Modified CARs With Reduced ITAMs for T Cell Persistence
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) therapies for cancer and pathogens face challenges in maintaining antigen-specific immune responses over time without compromising cellular function, particularly due to limitations in the durability and efficacy of T cell activation and expansion.
Innovation Solution
Development of novel CAR designs featuring a modified CD3ζ chain with reduced or deleted immunoreceptor tyrosine-based activation motifs (ITAMs) and basic-rich stretches, combined with co-stimulatory signaling domains, to enhance T cell persistence and function, thereby improving therapeutic potency and reducing exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR designs with full CD3ζ ITAMs are used, then strong initial T cell activation is achieved, but T cell exhaustion occurs and persistence is reduced
Solution Approach 1:
The patent removes ITAM2 from the CD3ζ chain in the CAR construct, creating a modified signaling domain that reduces excessive activation signals. This extraction of the problematic ITAM motif prevents T cell exhaustion while preserving necessary activation functions, thereby extending T cell persistence and duration of immune response.
Solution Approach 2:
The patent modifies the signaling parameters of the CAR by altering the CD3ζ chain composition - specifically reducing the number of ITAM motifs from three to two. This parameter change in the signaling domain creates an optimized balance between activation strength and durability, enabling sustained T cell function without exhaustion.
2Reliability
If CAR therapies use modified CD3ζ with reduced ITAMs, then T cell exhaustion is reduced and persistence is improved, but signal transduction capacity may be compromised
Solution Approach 1:
The patent combines the modified CD3ζ chain (with reduced ITAMs) with co-stimulatory signaling domains in a single CAR construct. This merging of activation and co-stimulation functions compensates for the reduced ITAM-mediated signaling, maintaining adequate signal transduction capacity while preventing T cell exhaustion through the balanced signaling profile.
Data Source
AI summary
The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to novel designs of chimeric antigen receptors (CARs) and engineered immunoresponsive cells comprising the same. The engineered immunoresponsive cells comprising the novel CARs are antigen-directed and have extended persistence without compromising function.