Engineered PEG10 Endogenous Virus-Like Particles Carrying Genetically Encoded Neoantigen Peptides for Effective Cancer Vaccination

Core Concepts

Engineered PEG10-based endogenous virus-like particles (eVLPs) carrying genetically encoded neoantigen peptides, termed ePAC, can efficiently target and activate dendritic cells to induce robust neoantigen-specific T cell responses, leading to significant antitumor efficacy in mouse models.

Abstract

The authors designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous virus-like particles (eVLPs) with high protein loading and transfection efficiency. They then engineered a tumor vaccine, named ePAC, by packaging genetically encoded neoantigens into the eVLPs and further modifying the surface with CpG-ODN to serve as an adjuvant and targeting unit to dendritic cells (DCs).
The key highlights are:

ePAC can efficiently target and transport neoantigens to DCs, and promote DC maturation to induce neoantigen-specific T cell responses.
In mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy.
The authors also demonstrated that ePAC can elicit antigen-specific immune responses in humanized mice with HLA-A*0201 restriction, highlighting its potential as an effective immunotherapeutic strategy for targeting HBV-associated tumors.

Overall, the engineered PEG10-based eVLP platform represents a promising approach for developing effective cancer vaccines.

Stats

The total amount of proteins produced from one 10-cm dish of transfected HEK293T cells was 212±7.388 μg for eVLP vs 76.59±7.463 μg for control.
The percentage of effector memory CD8+ T cells in the spleen was 31.60±1.48% in the ePAC treated group, compared to 14.22±1.377% in the eVLP group and 20.73±2.209% in the eVLP + CpG-ODN group.
The percentage of CD8+ T cell infiltration in the tumors was 55.72±2.733% in the ePAC + αTIM-3 group, compared to 40.16±1.435% in the ePAC group and 37.79±2.278% in the αTIM-3 group.
The percentage of neoantigen-specific CD8+ T cells in the infiltrated CD8+ T cells in the tumors was 9.06±1.258% in the ePAC + αTIM-3 group, compared to 4.50±0.7195% in the ePAC group and 0.89±0.0746% in the αTIM-3 group.

Quotes

"Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells."
"Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy."
"These results suggested that human derived DCs could also be activated to present HLA-A*0201-restricted antigen by ePAC in vitro."

Key Insights Distilled From

Engineering PEG10 assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination

by Tang,R., Guo... at www.biorxiv.org 04-27-2024

https://www.biorxiv.org/content/10.1101/2024.04.25.591213v1

Deeper Inquiries

How could the PEG10-based eVLP platform be further optimized to enhance its targeting and delivery efficiency in vivo?

To enhance the targeting and delivery efficiency of the PEG10-based eVLP platform in vivo, several optimization strategies can be considered:

Surface Modification: Further modification of the eVLP surface with targeting ligands or antibodies specific to dendritic cells (DCs) can improve the specificity and efficiency of delivery to the desired immune cells. This could involve conjugating specific ligands that enhance DC uptake and activation.

Optimization of Cargo Loading: Ensuring optimal loading of neoantigens or therapeutic cargo onto the eVLP is crucial for maximizing the immune response. Fine-tuning the ratio of cargo to eVLP components can improve the efficiency of antigen presentation and immune activation.

Enhanced Stability: Improving the stability of eVLP during circulation in the body can increase its half-life and enhance its ability to reach target cells. This could involve modifications to the eVLP structure or the addition of stabilizing agents.

In Vivo Imaging: Incorporating imaging agents into the eVLP structure can enable real-time tracking of eVLP distribution and uptake in vivo, providing valuable insights into its pharmacokinetics and biodistribution.

Combination Therapies: Exploring combination therapies with immune checkpoint inhibitors or other immunomodulatory agents can further enhance the antitumor immune response elicited by the ePAC vaccine, leading to improved therapeutic outcomes.

What are the potential limitations or drawbacks of using endogenous virus-like proteins like PEG10 compared to viral-derived VLPs, and how could these be addressed?

Some potential limitations or drawbacks of using endogenous virus-like proteins like PEG10 compared to viral-derived VLPs include:

Lower Immunogenicity: Endogenous virus-like proteins may have lower immunogenicity compared to viral-derived VLPs, potentially impacting their ability to activate immune responses effectively. This could be addressed by incorporating potent adjuvants or immune stimulants into the eVLP structure.

Limited Targeting Abilities: Endogenous virus-like proteins may lack specific targeting abilities for immune cells or tumor tissues, leading to reduced efficiency in antigen delivery. Strategies such as surface modification with targeting ligands or antibodies can help overcome this limitation.

Complexity of Production: The production of endogenous virus-like proteins like PEG10 may be more complex and time-consuming compared to viral-derived VLPs. Streamlining the production process and optimizing purification methods can help address this challenge.

Potential Safety Concerns: Endogenous virus-like proteins may raise safety concerns related to their interaction with host cells or immune responses. Conducting thorough preclinical safety assessments and toxicity studies can help mitigate these risks.

Given the promising results in mouse models, what are the key considerations and challenges in translating this ePAC vaccine approach to clinical trials for cancer patients?

Key considerations and challenges in translating the ePAC vaccine approach to clinical trials for cancer patients include:

Safety and Toxicity: Ensuring the safety profile of the ePAC vaccine in human subjects is paramount. Comprehensive preclinical studies and toxicity assessments are essential before moving to clinical trials.

Optimal Dosing and Administration: Determining the optimal dosing regimen and route of administration for the ePAC vaccine in humans is crucial for achieving therapeutic efficacy. This may require dose escalation studies and pharmacokinetic evaluations.

Patient Selection: Identifying the appropriate patient population for clinical trials, such as specific cancer types or disease stages that are most likely to benefit from the ePAC vaccine, is important for demonstrating efficacy.

Immune Monitoring: Implementing robust immune monitoring strategies in clinical trials to assess the vaccine-induced immune responses, including T cell activation, cytokine profiles, and antigen-specific immune cell populations.

Regulatory Approval: Navigating the regulatory pathways for approval of the ePAC vaccine as a novel cancer immunotherapy requires close collaboration with regulatory authorities and adherence to regulatory guidelines.

Manufacturing Scale-Up: Scaling up the production of the ePAC vaccine for clinical trials and potential commercialization poses challenges in terms of manufacturing consistency, quality control, and scalability.

Clinical Trial Design: Designing well-controlled clinical trials with appropriate endpoints, patient cohorts, and statistical analyses is essential for generating robust clinical data to support the efficacy of the ePAC vaccine.

Addressing these considerations and challenges will be critical in advancing the ePAC vaccine approach from preclinical studies to clinical trials for cancer patients.