Compositions and methods for immunotherapy
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Solution Overview
Problem
Existing immunotherapy approaches using CRISPR/Cas systems for T cells produce T cells with less than desired activity against targeted antigens due to undesired reactivity from endogenous TRBC and TRAC gene products, leading to tonic CAR signaling and T-cell exhaustion.
Innovation Solution
Utilizing guide RNAs and RNA-guided DNA binding agents to target and knockout or reduce expression of the TRBC and/or TRAC genes, enabling precise editing of T cells to lack endogenous T-cell receptors and introduce exogenous receptors like CARs, enhancing antigen-specific activity and reducing autoimmunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CRISPR-Cas9 systems are used to engineer T cells with chimeric antigen receptors, then tumor rejection capability is enhanced, but undesired reactivity from endogenous TRBC and TRAC gene expression reduces T cell activity
Solution Approach 1:
The patent applies the 'Taking out' principle by using CRISPR-Cas9 to specifically remove or knock out the endogenous TRAC and TRBC genes from T cells. This extraction of harmful genetic elements eliminates the source of undesired reactivity while preserving the desired tumor-targeting capabilities of the engineered chimeric antigen receptors.
Solution Approach 2:
The patent segments the T cell receptor complex into its component genes (TRAC and TRBC) and individually targets them for knockout. By dividing the problem into specific genetic targets, the patent can precisely eliminate harmful endogenous expression without affecting other critical T cell functions.
2Manufacturing precision
If endogenous TRBC and TRAC genes are knocked out to reduce undesired reactivity, then T cell selectivity is improved, but T cell activity may be reduced without proper compensation
Solution Approach 1:
The patent applies 'Local quality' by introducing modified or mutant T-cell receptor genes specifically at the TRAC and/or TRBC loci. This localized genetic modification ensures that the knockout of endogenous genes is compensated by the expression of engineered receptors with enhanced specificity and activity, maintaining local functional quality while improving overall selectivity.
Solution Approach 2:
The patent changes the genetic parameters by introducing modified or mutant versions of TRAC and/or TRBC genes with altered sequences that encode T-cell receptors with improved properties. These parameter changes in the genetic code result in T cells with enhanced selectivity and activity profiles compared to wild-type receptors.
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 method achieves enhanced antigen-specific activity and reduced autoimmunity in engineered T cells by selectively knocking out TRBC and/or TRAC genes, allowing for greater expression and selectivity of exogenous T-cell receptors, such as CARs, thereby improving immunotherapy efficacy.
Implementation Method 1
a guide RNA with an RNA-guided DNA binding agent such as the CRISPR/Cas system to substantially reduce or knockout expression of the TRBC and/or TRAC genes
Implementation Method 2
The introduction of site-specific single strand breaks (SSBs) or double strand breaks (DSBs) allows for target sequence alteration through, for example, non-homologous end-joining (NHEJ) or homology-directed repair (HDR)
Data Source
AI summary
Compositions and methods for editing, e.g., altering a DNA sequence, within the TRBC1, TRBC2 and/or TRAC genes are provided. Compositions and methods for immunotherapy are provided, for example.