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Title: An investigation into the potential toxicity of ErbB targeting T4 immunotherapy
Author: Van Der Stegen, Sjoukje
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2013
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available