T Cell Expansion via BAFF-R Antagonism and Anti-CD3/28 Activation
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Solution Overview
Problem
Current methods for T-cell immunotherapy are hindered by the lack of rapid, cost-effective, and efficient methods for selecting and expanding clinical-grade T cell products that proliferate and persist in vivo, limiting their widespread utilization for treating malignancies and infectious diseases.
Innovation Solution
A method involving the reduction of BAFF-R receptor activity in T cells, followed by culturing them with anti-CD3 and anti-CD28 antibodies, and optionally providing a chimeric antigen receptor, to activate and expand T cells for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional T cell expansion methods (IL-2, antigen presenting cells, anti-CD3/CD28) are used, then T cells can be activated, but the methods are not rapid, cost-effective, or efficient for producing clinical-grade therapeutic T cell products
Solution Approach 1:
The patent modifies the culture conditions by reducing BAFF-R receptor activity through specific antibodies or genetic modification, which changes the signaling parameters of T cells to enhance their proliferation and persistence. This parameter change enables more efficient and cost-effective expansion compared to conventional methods.
Solution Approach 2:
The patent introduces BAFF-R antagonists (such as specific antibodies) as intermediary substances that mediate between the T cells and their environment. These antagonists block harmful BAFF-R signaling while allowing beneficial activation signals to proceed, thereby optimizing T cell expansion efficiency and cost-effectiveness.
2Reliability
If T cells are expanded using conventional methods, then some activation occurs, but the T cells do not proliferate and persist sufficiently in vivo for therapeutic use
Solution Approach 1:
The patent applies preliminary anti-action by pre-treating T cells with BAFF-R antagonists or genetic modification to block inhibitory BAFF-R signaling before activation. This preliminary intervention prevents harmful signals from interfering with subsequent proliferation and persistence, ensuring reliable therapeutic performance.
Solution Approach 2:
By changing the BAFF-R receptor activity parameter in T cells through antagonism or genetic modification, the patent creates a favorable signaling environment that simultaneously enhances both proliferation and persistence, resolving the contradiction between these two parameters.
3Productivity
If BAFF-R receptor activity is reduced in T cells, then activation and proliferation are enhanced, but additional steps and reagents are required
Solution Approach 1:
The patent uses BAFF-R antagonists (such as specific antibodies) as intermediary substances that can be easily incorporated into existing culture protocols. These intermediaries provide the necessary BAFF-R blocking function without requiring complex genetic modification procedures, thereby enhancing activation efficiency while minimizing protocol complexity.
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
This approach effectively activates and expands T cells, including cytotoxic CD8+ T cells, enhancing their therapeutic potential for treating cancer and infections by increasing proliferation and persistence in vivo.
Implementation Method 1
culturing the T cells for about 3 to about 14 days in the presence of an anti-CD3 antibody, or a CD3-binding fragment thereof, and an anti-CD28 antibody, or a CD28-binding fragment thereof, under conditions appropriate for activating cytotoxic T cells
Implementation Method 2
the method comprising reducing BAFF-R receiver activity in the T cells
Implementation Method 3
contacting T cells with a BAFF-R specific shRNA
Implementation Method 4
providing in the T cells a chimeric antigen receptor, to generate a population of activated T cells comprising the chimeric antigen receptor
Data Source
AI summary
The present disclosure relates to methods, cells, and compositions for preparing T cell populations and compositions for adoptive cell therapy. In particular, provided herein are methods for efficiently expanding and activating T cell populations for genetic engineering and adoptive T cell immunotherapies. Also provided are cells and compositions produced by the methods and methods of their use.