New Advances in CAR T-Cell Therapy for Colorectal Cancer
Researchers in the Mahata Group , in collaboration with Prof Sir David Klenerman and colleagues, have uncovered a key reason why anti-CEACAM5 CAR T-cell therapies — a promising form of immunotherapy — have so far struggled to treat colorectal cancer (CRC), and have identified a potential strategy to overcome this barrier.
In a study published in Advanced Science, scientists show that although CAR T cells targeting CEACAM5 (a tumour antigen frequently expressed on CRC cells) can recognise cancer cells, they fail to engage and kill them effectively due to physical barriers in the tumour microenvironment.
What’s limiting CAR T-cell success?
The researchers found that colorectal cancer cells possess a number of structural defences that hinder immune attack:
A thick glycocalyx — a sugar-rich coating on the surface of tumour cells — physically restricts close contact between CAR T-cells and their targets.
CEACAM5 proteins are often sequestered within tight intercellular junctions, making them less accessible to CAR T-cell receptors.
Together, these features delay immune activation and reduce the strength and durability of the CAR T-cell response.
However, please note that this is one of the barriers that the team focused on and studied.
Turning barriers into opportunities
The study demonstrates that enzymatic remodelling of the tumour surface can significantly enhance CAR T-cell performance. Treatment with enzymes such as trypsin or hyaluronidase was shown to:
Increase antigen accessibility
Reduce glycocalyx thickness
Improve CAR T-cell activation and persistence
Enhance tumour cell killing and cytokine release
These findings indicate that modifying the tumour microenvironment can restore the effectiveness of CAR T cells against solid tumours such as colorectal cancer.
Clinical significance
Notably, hyaluronidase is already approved for human use, highlighting a potential translational pathway to improve CAR T-cell therapies in colorectal cancer, a disease with limited effective immunotherapy options.
Why this matters
Rather than pointing to an inherent failure of CAR T-cells in solid tumours, this research reframes the problem as one of physical accessibility. By targeting the tumour microenvironment itself, the study opens new avenues for making cellular immunotherapies more effective in hard-to-treat cancers. The study provides a new hope.
Read the article here: https://doi.org/10.1002/advs.202509762