Targeting loss of heterozygosity for cancer-specific immunotherapy

Area of Science:

• Oncology
• Immunotherapy
• Genetics

Background:

• Developing targeted cancer therapies that spare normal tissues is a critical challenge.
• Clonal loss of heterozygosity (LOH) is a cancer-specific genetic alteration.
• Targeting LOH events could provide a unique therapeutic window.

Purpose of the Study:

• To develop a proof-of-concept for targeting LOH events in cancer using engineered T cells.
• To create a NOT-gate logic system for T cells to distinguish cancer cells based on LOH.
• To investigate the therapeutic potential of allele-sensing chimeric antigen receptors (CARs).

Main Methods:

• Engineered T cells with a NOT-gate comprising a chimeric antigen receptor (CAR) and an inhibitory CAR (iCAR).
• CAR targeted the retained human leukocyte antigen (HLA) allele, while iCAR targeted the lost HLA allele.
• In vitro and in vivo (mice) experiments to assess T cell activation and cancer cell killing.

Main Results:

• Engineered T cells demonstrated genetically predictable activation.
• The NOT-gate logic successfully enabled T cells to target cancer cells with specific LOH patterns.
• Demonstrated in vitro and in vivo efficacy in killing relevant cancer cells.

Conclusions:

• Engineered T cells with NOT-gate logic can effectively target cancer cells by exploiting LOH-specific antigens.
• The Neoplasm-targeting Allele-Sensing CAR (NASCAR) approach shows promise for cancer immunotherapy.
• This strategy could be extended to target LOH of other polymorphic genes in various cancers.