19 results found
Wahba J, Natoli M, Whilding LM, et al., 2018, Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer, Cancer Immunology, Immunotherapy, Vol: 67, Pages: 1753-1765, ISSN: 1432-0851
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.
Nagy I, Suosa-Valente J, Varga A, et al., 2017, Inflammation of peripheral tissues and injury to peripheral nerves induce diferring effects in the expression of the calcium-sensitive anandamide synthesising enzyme and related molecules in ratprimary sensory neuron, Journal of Comparative Neurology, Vol: 525, Pages: 1778-1796, ISSN: 1096-9861
Elevation of intracellular Ca2+ concentration induces the synthesis of N0arachydonoylethanolamine (anandamide) in a sub0population of primary sensory neurons. N0acylphosphatidylethanolamine phospholipase D (NAPE0PLD) is the only known enzyme, which synthesises anandamide in a Ca2+0dependent manner. NAPE0PLD mRNA, as well as anandamide's main targets, the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type 1 (CB1) receptor and the main anandamide0hydrolysing enzyme fatty acid amide hydrolase (FAAH) are all expressed by sub0populations of nociceptive primary sensory neurons. Thus, NAPE0PLD, TRPV1, the CB1 receptor and FAAH could form an autocrine signalling system, which could shape the activity of a major sub0population of nociceptive primary sensory neurons, hence contribute to the development of pain. While the expression patterns of TRPV1, the CB1 receptor and FAAH have been comprehensively elucidated, little is known about NAPE0PLD expression in primary sensory neurons under physiological and pathological conditions. We report that NAPE0PLD is expressed by about a third of primary sensory neurons, the overwhelming majority of which also express nociceptive markers as well as the CB1 receptor, TRPV1 and FAAH. Inflammation of peripheral tissues and injury to peripheral nerves induce differing but concerted changes in the expression pattern of NAPE0PLD, the CB1 receptor, TRPV1 and FAAH. Together these data indicate the existence of the anatomical basis for an autocrine signalling system, in a major proportion of nociceptive primary sensory neurons, and that alterations in that autocrine signalling by peripheral pathologies could contribute to the development of both inflammatory and neuropathic pain.
Chatterjee J, Dai W, Abd Aziz NH, et al., 2016, Clinical use of programmed cell death-1 (PD-1) and its ligand (PD-L1) expression as discriminatory and predictive markers in ovarian cancer, Clinical Cancer Research, Vol: 23, Pages: 3453-3460, ISSN: 1557-3265
Purpose We aimed to establish whether PD-1 and PD-L1 expression, in ovarian cancer (OC) tumour tissue and blood, could be used as biomarkers for discrimination of tumour histology and prognosis of OC. Experimental Design Immune cells were separated from blood, ascites and tumour tissue obtained from women with suspected OC and studied for the differential expression of possible immune biomarkers using flow cytometry. PD-L1 expression on tumour associated inflammatory cells was assessed by immunohistochemistry and tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. The relationships among immune markers were explored using hierarchical cluster analyses. Results Biomarkers from the discovery cohort that associated with PD-L1+ cells were found. PD-L1+ CD14+ cells and PD-L1+ CD11c+ cells in the monocyte gate showed a distinct expression pattern when comparing benign tumours and epithelial ovarian cancers (EOC) - confirmed in the validation cohort. Receiver operating characteristic curves showed PD-L1+ and PD-L1+ CD14+ cells in the monocyte gate performed better than the well-established tumour marker CA-125 alone. Plasma soluble PD-L1 was elevated in EOC patients compared to healthy women and patients with benign ovarian tumours. Low total PD-1+ expression on lymphocytes was associated with improved survival. Conclusions Differential expression of immunological markers relating to the PD-1/PD-L1 pathway in blood can be used as potential diagnostic and prognostic markers in EOC. These data have implications for the development and trial of anti PD-1/PD-L1 therapy in ovarian cancer.
Wahba J, Natoli M, Whilding L, et al., 2016, Synergistic immuno-chemotherapy for ovarian cancer, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 123, Pages: E6-E7, ISSN: 1470-0328
Wahba J, Natoli M, Whilding L, et al., 2016, Determining a mechanism of synergistic immuno-chemotherapy in ovarian cancer, 24th Biennial Congress of the European Association for Cancer Research, Publisher: Elsevier, Pages: S217-S218, ISSN: 0014-2964
Wahba J, Natoli M, Whilding L, et al., 2016, PD-1 blockade enhances synergistic killing of ovarian tumour cells by combination chemotherapy and T cell immunotherapy, 24th Biennial Congress of the European Association for Cancer Research, Publisher: Elsevier, Pages: S218-S218, ISSN: 0014-2964
Wahba J, Natoli M, Whilding L, et al., 2015, Synergistic immuno-chemotherapy for ovarian cancer, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 362-362, ISSN: 1470-0328
Wahba J, Jasmat I, Patel A, et al., 2015, An audit into the management of obesity in pregnancy at a major London teaching hospital, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 229-229, ISSN: 1470-0328
Ratnasekera L, Wahba J, Foo L, et al., 2014, A retrospective audit of the management of sepsis in labour at Queen Charlotte's and Chelsea hospital, London, Publisher: WILEY-BLACKWELL, Pages: 107-107, ISSN: 1470-0328
Garg N, Wahba J, Kothari A, 2013, Ambulatory management of PULs and ectopic pregnancies, Publisher: WILEY-BLACKWELL, Pages: 551-551, ISSN: 1470-0328
Wahba J, Cherfan L, Nicholas N, 2013, Referrals to colposcopy with clinical indications the Hillingdon experience, Publisher: WILEY-BLACKWELL, Pages: 232-233, ISSN: 1470-0328
Garg N, Wahba J, Gould D, et al., 2013, Dilemma in diagnosing unusual locations of ectopic pregnancies, Publisher: WILEY-BLACKWELL, Pages: 547-547, ISSN: 1470-0328
Chatterjee J, Hopkins T, Wahba J, et al., 2013, Early stage mucinous ovarian carcinomas: 10 years of experience in a tertiary centre, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 120, Pages: 282-283, ISSN: 1470-0328
Wahba J, Jaspal R, Tailor V, et al., 2012, W257 NEW-ONSET IMMUNE THROMBOCYTOPENIC PURPURA (ITP) IN PREGNANCY, International Journal of Gynecology & Obstetrics, Vol: 119, Pages: S788-S789, ISSN: 0020-7292
Wahba J, Cherfan L, Nicholas N, 2012, M302 REFERRALS TO COLPOSCOPY WITH CLINICAL INDICATIONS - THE HILLINGDON EXPERIENCE, International Journal of Gynecology & Obstetrics, Vol: 119, Pages: S628-S629, ISSN: 0020-7292
Wahba J, O'Reilly R, Miskry T, 2012, Adherence to published guidelines for the management of menorrhagia in primary and secondary care, Publisher: WILEY-BLACKWELL, Pages: 208-208, ISSN: 1470-0328
Wahba J, Garg N, Kothari A, 2012, A rare case of a cervical ectopic pregnancy, Publisher: WILEY-BLACKWELL, Pages: 223-224, ISSN: 1470-0328
Nagy B, Fedonidis C, Photiou A, et al., 2009, CAPSAICIN-SENSITIVE PRIMARY SENSORY NEURONS IN THE MOUSE EXPRESS N-Acyl PHOSPHATIDYLETHANOLAMINE PHOSPHOLIPASE D, NEUROSCIENCE, Vol: 161, Pages: 572-577, ISSN: 0306-4522
Nagy I, Fedonidis C, Paule CC, et al., 2009, NAPE-PLD is involved in anandamide synthesis in capsaicin-sensitive primary sensory neurons, IUPS World Congress
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