Synergistic immuno-chemotherapy in ovarian cancer
File(s)
Author(s)
Wahba, John
Type
Thesis
Abstract
Epithelial ovarian cancer (EOC) is the most lethal of all gynaecological malignancies due to its non-specific signs and symptoms, lack of a reliable screening tool and development of treatment resistant cancer. Cancers have developed strategies to evade immune recognition including the programmed death (PD) pathway. Tumour cells express the ligand PD-L1 which binds to its receptor, PD-1 on T cells, dampening T cell effector function and leading to immunosuppression. Immunotherapy aims to re-address the status quo by breaking peripheral immunosuppression, and this has great potential in immunogenic cancers like ovarian cancer.
The aim of this project was to explore the relationship between conventional chemotherapy and novel adoptive immunotherapeutic strategies such as the chimeric antigen receptor (CAR) T cells (T4 cells) for ovarian cancer and whether this effect could be enhanced with PD-1 receptor blockade.
We were able to demonstrate the effective application of combination treatment in in vitro and in vivo models of EOC. Both paclitaxel and carboplatin synergised with ErbB-targeted T4 cells, significantly reducing tumour burden, with further enhancement following PD-1 receptor blockade by nivolumab. This most likely occurs by counteracting the increased up-regulation of PD-L1 on tumour cells which was observed following treatment of tumour cells with chemotherapy.
We identified mechanisms which significantly contribute to this synergy such as the effect of chemotherapy on the tumour cell cycle dynamics, apoptosis machinery and autophagy. The mechanism of synergy is multifaceted and multifactorial, and is likely to involve other pathways which still remain to be investigated. Targeting these pathways may prove beneficial in order to maximise the benefit from chemo-immunotherapy.
Our work demonstrates a therapeutic advantage of chemo-immunotherapy in the treatment of ovarian cancer by targeting cancer’s immunosuppressive nature and breaking peripheral tolerance mechanisms.
The aim of this project was to explore the relationship between conventional chemotherapy and novel adoptive immunotherapeutic strategies such as the chimeric antigen receptor (CAR) T cells (T4 cells) for ovarian cancer and whether this effect could be enhanced with PD-1 receptor blockade.
We were able to demonstrate the effective application of combination treatment in in vitro and in vivo models of EOC. Both paclitaxel and carboplatin synergised with ErbB-targeted T4 cells, significantly reducing tumour burden, with further enhancement following PD-1 receptor blockade by nivolumab. This most likely occurs by counteracting the increased up-regulation of PD-L1 on tumour cells which was observed following treatment of tumour cells with chemotherapy.
We identified mechanisms which significantly contribute to this synergy such as the effect of chemotherapy on the tumour cell cycle dynamics, apoptosis machinery and autophagy. The mechanism of synergy is multifaceted and multifactorial, and is likely to involve other pathways which still remain to be investigated. Targeting these pathways may prove beneficial in order to maximise the benefit from chemo-immunotherapy.
Our work demonstrates a therapeutic advantage of chemo-immunotherapy in the treatment of ovarian cancer by targeting cancer’s immunosuppressive nature and breaking peripheral tolerance mechanisms.
Version
Open Access
Date Issued
2018-08
Date Awarded
2018-11
Advisor
Ghaem-Maghami, Sadaf
Smith, James Richard
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)