Preclinical and Clinical Observations Implying Combination Therapy to Enhance the Efficacy of the Her-2/neu B-Cell Peptide-Based Vaccine HER-Vaxx and to Prevent Immune Evasion

• Published in: International journal of molecular sciences 2023-12, Vol.25 (1), p.287
• Main Authors: Tobias, Joshua, Högler, Sandra, Raigel, Martin, Lin, Diego Shih-Chieh, Chao, Yee, Kenner, Lukas, Garner-Spitzer, Erika, Yavrom, Sharon, Ede, Nicholas J, Zielinski, Christoph C, Kundi, Michael, Wiedermann, Ursula
• Format: Article
• Language: English
• Subjects: Antibodies; B cells; Biotechnology industry; Cancer therapies; Cell death; Chemotherapy; Combination therapy; Communication; Development and progression; expression; Gastric cancer; Her-2/neu; immune evasion; Immunization; Immunohistochemistry; Lungs; Medical colleges; Medical prognosis; Metastasis; Patients; PD-L1; Peptides; Pertuzumab; preclinical and clinical settings; Prevention; Protein expression; Proteins; Stomach cancer; Tumors; Vaccination; Vaccines
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25010287

Her-2/neu-targeting therapy by passive application with trastuzumab is associated with acquired resistance and subsequent metastasis development, which is attributed to the upregulation of tumoral PD-L1 expression and the downregulation of Her-2/neu. We aimed to investigate this association, following active immunization with our recently constructed B-cell peptide-based Her-2/neu vaccines in both preclinical and clinical settings. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and combined positive score (CPS) were applied to evaluate Her-2/neu and PD-L1 expression using a murine syngeneic tumor model for Her-2/neu lung metastases and tumor biopsies from a gastric cancer patient with disease progression. A significant and concomitant reduction in Her-2/neu and the upregulation of PD-L1 expression was observed in vaccinated mice after 45 days, but not after 30 days, of metastases development. A significant increase in tumor-infiltrating B lymphocytes was observed at both time points. The downregulation of Her-2/neu and the upregulation of PD-L1 were observed in a patient's primary tumor at the disease progression time point but not prior to vaccination (Her-2/neu IHC: 3 to 0, FISH: 4.98 to 1.63; PD-L1 CPS: 0% to 5%). Our results further underline the need for combination therapy by targeting PD-L1 to prevent metastasis formation and immune evasion of Her-2/neu-positive and PD-L1-negative tumor cells.