Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological malignancies but faces challenges with "on-target, off-tumor" toxicities, particularly when targeting tumor-associated antigens (TAAs) present on healthy tissues.
• Improving the safety profile of CAR T-cells is crucial for their clinical translation, especially for solid tumors where TAAs often exhibit broader expression patterns.

Purpose of the Study:

• To develop novel switchable adaptor CAR systems, specifically the RevCAR and Dual-RevCAR platforms, to enhance tumor specificity and reduce off-tumor toxicities.
• To engineer and validate new target modules (RevTMs) for targeting colorectal cancer (CRC)-associated antigens, carcinoembryonic antigen (CEA) and epithelial cell adhesion molecule (EpCAM).

Main Methods:

• Development of four novel, structurally distinct RevTMs targeting CEA and EpCAM.
• Validation of anti-CEA and anti-EpCAM RevTMs for monospecific and AND-gated targeting using the RevCAR and Dual-RevCAR platforms.
• Assessment of Dual-RevCAR T-cell efficacy through in vitro and in vivo killing assays of CEA+ and EpCAM+ cancer cells.

Main Results:

• Successful validation of novel anti-CEA and anti-EpCAM RevTMs.
• Demonstration that Dual-RevCAR T-cells, utilizing these RevTMs, can simultaneously target CEA+ and EpCAM+ cancer cells.
• Specific in vitro and in vivo killing of colorectal cancer cells was achieved by Dual-RevCAR T-cells, indicating enhanced tumor targeting and specificity.

Conclusions:

• The development of CEA and EpCAM specific adaptor RevTMs provides a versatile tool for monospecific and AND-gated targeting of colorectal cancer cells.
• The RevCAR platform, enhanced by these novel RevTMs, represents an improved approach to increase tumor specificity and safety in CAR T-cell therapies.
• This strategy holds potential for broader application in solid tumor treatment, mitigating risks associated with TAAs expressed on healthy tissues.