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 this issue 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. 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.