Chemokine receptor CCR2b expressing anti-Tn-MUC1 CAR-T cells enhanced anti-breast cancer activity

Lin, Y; An, H; Yin, H; Chen, S; McGowan, E

Chemokine receptor CCR2b expressing anti-Tn-MUC1 CAR-T cells enhanced anti-breast cancer activity

Lin, Y

An, H Yin, H Chen, S McGowan, E

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Publisher:: Oxford University Press (OUP)
Publication Type:: Journal Article
Citation:: Annals of Oncology, 2019, 30, (Supplement 11), pp. xi12-xi12
Issue Date:: 2019-12-09

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Field	Value	Language
dc.contributor.author	Lin, Y https://orcid.org/0000-0002-4637-9701
dc.contributor.author	An, H
dc.contributor.author	Yin, H
dc.contributor.author	Chen, S
dc.contributor.author	McGowan, E https://orcid.org/0000-0001-6371-3751
dc.date.accessioned	2022-04-01T05:29:01Z
dc.date.available	2019-10-23
dc.date.available	2022-04-01T05:29:01Z
dc.date.issued	2019-12-09
dc.identifier.citation	Annals of Oncology, 2019, 30, (Supplement 11), pp. xi12-xi12
dc.identifier.issn	0923-7534
dc.identifier.issn	1569-8041
dc.identifier.uri	http://hdl.handle.net/10453/155890
dc.description.abstract	Background: Enhanced anti-tumour activity is required for eradication of solid tumours by CART cells. One possibility of enhancing anti-tumour activity is by programming CART cells to express chemokine receptors that match chemokines produced either by the tumours or tumour-associated cells, thereby improving the infiltrating capacity of the CART cells. In this study, we engineered CCR2b expressing anti-Tn-MUC1 CAR T cells for the treatment of breast cancer. Methods: Anti-Tn-MUC1-CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. CCR2b expressing anti-Tn-MUC1 CAR T cells were prepared using PLV-CAR-5E5-CCR2b lentivirus. The susceptibility of MCF-7 cells to either anti-MUC1 CART or CCR2b expressing anti-MUC1 CART cell-mediated lysis was assessed using in vitro killing assays. For cytolytic analysis, CART-cells were cocultured 10:1 (effector:target) ratio with MCF-7 cells. The effects of CCR2b expressing CART cells on anti-tumour activity and infiltration were also assessed in an in vivo murine xenograft model. Results: Activated T cells co-modified with both CCR2b and anti-MUC1-CAR had greater anti-tumour activity both in vivo and in vitro. When the effector / target cell ratio was 10, the killing rates of CART and CART-CCR2b were 56.9% and 83.9%, respectively. Tumour size was significantly smaller (P < 0.001) in the CAR-CCR2b group compared to the CAR alone group. At day 7 post-injection of CART cells, the infiltrated T cells was significantly increased (~2 folds) in the CAR-CCR2b group compared with the CART only group. Conclusions: Our data demonstrated that the anti-tumour activity of the CCR2b expressing anti-Tn-MUC1 CART cells is 1.5 times more potent than CART cells without CCR2b. Augmentation of tumour suppression was also demonstrated in vivo in a murine xenograft model. These pre-clinical results show translational potential to the clinic for treatment of solid breast tumours.
dc.language	English
dc.publisher	Oxford University Press (OUP)
dc.relation.ispartof	Annals of Oncology
dc.relation.isbasedon	10.1093/annonc/mdz448.002
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.title	Chemokine receptor CCR2b expressing anti-Tn-MUC1 CAR-T cells enhanced anti-breast cancer activity
dc.type	Journal Article
utslib.citation.volume	30
utslib.location.activity	Geneva, SWITZERLAND
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	true
dc.date.updated	2022-04-01T05:29:00Z
pubs.issue	Supplement 11
pubs.publication-status	Published
pubs.volume	30
utslib.citation.issue	Supplement 11

Abstract:

Background: Enhanced anti-tumour activity is required for eradication of solid tumours by CART cells. One possibility of enhancing anti-tumour activity is by programming CART cells to express chemokine receptors that match chemokines produced either by the tumours or tumour-associated cells, thereby improving the infiltrating capacity of the CART cells. In this study, we engineered CCR2b expressing anti-Tn-MUC1 CAR T cells for the treatment of breast cancer. Methods: Anti-Tn-MUC1-CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. CCR2b expressing anti-Tn-MUC1 CAR T cells were prepared using PLV-CAR-5E5-CCR2b lentivirus. The susceptibility of MCF-7 cells to either anti-MUC1 CART or CCR2b expressing anti-MUC1 CART cell-mediated lysis was assessed using in vitro killing assays. For cytolytic analysis, CART-cells were cocultured 10:1 (effector:target) ratio with MCF-7 cells. The effects of CCR2b expressing CART cells on anti-tumour activity and infiltration were also assessed in an in vivo murine xenograft model. Results: Activated T cells co-modified with both CCR2b and anti-MUC1-CAR had greater anti-tumour activity both in vivo and in vitro. When the effector / target cell ratio was 10, the killing rates of CART and CART-CCR2b were 56.9% and 83.9%, respectively. Tumour size was significantly smaller (P < 0.001) in the CAR-CCR2b group compared to the CAR alone group. At day 7 post-injection of CART cells, the infiltrated T cells was significantly increased (~2 folds) in the CAR-CCR2b group compared with the CART only group. Conclusions: Our data demonstrated that the anti-tumour activity of the CCR2b expressing anti-Tn-MUC1 CART cells is 1.5 times more potent than CART cells without CCR2b. Augmentation of tumour suppression was also demonstrated in vivo in a murine xenograft model. These pre-clinical results show translational potential to the clinic for treatment of solid breast tumours.

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http://hdl.handle.net/10453/155890