- Loaded NVs with a programmed death-ligand 1 (PD-L1) antibody and cyclophosphamide (CP).
- Prepared CD64-NVs-aPD-L1-CP as a dual-action immunotherapeutic agent.
Main Results:
- The CD64-NVs-aPD-L1-CP effectively disrupted the immunosuppressive programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling axis.
- The formulation demonstrated simultaneous inhibition of regulatory T cells (Tregs) and enhancement of cytotoxic CD8+ T cells.
- Significant tumor growth suppression and extended survival time were observed in preclinical models.
Conclusions:
- Cluster of differentiation 64 (CD64)-expressing nanovesicles (NVs) serve as effective carriers for combined cancer immunotherapy.
- This approach enables simultaneous checkpoint blockade and delivery of immunomodulatory drugs.
- CD64-NVs offer a promising platform for developing advanced combination cancer therapies.
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