Radiation-guided theranostic agents to monitor response to oral cancer treatment

About This Grant

ABSTRACT Despite aggressive treatments, the five-year overall survival rate for advanced head and neck squamous cell carcinoma (HNSCC) remains below 50%. The global burden of HNSCC is influenced by tobacco-derived carcinogens and excessive alcohol consumption, with oropharyngeal tumors increasingly linked to oncogenic human papillomavirus (HPV) infections. Current treatments for locoregionally advanced HNSCC include surgery followed by adjuvant external beam radiation therapy (XRT) or definitive concurrent chemoradiation, but radiation resistance is common, leading to poor outcomes. Novel strategies are needed for better detection, treatment, and monitoring of treatment responses. Our research is based on the discovery of radiation-inducible antigens that are upregulated on cancer cell surfaces post-XRT. We identified Tax-interacting protein 1 (TIP1) as a tumor- associated antigen upregulated following XRT. Anti-TIP1 antibodies undergo endocytosis, delivering payloads specifically to tumor cells and show XRT-induced tumor-specific delivery in vivo. We aim to leverage XRT- induced TIP1 expression to guide theranostic (therapy+diagnostic) radioimmunoconjugates for detection, treatment, and monitoring response to treatment. Radiopharmaceuticals are emerging as effective treatments for various cancers. In our recent publication, we developed human anti-TIP1 antibodies (L111) and labeled them with [89Zr]Zr, demonstrating specific cancer detection by PET imaging in preclinical cancer models. We propose radiolabeling L111 antibodies with the β-emitter [177Lu]Lu and evaluating their therapeutic potential for HNSCC. We hypothesize that Immuno-PET using [89Zr]Zr-L111 will monitor HNSCC response to treatment and that [177Lu]Lu-L111 will treat residual tumors unresponsive to XRT. Our objectives include assessing [89Zr]Zr- L111 for non-invasive PET imaging of HNSCC tumors after XRT and [177Lu]Lu-L111 therapy and determining if this strategy applies to both HPV+ and HPV- HNSCC subtypes. Aim 1 will evaluate the efficacy of TIP1-targeted radioimmunoconjugates in vitro using HPV+ and HPV- HNSCC cell lines, exploring XRT-driven TIP1 upregulation, enhanced binding, internalization, and cell killing efficacy of [177Lu]Lu-L111. We will also optimize radiation doses and schedules. Aim 2 will evaluate these conjugates in vivo using syngeneic orthotopic murine models treated with XRT, studying biodistribution, PET imaging, dosimetry, maximum tolerated dose, and therapeutic efficacy. Our study aims to revolutionize HNSCC management by improving detection, treatment, and monitoring, potentially leading to tailored therapies based on HPV status and enhancing survival rates through personalized interventions, marking a significant advancement in clinical practice.