Frosch, Jennifer Vanessa; (2021) Overcoming suppressive myeloid cells for neuroblastoma therapeutics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neuroblastoma is a paediatric solid tumour with poor survival rates among patients within the high-risk group, despite advances in therapy. Although chimeric antigen receptor (CAR) T cells have proven to be an effective cell-based treatment in blood cancers, the immunosuppressive environment that is formed by the tumour and infiltrating alternatively activated immune cells heavily affects the efficacy of such immunotherapies when translated. Myeloid derived suppressor cells (MDSC) are a key group among tumour-induced immune cells and have been shown to correlate with cancer stage, disease progression, and resistance to standard therapies. Therefore, the aim of this work was to provide a neuroblastoma-based model to study interactions between CAR T cells and suppressive myeloid cells, and to investigate ways to overcome the suppressive effects. We have shown that an in vitro polarisation assay, using neuroblastoma- conditioned media, drives healthy monocytes towards MDSC-like phenotypes. Furthermore, these neuroblastoma-conditioned monocytes (NbM) significantly inhibited proliferation and activation (IFN-g release) in co-cultures with primary and CAR- modified T cells. In a drug retargeting context, Sunitinib malate, a tyrosine kinase inhibitor, could partially recover T cell functions through inhibition of NbM. Moreover, a preliminary chemical library screen showed that the assay can achieve high throughput results suitable to investigate drug effects on suppressive monocytes. As an alternative approach to overcome myeloid cells in a solid tumour context, we designed an inducible anti-CD33 CAR under the control of a neuroblastoma driven synthetic Notch receptor, to enable the localised targeting of myeloid population only in the presence of tumour markers. However, we show that, in contrast to the prototypic CD19 induction, substitution with neuroblastoma-specific binding domains results in tonic signalling and failure of responder induction by tumour cells despite successful induction by cross-linking. Taken together, we have successfully developed a neuroblastoma-based model to screen for strategies to overcome myeloid cell-mediated T cell suppression in the tumour microenvironment and have provided the basis for both drug retargeting and cell engineering-based approaches.

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