The Tmod cellular logic gate as a solution for tumor-selective immunotherapy

Immune cells that are engineered with receptors to integrate signals from multiple antigens offer a promising route to achieve the elusive property of therapeutic selectivity in cancer patients. Several types of multi-signal integrators have been described, among them mechanisms that pair activating and inhibitory receptors which are termed NOT gates by analogy to logical operations performed by machines. Here we review one such NOT-gated signal integrator called the Tmod system which is being developed for patients with solid tumors. Coupled with rigorous selection for patients with defined lesions in their tumor genomes (loss of heterozygosity), the Tmod approach presents an unusual opportunity to create truly selective therapies for certain cancer patients. Several of these agents are advancing toward the clinic, supported by a large body of quantitative preclinical data. •Cells can integrate signals from multiple antigens to kill tumors selectively.•With NOT logic gate systems, effector cells can recognize antigens lost via LOH.•Tmod uses a LIR-1-based blocker to target tumor cells with specific HLA deletions.•Therapeutic CEA and MSLN Tmod constructs target cancers with loss of HLA-A*02.•Platform modularity enables Tmod extension to additional patient populations.