T Cell Expansion via mRNA Electroporation
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Solution Overview
Problem
Current methods for expanding T cells for adoptive immunotherapy are inefficient and result in varying T cell phenotypes and functions, limiting their effectiveness in vivo.
Innovation Solution
Electroporation of T cells with mRNA encoding a chimeric membrane protein comprising an antigen binding domain and a co-stimulatory intracellular domain, such as CD28 and 4-1BB, to enhance T cell expansion and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional methods (anti-CD3/CD28 beads, antibodies, or antigen presenting cells) are used to stimulate and expand T cells, then T cell expansion is achieved, but the T cells display varying phenotypes and in vitro/in vivo functions with limited effectiveness
Solution Approach 1:
The invention changes the stimulation parameters by using chimeric membrane proteins with specific intracellular domains (CD28 and 4-1BB) that provide optimized co-stimulatory signals. This parameter change in the stimulation mechanism produces T cells with consistent, enhanced phenotypes and improved in vivo effectiveness compared to conventional stimulation methods
Solution Approach 2:
The invention uses composite chimeric membrane proteins that combine extracellular antigen-binding domains with intracellular co-stimulatory domains (CD28 and 4-1BB). This composite structure provides both antigen recognition and optimized co-stimulation in a single molecule, resulting in T cells with improved and consistent functional phenotypes
2Productivity
If T cells are expanded using conventional clinical methods, then sufficient numbers of T cells can be obtained, but the expansion efficiency is insufficient and the T cell functions are compromised
Solution Approach 1:
The invention optimizes the co-stimulatory parameters by selecting specific intracellular domains (CD28 and 4-1BB) that enhance both expansion efficiency and effector function maintenance. This parameter optimization allows high-productivity expansion while preserving T cell functionality
Solution Approach 2:
The invention applies preliminary co-stimulatory signaling through chimeric membrane proteins before T cell expansion, pre-programming the T cells to maintain enhanced effector functions throughout the expansion process and upon adoptive transfer, rather than relying on post-expansion functional assessment
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 significant expansion of T cells (at least 10-fold) with improved phenotypes and functions, enhancing their efficacy in adoptive cell transfer therapies for cancer and autoimmune disease treatment.
Implementation Method 1
the chimeric membrane protein comprises an extracellular domain comprising an antigen binding domain comprising an antibody or fragment thereof to a molecule
Implementation Method 2
an intracellular domain comprising a fragment of an intracellular domain of CD28 and 4-1BB
Implementation Method 3
electroporating a population of cells comprising T cells with mRNA encoding a chimeric membrane protein
Data Source
AI summary
The present invention includes a method for expanding a population of electroporated T cells. The method includes electroporating a population of cells comprising T cells with mRNA encoding a chimeric membrane protein comprising an antigen binding domain to a molecule and an intracellular domain of a co-stimulatory molecule, wherein the cultured T cells expand at least 10 fold. The invention further includes an expanded population of T cells, compositions comprising the cells and methods of treatment.