Next Gen CAR-Ts: Synthetic Biology and Precision cell Therapies, Day 58

𝗨𝗻𝗶𝗖𝗔𝗥 (universal CAR) uses an inert CAR that recognizes a short peptide epitope (e.g., E5B9). Separately administered target modules (TMs) carry the epitope plus an scFv against the tumour antigen, are targeting tumor. TMs are short-lived, so stopping TM infusion rapidly switches UniCAR activity off. UniCAR has preclinical, early clinical data and active German trials. [1][2] 

𝗦𝗨𝗣𝗥𝗔-𝗖𝗔𝗥 (split, universal, programmable CAR) splits receptor and antigen binder into two parts: a zipCAR (on the T cell) with a leucine-zipper and a soluble zipFv adaptor with the cognate zipper fused to an scFv. By changing zipper affinity, adaptor dose, or combining zipFvs, activity and specificity can be tuned, gated, or multiplexed. [3] 

𝗢𝗺𝗻𝗶𝗖𝗔𝗥 is a modular ´universal receptor´ design that enables post-translational covalent loading of binders and allows retargeting with administered ligands. The decoupling of recognition and signaling gives on-demand control and multi-antigen targeting potential. [4] 

𝗦𝘆𝗻𝗡𝗼𝘁𝗰𝗵 & 𝗹𝗼𝗴𝗶𝗰-𝗴𝗮𝘁𝗲𝗱 𝗖𝗔𝗥𝘀 are synthetic receptor circuits: SynNotch receptors sense antigen A and, conditional on that input, induce expression of a CAR against antigen B (a serial AND gate). These enable highly selective, context-dependent activation inside the tumor. [5]  

𝗚𝗿𝗼𝘂𝗽𝘀 
UniCAR/RevCAR – German groups (e.g. Prof. Bachmann) have driven UniCAR preclinical and early clinical development. [1][2] 
SUPRA-CAR – origin and major work from Cho and colleagues. [3] 
OmniCAR – translational/commercial by Prescient Therapeutics. [4] 
Dr. Patrick Ho (University Hospital Würzburg) works on biosensor-regulated CAR platforms and synthetic receptor research. [6]   

𝗦𝗽𝗲𝗰𝘂𝗹𝗮𝘁𝗶𝘃𝗲 𝗵𝘆𝗽𝗼𝘁𝗵𝗲𝘀𝗶𝘀 
A senolytic, modular UniCAR concept could combine: (a) UniCAR T cells as a backbone, (b) a TM that targets senescent-cell markers, (c) controlled local IL-15 expression to improve persistence and metabolic fitness, and (d) an inducible suicide switch (e.g., iCasp9) to abort activity if CRS/neurotoxicity emerges. [1][3][4] 

𝗤𝘂𝗲𝘀𝘁𝗶𝗼𝗻 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗮𝘂𝗱𝗶𝗲𝗻𝗰𝗲: Why are both OmniCAR and UniCAR considered as universal CARs?

Stay tuned for 𝗗𝗮𝘆 𝟱𝟵: 𝗢𝗻𝗰𝗼𝗹𝘆𝘁𝗶𝗰 𝗩𝗶𝗿𝘂𝘀𝗲𝘀 – 𝗧𝘂𝗿𝗻𝗶𝗻𝗴 𝗜𝗻𝗳𝗲𝗰𝘁𝗶𝗼𝗻 𝗶𝗻𝘁𝗼 𝗜𝗺𝗺𝘂𝗻𝗶𝘁𝘆 

𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲𝘀 
1. DOI: 10.1016/j.omto.2020.04.009 
2. DOI: 10.1016/j.addr.2022.114358 
3. DOI: 10.1038/s41467-021-21078-7 
4. https://ptxtherapeutics.com/technology/ 
5. https://www.cell.com/cell/fulltext/S0092-8674(16)00052-0 
6. https://sciprofiles.com/profile/author/VG5rNzlIeWlnWEs2UWJTampycXFadz09 

#100DaysOfImmunology #CAR_T #SyntheticBiology #UniCAR #SUPRACAR #OmniCAR #SynNotch #ModularTherapies #CellTherapy #ImmunoEngineering #TranslationalScience #TumorMicroenvironment