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Geometric parameters that affect the behavior of logic-gated CAR T cells
Alexander C Partin1, Richele Bruno1, Sanam Shafaattalab1
1A2 Biotherapeutics, Inc., Agoura Hills, CA, United States.
Abstract:
Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod™, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.
Insights
CAR-T cell therapy faces challenges with tumor specificity and off-tumor toxicities. This study enhances Tmod™ logic-gated systems by engineering modular hinges, enabling broader targeting beyond HLA-I antigens for improved cancer treatment selectivity.
Area of Science:
- Immunology
- Biotechnology
- Cancer Therapy
Background:
- Chimeric antigen receptor T (CAR-T) cell therapy shows promise but is limited by tumor target scarcity and on-target/off-tumor toxicities.
- Logic-gated, two-receptor systems, like Tmod™, offer a strategy to enhance tumor selectivity by employing NOT gates.
- Current Tmod™ systems, utilizing blocking inhibitory receptors against HLA-I, face limitations with non-HLA-I antigens, particularly their size and proximity to the cell surface.
Purpose of the Study:
- To investigate the functional dependence of Tmod™ blockers on antigen height for non-HLA-I targets.
- To develop a method to overcome limitations associated with small, membrane-proximal blocker antigens.
- To broaden the applicability of logic-gated CAR-T cell therapies by enabling targeting of diverse antigens.
Main Methods:
- Incorporation of modular hinge units into Tmod™ receptor constructs to modulate ligand-binding domain proximity.
- Systematic evaluation of Tmod™ activator and blocker function with varying hinge lengths and antigen types.
- Development of geometric parameters for Tmod™ receptor design based on structural differences between activator and blocker targets.
Main Results:
- Tmod™ blocker function against non-HLA-I antigens is influenced by antigen height and generally compatible with small, membrane-proximal targets.
- Modular hinge units effectively extended or retracted ligand-binding domains, thereby modulating Tmod™ activator and blocker activity.
- The developed geometric design parameters successfully enabled targeting of blocker antigens beyond HLA-I.
Conclusions:
- Engineering modular hinges in Tmod™ systems overcomes limitations associated with antigen size and proximity.
- The refined Tmod™ design strategy broadens the scope of logic-gated cell therapies for enhanced tumor selectivity.
- This approach holds significant potential for developing safer and more effective CAR-T cell treatments against a wider range of cancers.
