CAR-T Therapy Development for Breast Cancer and Other Solid Tumours

Background

There are around 55,900 new breast cancer cases in the UK every year and it is the fourth most common cause of cancer death in the UK, accounting for 7% of all cancer deaths. The majority of breast cancer deaths are due to metastatic disease. Breast cancer metastasis is a multi-step process influenced by many factors, including the tumour microenvironment (TME). Key interactions between the TME and tumour cells have been identified as promoting metastasis, thus presenting novel clinical targets.

One such target is endosialin, a transmembrane glycoprotein expressed in both developing and adult tissues that are undergoing active physiological or pathological angiogenesis. Endosialin has limited expression in healthy tissues but is strongly upregulated on tumour-associated pericytes and fibroblasts in most solid cancers, including breast cancer.

Technology Overview

Using endosialin knockout mice, which show no overt phenotypic abnormalities, the research team has demonstrated that expression of endosialin in the tumour stroma promotes tumour cell intravasation into blood vessels, thereby promoting metastatic dissemination. Endosialin-expressing cells present an interesting target for CAR T-cell therapy as they are relatively accessible to infiltrating CAR T-cells.

Based on an in-house generated monoclonal antibody, a CAR construct that recognises both mouse and human endosialin was generated. Experiments comparing the effects of endosialin-directed CAR T-cells (Endo3 CARs) and mock transduced T-cells (mock T-cells) in a spontaneously metastatic BALB/c breast cancer mouse model revealed that Endo3 CAR treatment significantly reduces the number of metastatic deposits in the lungs. Endo3 CARs expanded by at least two-fold in tumour-bearing mice, with endosialin staining confirming that Endo3 CAR treatment resulted in the depletion of endosialin-positive cells in the tumour stroma, without affecting normal tissue. Strikingly, Endo3 CAR treatment also resulted in significant growth inhibition and necrosis of the primary tumour. No off-target or on-target/off-tumour activity was observed in experiments with non-tumour bearing wildtype mice, in wounding models which display an activated stroma or tumour-bearing endosialin knockout mice.

The proof-of-concept results show that targeting endosialin via CAR-T therapy could be a viable option to treat not only breast cancer but also other solid tumours and metastatic cancers ().

Further Details

Viski C, et al. Endosialin-Expressing Pericytes Promote Metastatic Dissemination. Cancer Res September 15 2016 (76) (18) 5313-5325;DOI: 10.1158/0008-5472.CAN-16-0932.

Ash S et al. Targeting the tumor stroma using CAR T-cells. Cancer Res August 15 2020 (80)(16 Supplement) 3241; DOI: 10.1158/1538-7445.AM2020-3241.

Opportunity

The Institute of Cancer Research, London, is seeking a partner to continue the development of CAR-T technology targeted against transmembrane glycoprotein Endosialin – also known as CD248 – in breast cancer and other solid tumours.

No patents have been filed to date, but there is significant know-how within the research team.