302 Signal 1 boosters for Tmod: addressing the next obstacle in cell therapy for solid tumors

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Background Cell therapies for solid tumors are associated with unique challenges compared with liquid tumors, such as lower access to tumor tissues that express target antigen. Antigen (signal 1) is the ignition and fuel for T cell responses and is necessary to induce chimeric antigen receptor (CAR) T-cell activation and expansion. Efforts to boost cell therapy activity have focused on improving the sensitivity of the CAR ligand-binding domains and enhancing the CAR through added intracellular domains from other signaling proteins (eg, CD28 and 4-1BB), thus boosting sensitivity and persistence while preserving antigen dependence. Little effort, other than vaccination,1 has been expended to enhance signal 1 (antigen), which may be essential to optimize responses in solid tumors. We sought to create a signal 1 booster that mimics an antigen stimulus with a small molecule that triggers signaling by the CAR or T-cell receptor (TCR). Methods Expression constructs were designed to control tonic signaling of T cells engineered with CARs and TCRs. These constructs contained FK506-binding protein (FKBP), ligand-binding domains that mediate protein multimerization in the presence of the small molecule rimiducid.2 Results A variety of constructs, including fusions to LAT or to CD3E, were shown to produce the desired effects on tonic signaling (figure 1). In the absence of rimiducid, these constructs produced only small elevations of tonic signaling in Jurkat or primary T cells. The addition of rimiducid induced dose-dependent increases in tonic signaling 2- to 10-fold. The constructs also enhanced tonic signaling in the context of TmodTM, a dual-receptor NOT gate based on the LIR-1 inhibitory receptor.3 Conclusions Signal 1 boosters that mimic an antigen stimulus with a small molecule that triggers signaling by the CAR or TCR were generated. The signal 1 mimetics allow tuned stimulation, which could improve the quality and performance of the T cell product in patients. Critically, they bypass the need for antigen exposure in the patient’s blood, a key difference between blood and solid tumor therapy. References Mackensen A, et al. Nat Med. 2023;29(11):2844–2853. National center for biotechnology information. PubChem Compound Summary for CID 16135625, Rimiducid. https://pubchem.ncbi.nlm.nih.gov/compound/Rimiducid. Accessed June 24, 2024. Hamburger AE, et al. Mol Immunol. 2020;128:298–310.

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