AbstractThe five-‐year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) has remained stable at 50% over the past five decades. Consequently, new treatment options are required. In approximately 90% of cases, over-‐expression of the tumour associated antigen ErbB1 is seen. T4 immunotherapy retargets T-‐cells against the extended ErbB-‐receptor family and could be beneficial for HNSCC patients. T4 immunotherapy comprises the combined expression of the ErbB-‐targeting chimeric
antigen receptor T28ζ and the chimeric cytokine receptor 4αβ. Human T4+ T-‐cells have a potent anti-‐tumour effect. However, ErbB expression is not exclusive to tumour tissue, raising the concern of toxicity in healthy tissue. Here, I have investigated the potential toxicity of T4 immunotherapy in a SCID/Beige immunodeficient mouse model. Human T4+ T-‐cells are activated by mouse ErbB receptors and consequently destroy both healthy and transformed mouse cells. Intravenous or intra-‐tumoural T4+ T-‐cell administration did not result in any clinical or histopathological toxicity. However, intraperitoneal T4+ T-‐cell administration resulted in severe cytokine release syndrome (CRS). Target recognition in the peritoneal cavity resulted in elevated levels
of serum human IL-‐2 and IFNγ, as well as mouse IL-‐6. The severity of CRS is hypothesized to be due to a combination of the T4+ T-‐cell dose, magnitude of target recognition, and macrophage content within the peritoneal cavity. In keeping with this, macrophage depletion ameliorates both IL-‐6 production and toxicity. Together, these data show that the SCID/Beige mouse is an adequate model to study T4 immunotherapy related toxicity. Furthermore, these results suggest that there may be a window for therapeutic application of T4+ T-‐cells since anti-‐tumour efficacy has been demonstrated at lower cell doses without the induction of toxicity. These findings, support progression to a Phase-‐I clinical trial in which patients with locally recurrent HNSCC are treated with intra-‐tumoural T4+ T-‐cells.
|Date of Award||2013|
|Supervisor||John Maher (Supervisor) & Joy Burchell (Supervisor)|