Virus-Specific T-Cell Expansion Using IL-7 and IL-15 Stimulation
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Solution Overview
Problem
Current methods for activating tumor antigen-specific T-cells from cancer patients face challenges such as T-cell anergy, the need for large amounts of autologous antigen-presenting cells, and the difficulty in expanding exclusively antigen-specific CD4+ and CD8+ T-cells without activating non-specific bystander cells.
Innovation Solution
The development of virus-specific T-cells (VSTs) using antigen-presenting cells exposed to peptide libraries, stimulated with IL-7 and IL-15, and optionally with co-stimulatory cells, to generate therapeutic T-cells targeting viral antigens like EBV, CMV, adenovirus, and VZV, which can be used for treating virus-associated diseases and malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous dendritic cells are used as antigen-presenting cells for T-cell expansion, then antigen-specific T-cell activation is improved, but the quantity of available antigen-presenting cells is insufficient
Solution Approach 1:
The patent uses EBV-transformed B-lymphoblastoid cells (LCLs) as intermediary antigen-presenting cells that can be expanded in culture to provide sufficient numbers while maintaining antigen-presenting function. These LCLs serve as a mediator between the limited autologous dendritic cells and the need for large-scale T-cell expansion, allowing generation of therapeutic T-cell numbers without being constrained by the limited number of autologous DCs available from patient blood samples
2Productivity
If stimulation is too potent to expand antigen-specific T-cells, then T-cell proliferation is improved, but non-specific bystander cells are expanded diluting the antigen-specific T-cells
Solution Approach 1:
The patent applies local quality by using peptide libraries that present specific viral antigens (EBV, CMV, adenovirus, VZV) to T-cells, ensuring that only T-cells with specificity for these particular antigens receive the activation signals. This localized antigen presentation approach allows potent stimulation of the desired antigen-specific T-cell population while leaving bystander cells without corresponding antigen recognition unactivated and undiluted in the final product
3Reliability
If autologous LCLs are used as antigen-presenting cells, then antigen presentation capability is improved, but the establishment time is too long
Solution Approach 1:
The patent employs preliminary action by pre-expanding and characterizing a panel of allogeneic EBV-transformed LCL lines that express common HLA alleles before patient treatment. These pre-prepared LCLs can be immediately used as antigen-presenting cells for patient T-cell stimulation, eliminating the need to wait 6+ weeks for autologous LCL establishment while maintaining effective antigen presentation capability through peptide library pulsing
Data Source
AI summary
Embodiments of the disclosure concern methods and compositions for immunotherapy for diseases and malignancies associated with viruses other than HPV or with non-virus-associated diseases and malignancies, such as wherein the VST encodes a CAR specific for a non-viral cancer and the VST can be stimulated in vitro or in vivo using viruses, viral vaccines or oncolytic viruses. In specific embodiments, methods concern production of immune cells that target one or more antigens of HIV, EBV, CMV, adenovirus, vaccinia virus, and/or VZV, including methods with stimulation steps that employ IL-7 and IL-15, but not IL-2, IL-4, or both. Other specific embodiments utilize stimulations in the presence of certain cells, such as costimulatory cells and certain antigen presenting cells.