Abstract
Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients.
Highlights
Epithelial ovarian cancer (EOC) is the fifth commonest malignancy in women with up to a quarter of a million new diagnoses per year worldwide [1, 2]
To determine the effect of combining chemotherapy, in the form of carboplatin or paclitaxel, with T4 immunotherapy, tumor cells were treated with either drug for a period of 48 h followed by the addition of T4 cells for a further 24 h
We have shown that combination treatment of ovarian cancer cells with paclitaxel or carboplatin and adoptive T cell therapy in the form of ErbB-targeted chimeric antigen receptor (CAR) T cells resulted in an enhanced anti-tumor effect; greater than when either therapy was used alone
Summary
Epithelial ovarian cancer (EOC) is the fifth commonest malignancy in women with up to a quarter of a million new diagnoses per year worldwide [1, 2]. It presents at a late stage in up 75% of the cases [3]. Cancer Immunology, Immunotherapy (2018) 67:1753–1765 low at around 40% and even less for advanced disease [4]. Poor survival is thought to be attributed to various factors including the non-specific symptoms of the disease, the advanced disease stage at diagnosis and acquisition of chemo-resistance following treatment [5,6,7,8]. There is a need for novel, more targeted and personalized therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
