Antibody peptide epitope conjugates for αPD-1 therapy-resistant head and neck squamous cell carcinoma

Shui, Y. I.; Millar, D. G.; Altenburger, L. M.; Chrisikos, T.; Kalbfleisch, M. J.; Hata, A.; Sadow, P. M.; Faquin, W. C.; Martinot, A. J.; Snyder, C. M.; Pittet, M. J.; Pai, S. I.; Cobbold, M.; Mempel, T. R.

doi:10.64898/2025.11.28.691238

bioRxiv · 10.64898/2025.11.28.691238

Antibody peptide epitope conjugates for αPD-1 therapy-resistant head and neck squamous cell carcinoma

Shui, Y. I.·Millar, D. G.·Altenburger, L. M.·Chrisikos, T.·Kalbfleisch, M. J.·Hata, A.·Sadow, P. M.·Faquin, W. C.·Martinot, A. J.·Snyder, C. M.·Pittet, M. J.·Pai, S. I.·Cobbold, M.·Mempel, T. R.

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Abstract

Poor tumor antigenicity is an important cause of non-response to immune checkpoint blockade (ICB)-therapy in many cancer patients and mandates new treatment strategies. Here we explore the use of proteolytically activated antibody-peptide epitope conjugates (APECs) to redirect the immunological effector activities of tumor-infiltrating antiviral bystander CTLs against head and neck squamous cell carcinoma (HNSCC) by loading cancer cell surface MHC I proteins with viral peptides. We find that inflationary T cell memory responses against common viral pathogens such as CMV and EBV unfold superior anti-tumor activity compared to conventional memory responses under APEC therapy in an ICB-resistant preclinical model of HNSCC. Mechanistically, APEC activation required cancer cell-intrinsic protease activity, even for proteases expressed by cells of the tumor stroma. Data mining and functional screening identified the protease activity of plasminogen activator urokinase (PLAU) as widely shared between human HNSCC cancers and as a highly efficient proteolytic activator of APECs. Furthermore, peripheral blood analysis in HNSCC patients reliably predicts the specificity, magnitude, and quality of intratumoral bystander CTL, thus allowing for the screening of HNSCC patients who may benefit most from APEC therapy.

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Shui, Y. I., Millar, D. G., Altenburger, L. M., Chrisikos, T., Kalbfleisch, M. J., Hata, A., Sadow, P. M., Faquin, W. C., Martinot, A. J., Snyder, C. M., Pittet, M. J., Pai, S. I., Cobbold, M., Mempel, T. R.. 2025-12-02. Antibody peptide epitope conjugates for αPD-1 therapy-resistant head and neck squamous cell carcinoma. https://doi.org/10.64898/2025.11.28.691238

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