Mutated DAP10 Costimulatory Domain CAR-T Cell Exhaustion
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) T cell therapies for cancer face challenges such as poor persistence and excessive activation, leading to relapses and toxicities, despite improved efficacy with co-stimulatory domains.
Innovation Solution
Development of CAR polypeptides with a mutated form of the cytoplasmic domain of DAP10 that enhances CAR-T cell function, reduces exhaustion, and includes a costimulatory signaling region to improve anti-tumor efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If co-stimulatory domains (CD28 or 41BB) are added to CARs to improve efficacy, then tumor killing capability is enhanced, but biologic complications including excessive T cell activation and toxicities occur
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the DAP10 costimulatory domain (e.g., K706Q, T709A mutations) to alter its signaling properties. These parameter changes in the molecular structure enable the domain to provide costimulatory signals that enhance CAR-T cell function and persistence while reducing excessive activation and toxicities compared to wild-type CD28 or 41BB domains
Solution Approach 2:
The patent creates a composite costimulatory domain by fusing mutated DAP10 intracellular domain with the extracellular domain of CD28 or 41BB. This composite structure combines the antigen recognition capability of the original CAR with the modified costimulatory signaling of DAP10, achieving enhanced efficacy with reduced harmful effects
2Productivity
If co-stimulatory domains are added to CARs, then CAR-T cell efficacy is improved, but CAR-T cell persistence becomes poor
Solution Approach 1:
The patent uses parameter changes by introducing specific mutations in the DAP10 domain that modify its signaling duration and intensity. The mutated DAP10 domain provides sustained costimulatory signals that enhance CAR-T cell persistence without causing excessive activation, addressing both efficacy and durability requirements
3Reliability
If standard DAP10 domain is used in CARs, then costimulatory signaling is provided, but CAR-T cell exhaustion occurs
Solution Approach 1:
The patent applies parameter changes by mutating specific residues in the DAP10 domain (such as K706Q, T709A) to alter its phosphorylation patterns and signaling dynamics. These parameter changes reduce CAR-T cell exhaustion while maintaining reliable costimulatory signaling function
Data Source
AI summary
Disclosed herein are chimeric antigen receptor (CAR) polypeptides, which can be used with adoptive cell transfer to target and kill cancers, that comprise a co-stimulatory signaling region having a mutated form of a cytoplasmic domain of DAP10 that enhances CAR-T cell function, e.g. by reducing CAR-T cell exhaustion. Also disclosed are immune effector cells, such as γδ T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a tumor associated antigen-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.