Development of T cell-mediated targeted gene delivery of immunotoxin in HNSCC
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer
worldwide, with more than 500,000 new cases diagnosed annually. Chemotherapy, targeted
treatment, and immunotherapy have been approved by the FDA for HNSCC treatment. While a
minority of patients experience dramatic long-lasting and favorable clinical responses, the
majority of patients fail to achieve durable clinical response. Thus, alternative options with
improved beneficial response are urgently needed. In HNSCC, over 90% of tumors overexpress
cell surface EGFR. Recombinant immunotoxin (RIT) is a fused protein often consisting of an
antibody that targets a tumor antigen and a toxin (e.g., diphtheria toxin [DT]) that kills tumor
cells. RIT has been shown to be extremely effective for the treatment of some hematopoietic
malignancies. However, RIT is a highly immunogenic and very toxic protein, preventing its use
as an effective treatment for solid tumors, including HNSCC. In our previous studies, we
produced a humanized RIT DT390-HuBiscFv806 (hDT806) targeting EGFR and demonstrated
the efficacy of hDT806 in treating HNSCC and glioma. In this proposal, we will develop a novel
approach to overcome the critical limitations of the current RIT application for treating HNSCC
with two specific aims. Aim 1: to eliminate systemic immunogenicity and reduce RIT-induced
toxicity, we will engineer synthetic Notch T cells to deliver hDT806, specifically targeting
HNSCC tumor cells that overexpress EGFR. Aim 2: we will determine the efficacy of hDT806
for killing tumor cells and toxicity in immunodeficient and immunocompetent mice. The
validation of scientific principles to effectively and safely deliver RIT will provide a solid rationale
for a subsequent research project grant (R01) application to use RIT as a therapeutic agent in
recurrent or metastatic HNSCC for which treatment options remain extremely limited.