Targeting the tumour microenvironment with endosialin-directed CAR T-cells

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Authors

Ash, S

Document Type

Thesis or Dissertation

Date

2022-05-31

Date Accepted

Abstract

Advances in T-cell engineering have facilitated the generation of CAR T-cells that successfully deplete malignant cells of haematological cancers. However, attempts to target solid tumours with CAR T-cells have been hindered by the unfavourable environments surrounding the malignant cells in this setting. An alternative approach that circumvents the arduous journey to reach tumour cells is to target cells of the tumour microenvironment, especially those proximal to the vasculature. Endosialin is a transmembrane glycoprotein upregulated on tumour-associated pericytes and fibroblasts which has previously been shown by our laboratory to have a role in promoting tumour cell intravasation and metastatic dissemination. The aim of this PhD was to evaluate endosialin-targeting CAR T-cells, known as Endo3 CAR T-cells, in the context of solid tumours. In vitro characterisation of Endo3 CAR T-cells demonstrated endosialin-specific activation and cytotoxicity against both mouse and human cells. Endo3 CAR T-cells were evaluated in vivo in the context of three synegeneic models of cancer: 4T1, AT-3 and LLC. Modest effects on primary tumour growth were observed in 4T1 and LLC tumour-bearing mice, however a significant reduction in spontaneous lung metastasis was observed in these models. Conversely, in AT-3 tumour-bearing mice, Endo3 CAR T-cell therapy resulted in a significant reduction of primary tumour growth but did not limit metastatic lung disease. Endo3 CAR T-cell therapy was associated with toxicity in BALB/c 4T1 tumour-bearing mice that was not alleviated by anti-IL-6R treatment or delivering multiple low T-cell doses. Interrogation of the strain-specific Endo3 CAR T-cell products revealed differences in the CD4+:CD8+ T-cell ratio and distinct efficacies in an immunodeficient setting. This thesis proposes that Endo3 CAR T-cell therapy is a potential candidate for targeted therapy of solid tumours. Further studies are required to gain better understanding of Endo3 CAR T-cell dosing and tolerability in the context of different endogenous immune systems

Citation

2022

DOI

Source Title

Publisher

Institute of Cancer Research (University Of London)

ISSN

eISSN

Research Team

Molecular Cell Biology

Notes