Imperial College London
Dr John Wahba

DrJohnWahba

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Clinical Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 2125john.wahba04

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Wahba:2018:10.1007/s00262-018-2199-8,
author = {Wahba, J and Natoli, M and Whilding, LM and Parente-Pereira, AC and Jung, Y and Zona, S and Lam, EW-F and Smith, JR and Maher, J and Ghaem-Maghami, S},
doi = {10.1007/s00262-018-2199-8},
journal = {Cancer Immunology, Immunotherapy},
pages = {1753--1765},
title = {Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer},
url = {http://dx.doi.org/10.1007/s00262-018-2199-8},
volume = {67},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Wahba,J
AU  - Natoli,M
AU  - Whilding,LM
AU  - Parente-Pereira,AC
AU  - Jung,Y
AU  - Zona,S
AU  - Lam,EW-F
AU  - Smith,JR
AU  - Maher,J
AU  - Ghaem-Maghami,S
DO  - 10.1007/s00262-018-2199-8
EP  - 1765
PY  - 2018///
SN  - 1432-0851
SP  - 1753
TI  - Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer
T2  - Cancer Immunology, Immunotherapy
UR  - http://dx.doi.org/10.1007/s00262-018-2199-8
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30167862
UR  - http://hdl.handle.net/10044/1/62297
VL  - 67
ER  -
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