CAR T Cell Persistence via NFkB Signaling Mutations
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Solution Overview
Problem
Current chimeric antigen receptor (CAR) T cell therapies for cancer, such as those targeting CD19, face challenges with CAR T cell persistence and excessive activation leading to relapses and toxicities, indicating a need for enhanced co-stimulation strategies to improve efficacy and reduce exhaustion.
Innovation Solution
Development of CAR polypeptides with mutated costimulatory signaling regions in CD28 and/or 41BB domains that enhance signaling, including specific mutations in intracellular subdomains and increased NFκB activation through TRAF proteins, to improve CAR-T cell function and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If co-stimulatory domains (CD28 or 41BB) are added to CAR to enhance T cell activation and efficacy, then antitumor activity is improved, but T cell exhaustion and toxicities increase
Solution Approach 1:
The patent applies parameter changes by introducing specific point mutations in the CD28 and 41BB cytoplasmic domains (e.g., Y222F in CD28, Y216F in 41BB) that modify phosphorylation states and signaling intensity. These parameter changes in the signaling pathways enhance NF-κB activation while reducing excessive T cell activation and exhaustion, thereby improving both antitumor activity and T cell persistence simultaneously
Solution Approach 2:
The patent creates composite signaling structures by combining mutated CD28 and/or 41BB domains with the CAR structure, forming hybrid costimulatory regions that integrate beneficial signaling properties. The composite costimulatory domains (e.g., CD28-41BB hybrids) provide balanced signaling that improves efficacy while reducing toxicity and exhaustion
2Productivity
If signaling intensity is increased to improve CAR-T cell function, then proliferation and cytotoxicity are enhanced, but NFκB overactivation leads to exhaustion
Solution Approach 1:
The patent modifies signaling parameters by introducing mutations that adjust phosphorylation dynamics in the costimulatory domains. Specific mutations (e.g., Y222F in CD28) reduce excessive NF-κB activation while maintaining sufficient signaling for proliferation, thereby extending CAR-T cell persistence without sacrificing productivity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The enhanced co-stimulation strategies lead to improved CAR-T cell persistence, proliferation, and antitumor efficacy, reducing exhaustion and toxicities, thereby increasing the effectiveness of CAR T cell therapies.
Implementation Method 1
the level of nuclear factor kappaB (NFκB) signaling supported by chimeric antigen receptors (CARs) correlates with their function. Therefore, disclosed herein are chimeric antigen receptors (CARs) with enhanced NFκB signaling
Implementation Method 2
the co-stimulatory protein 41BB (CD137) activates NFκB signaling in T-cells through tumor necrosis factor receptor-associated factor (TRAF). Therefore, the disclosed CARs can enhance 41BB activation by TRAF proteins
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 CD28 that enhances CAR-T cell function, a mutated form of a cytoplasmic domain of 41BB that enhances nuclear factor kappaB (NFκB) signaling, or a combination thereof. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Also disclosed are immune effector cells co-expressing a CAR and one or more TRAF proteins. 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.