Targeting of glycosylation pathways to empower CAR-T therapy of solid tumors.

Introduction

Chimeric Antigen Receptor (CAR) T cell therapy uniquely can provide life-long protection against tumor re-emergence upon clearance of even advanced-stage leukemia. However, for the more frequent solid tumor types (carcinomas, lymphomas), clearance of advanced-stage tumors, and especially the subsequent long-term protection, is only rarely achieved.

Challenges in Solid Tumor Treatment

The main reason for this is the multi-pathway immunosuppressive environment that these tumors evolve to overcome the selective pressure imposed by the patient’s immune system. This environment:

• Hampers the initial attack by CAR-Ts
• Often leads to low numbers of long-term persisting CAR-T cells
• Results in CAR-T cells that tend to be in a state of functional exhaustion

Most attempts at overcoming these challenges target particular CAR-T cell proteins involved in individual pathways of immunosuppression. However, it is clear from early-stage clinical trials with such engineered CAR-T cells that multiple pathways will need to be tackled at the same time.

Innovative Approach

Inspired by this challenge, I have chosen a radically different path: we are targeting the CAR-T cell glycocalyx, i.e., the assembly of glycosylated structures that forms the outer layer of the cell.

Unique Properties of Glycosylation

The unique property of glycosylation pathways is that they often modulate a large range of cell surface receptor biology at the same time.

Promising Results

Excitingly, this new research line has now generated the first highly promising results with the discovery of a single CAR-T glycogene inactivation that results in robust clearance of a benchmark highly immunosuppressive carcinoma rechallenge, in mice that were CAR-T cured from their primary tumor months earlier.

Future Directions

Encouraged by these exciting results that demonstrate strong long-term functional persistence of these glyco-engineered CAR-T cells, we have defined a programme to build on this finding and to explore a candidate set of further glycosylation engineering concepts in CAR-T cells, to further improve CAR-T therapy of solid tumors.