CAR-Modified Gamma Delta T Cells for Tunable Cytotoxicity
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Solution Overview
Problem
Current CAR-T therapies face limitations such as 'on-target but off-tumor' toxicity, immune system compromise, and the development of resistance due to cancer cells modifying the target antigen, which restricts their effectiveness in treating solid tumors and infectious diseases.
Innovation Solution
Development of gamma delta (γδ) T cells modified with chimeric antigen receptors (CARs) that lack a functional CD3 zeta domain, allowing for MHC-independent antigen recognition and co-stimulatory signaling only in the presence of phosphoantigens, thereby reducing off-tumor toxicity and enhancing persistence and efficacy against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If CAR-T therapy is used to target cancer cells, then cytotoxic activity against tumor cells is improved, but off-tumor toxicity occurs when healthy cells expressing the target antigen are attacked
Solution Approach 1:
The patent applies local quality by making the CAR signaling domain (CD3 zeta) functional only in specific locations - namely, only when phosphoantigens are present to activate gamma delta T cells. This localized functionality allows the CAR to exert cytotoxic effects only under specific conditions (when phosphoantigens are present), thereby sparing healthy cells that express the target antigen but do not present phosphoantigens, thus reducing off-tumor toxicity while maintaining anti-tumor potency
2Reliability
If CAR-T therapy is used to eliminate target antigen expression on cancer cells, then tumor burden is reduced, but cancer cells develop resistance by modifying or losing the target antigen
Solution Approach 1:
The patent applies preliminary action by requiring dual activation signals before CAR-T cell cytotoxic activity is unleashed: (1) recognition of the target antigen on the cancer cell surface, and (2) simultaneous detection of phosphoantigens. This preliminary dual-check mechanism ensures that only cancer cells expressing both the target antigen and phosphoantigens (a hallmark of malignant transformation) are eliminated, while preventing escape through antigen modification alone, since phosphoantigen presence would still trigger selective killing
3Object-affected harmful factors
If gamma delta T cells are expanded autologously to avoid graft-versus-host disease, then immune system safety is improved, but treatment time and complexity increase due to patient-specific cell collection and expansion
Solution Approach 1:
The patent applies the principle of using disposable, off-the-shelf cellular products by developing allogeneic gamma delta T cell products with modified CAR signaling that do not require patient-specific customization. These standardized products can be manufactured in advance and stored, eliminating the need for time-consuming autologous cell collection, expansion, and quality control for each patient, thereby dramatically reducing treatment time and complexity while maintaining safety through controlled CAR signaling activation
Data Source
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AI summary
The present invention provides composition and methods for the treatment of cancer or infectious diseases in a human. The invention includes the generation and administration of gamma delta Τ cells that express chimeric antigen receptors (CARs) comprising an antigen binding domain, a hinge domain, a transmembrane domain, a costimulatory signalling domain with the inclusion or not of a CD3 zeta signalling domain. Expression of CAR sequence omitting the CD3 zeta signalling domain in gamma delta T cells, provides for a CAR-T therapy in vivo, which will effect cytolysis only on target cells providing ligands for activation of the gamma delta T cell receptor (TCR).