The 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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634156 |
| Date | January 2013 |
| Creators | Van Der Stegen, Sjoukje |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/an-investigation-into-the-potential-toxicity-of-erbb-targeting-t4-immunotherapy(5311189a-0949-4b68-a061-70032cf8cf75).html |
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