Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast
Valeria Rolih1, Jerri Caldeira2, Elisabetta Bolli1
1Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
Abstract:
Metastatic breast cancer (MBC) is the leading cause of cancer death in women due to recurrence and resistance to conventional therapies. Thus, MBC represents an important unmet clinical need for new treatments. In this paper we generated a virus-like particle (VLP)-based vaccine (AX09) to inhibit de novo metastasis formation and ultimately prolong the survival of patients with MBC. To this aim, we engineered the bacteriophage MS2 VLP to display an extracellular loop of xCT, a promising therapeutic target involved in tumor progression and metastasis formation. Elevated levels of this protein are observed in a high percentage of invasive mammary ductal tumors including triple negative breast cancer (TNBC) and correlate with poor overall survival. Moreover, xCT expression is restricted to only a few normal cell types. Here, we tested AX09 in several MBC mouse models and showed that it was well-tolerated and elicited a strong antibody response against xCT. This antibody-based response resulted in the inhibition of xCT's function in vitro and reduced metastasis formation in vivo. Thus, AX09 represents a promising novel approach for MBC, and it is currently advancing to clinical development.
Insights
A novel virus-like particle (VLP)-based vaccine, AX09, targeting xCT shows promise in preventing metastasis and improving survival for metastatic breast cancer (MBC) patients. This vaccine is advancing to clinical trials.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Metastatic breast cancer (MBC) is a significant cause of cancer mortality, often driven by recurrence and treatment resistance.
- There is a critical need for innovative therapies to address the unmet clinical challenges in MBC treatment.
- Elevated xCT protein levels in invasive mammary tumors, including triple-negative breast cancer (TNBC), correlate with poor prognosis and promote metastasis.
Purpose of the Study:
- To develop and evaluate a virus-like particle (VLP)-based vaccine (AX09) designed to inhibit de novo metastasis and extend survival in patients with MBC.
- To engineer the MS2 bacteriophage VLP to display a key extracellular loop of xCT, a target implicated in tumor progression.
Main Methods:
- Development of AX09, a vaccine utilizing bacteriophage MS2 VLPs engineered to display xCT extracellular loops.
- Testing of AX09 in preclinical metastatic breast cancer mouse models.
- Assessment of vaccine tolerability, immunogenicity (antibody response against xCT), and functional impact on xCT activity and metastasis.
Main Results:
- AX09 was well-tolerated in MBC mouse models.
- The vaccine successfully elicited a robust antibody response targeting xCT.
- The induced antibody response inhibited xCT function in vitro and significantly reduced metastasis formation in vivo.
Conclusions:
- AX09 demonstrates potential as a novel therapeutic strategy for metastatic breast cancer.
- The vaccine's ability to inhibit xCT function and reduce metastasis warrants further clinical investigation.
- AX09 is progressing to clinical development, offering a promising new avenue for MBC treatment.
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