Targeting tumour-associated macrophages with locally-expressed T cell engagers

Scott, E

Thesis

Targeting tumour-associated macrophages with locally-expressed T cell engagers

Abstract:: Tumour associated macrophages (TAMs) are implicated in cancer progression but can also exert anti-tumour activities. In this thesis, a strategy to redirect endogenous T cell cytotoxicity towards cancer supporting (M2-like) TAMs is explored. A panel of novel bi- and tri-valent T cell engagers (BiTEs/TriTEs) was generated, recognising CD3ε on T cells and M2-like macrophage markers CD206 or folate receptor β (FRβ). Primary human T cells activated by the BiTEs/TriTEs preferentially killed M2- over M1-polarised autologous macrophages, with EC50 values in the nanomolar range. This work represents the first to demonstrate the feasibility of redirecting T cells to kill macrophages.

To avoid on-target off-tumour toxicities, we propose localising BiTE/TriTE expression to the tumour with an engineered oncolytic virus. We confirmed the feasibility of this approach by modifying an oncolytic adenovirus in early-phase clinical trials for solid cancers, enadenotucirev (EnAd), to express the BiTEs. Critically, T cell engager-armed EnAd retained its oncolytic and replicative capacities, whilst mediating BiTE expression from infected cancer cells.

In immunosuppressive human malignant ascites samples, free and EnAd-encoded FRβ-targeting BiTEs (but not CD206-targeting T cell engagers) triggered endogenous T cell activation and IFN-γ production, leading to increased T cell numbers and a reduction in the number of CD11b+CD64+ ascites macrophages. Strikingly, surviving macrophages exhibited a general increase in M1-like marker expression, suggestive of a repolarisation of the microenvironment towards a more immune-responsive state. Taken together, this approach to deplete cancer-promoting TAMs in the context of the immune-stimulatory effects of BiTEs and oncolytic viruses offers a powerful new strategy for removing barriers to anti-tumour immunity in patients with cancer.

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Cite

Cite this record

APA Style

Scott, E. (2020). Targeting tumour-associated macrophages with locally-expressed T cell engagers [PhD thesis]. University of Oxford.

MLA Style

Scott, E. Targeting Tumour-Associated Macrophages with Locally-Expressed T Cell Engagers. University of Oxford, 2020.

Chicago Style

Scott, E. 2020. “Targeting Tumour-Associated Macrophages with Locally-Expressed T Cell Engagers.” PhD thesis, University of Oxford.
Share
Print