Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma
Abstract Background HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisi...
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2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06126-w |
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| author | Laura Scalambra Francesca Ruzzi Olga Maria Pittino Maria Sofia Semprini Chiara Cappello Stefania Angelicola Arianna Palladini Patrizia Nanni Louise Goksøyr Cyrielle Fougeroux Manuel L. Penichet Adam Frederik Sander Pier-Luigi Lollini |
| author_facet | Laura Scalambra Francesca Ruzzi Olga Maria Pittino Maria Sofia Semprini Chiara Cappello Stefania Angelicola Arianna Palladini Patrizia Nanni Louise Goksøyr Cyrielle Fougeroux Manuel L. Penichet Adam Frederik Sander Pier-Luigi Lollini |
| author_sort | Laura Scalambra |
| collection | DOAJ |
| description | Abstract Background HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9. Methods The therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells. Results Mice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4 months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1–2 months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1–2 mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells. Conclusions The results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy. |
| format | Article |
| id | doaj-art-979a9123f783461d83ea25fe2368b737 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-979a9123f783461d83ea25fe2368b7372025-02-02T12:40:31ZengBMCJournal of Translational Medicine1479-58762025-01-0123111510.1186/s12967-025-06126-wTargeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinomaLaura Scalambra0Francesca Ruzzi1Olga Maria Pittino2Maria Sofia Semprini3Chiara Cappello4Stefania Angelicola5Arianna Palladini6Patrizia Nanni7Louise Goksøyr8Cyrielle Fougeroux9Manuel L. Penichet10Adam Frederik Sander11Pier-Luigi Lollini12Department of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Molecular Medicine, University of PaviaDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaAdaptVac ApsAdaptVac ApsDivision of Surgical Oncology, Department of Surgery and Department of Microbiology, Immunology and Molecular GeneticsThe Molecular Biology InstituteJonsson Comprehensive Cancer Centre, University of CaliforniaAdaptVac ApsDepartment of Medical and Surgical Sciences (DIMEC), University of BolognaAbstract Background HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9. Methods The therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells. Results Mice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4 months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1–2 months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1–2 mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells. Conclusions The results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy.https://doi.org/10.1186/s12967-025-06126-wBreast cancerHER2Therapy resistanceCancer progressionPCSK9Therapeutic cancer vaccines |
| spellingShingle | Laura Scalambra Francesca Ruzzi Olga Maria Pittino Maria Sofia Semprini Chiara Cappello Stefania Angelicola Arianna Palladini Patrizia Nanni Louise Goksøyr Cyrielle Fougeroux Manuel L. Penichet Adam Frederik Sander Pier-Luigi Lollini Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma Journal of Translational Medicine Breast cancer HER2 Therapy resistance Cancer progression PCSK9 Therapeutic cancer vaccines |
| title | Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma |
| title_full | Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma |
| title_fullStr | Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma |
| title_full_unstemmed | Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma |
| title_short | Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma |
| title_sort | targeting pcsk9 through an innovative cvlp based vaccine enhanced the therapeutic activity of a cvlp her2 vaccine in a preclinical model of her2 positive mammary carcinoma |
| topic | Breast cancer HER2 Therapy resistance Cancer progression PCSK9 Therapeutic cancer vaccines |
| url | https://doi.org/10.1186/s12967-025-06126-w |
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