Antigen-Specific T Cell Expansion Without Exogenous IL-2
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Solution Overview
Problem
Existing methods for expanding antigen-specific T cells for immune reconstitution in bone marrow transplant patients are inefficient, time-consuming, and risk contamination, often resulting in exhausted or anergic cells, and require exogenous IL-2, which can lead to unwanted side effects.
Innovation Solution
A rapid in vitro expansion process using a gas permeable culture surface and alternative cytokines like IL-4 and IL-7, without exogenous IL-2, to culture PBMCs with target antigen peptides for 14 days or less, minimizing contamination and energy/exhaustion, and optimizing the balance of desired T cells to residual cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If exogenous IL-2 is used for T cell expansion, then T cell proliferation is enhanced, but unwanted side effects and contamination risk increase
Solution Approach 1:
The patent removes exogenous IL-2 from the T cell expansion system and replaces it with exosomes derived from dendritic cells. This extraction of the harmful element (exogenous IL-2) while retaining the essential function (T cell proliferation) resolves the contradiction between productivity and harmful factors.
Solution Approach 2:
The patent introduces exosomes as an intermediary substance that mediates T cell expansion. These exosomes, carried by dendritic cells, serve as a natural mediator that promotes T cell proliferation without the harmful side effects of exogenous IL-2, thus resolving the technical contradiction.
2Manufacturing precision
If prolonged expansion culture is performed to ensure high purity, then target cell purity increases, but expansion time and cell exhaustion increase
Solution Approach 1:
The patent performs preliminary action by using pre-generated exosomes from dendritic cells to initiate and accelerate T cell expansion. This preliminary preparation allows the expansion process to reach high purity faster, reducing the time required while maintaining manufacturing precision.
Solution Approach 2:
The patent changes the temporal parameter of the expansion process by using exosome-mediated stimulation that accelerates cell division. This parameter change allows achieving high purity in a shorter time frame, resolving the contradiction between purity and time.
3Quantity of substance
If repeated antigen stimulation is performed to maintain expansion, then cell population increases, but cell exhaustion and anergy increase
Solution Approach 1:
The patent ensures continuity of useful action by using exosomes that provide sustained, controlled stimulation. This continuous but regulated stimulation maintains cell population growth while preventing the exhaustion and anergy that result from repeated or excessive antigen stimulation.
Solution Approach 2:
The patent implements feedback control through the natural regulatory mechanisms of exosome-mediated stimulation. The system automatically adjusts the stimulation intensity based on the cellular response, maintaining optimal expansion while preventing over-stimulation and subsequent exhaustion.
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 process achieves efficient, safe, and cost-effective production of functional antigen-specific T cells within 18 days, ensuring high viability and functionality, while complying with GMP standards, using a small donor sample, and reducing the risk of graft vs. host disease.
Implementation Method 1
a gas permeable culture surface
Data Source
AI summary
An in vitro expansion process for rapid expansion of antigen specific T cells, such as allogeneic antigen specific T cells comprising the steps culturing in a gas permeable vessel a population of PBMCs (such as allogeneic PBMCs) in the presence of antigen, for example a peptide or peptide mix relevant to a target antigen(s), in the presence of an exogenous cytokine characterized in that the expansion to provide the desired population of T cells is 14 days or less, or example 9, 10, 11 or 12 days, such as 10 days. The disclosure also extends to T cell populations generated by and obtained from the method and the use of same in therapy.