Tumor-Infiltrating Lymphocyte Expansion With 4-1BB Agonist
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Solution Overview
Problem
Existing T-cell-based therapies for treating tumors face challenges in efficiently expanding tumor-infiltrating lymphocytes (TILs) from limited tumor tissue samples, particularly due to the low frequency of activated CD8+ T cells and the time-consuming nature of current expansion protocols, which can lead to patient withdrawal and reduced therapeutic efficacy.
Innovation Solution
A method involving culturing tumor fragments with IL-2 and a 4-1BB agonist to enhance TIL expansion, followed by secondary expansion with anti-CD3 and irradiated PBMC feeder cells, to enrich for tumor-specific CD8+ T cells and improve their tumor reactivity and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If tumor fragments are cultured using conventional IL-2 only method, then TILs can be expanded, but the expansion rate is slow and treatment time is prolonged
Solution Approach 1:
The patent changes the chemical parameters of the culture medium by adding 4-1BB agonist and OX40 ligand to the existing IL-2 formulation. This parameter modification transforms the culture conditions to achieve faster TIL expansion rates while maintaining tumor specificity, directly resolving the contradiction between expansion speed and treatment time.
Solution Approach 2:
The patent creates a composite cytokine cocktail combining IL-2, 4-1BB agonist, and OX40 ligand. This composite formulation synergistically enhances TIL proliferation and survival compared to IL-2 alone, enabling accelerated expansion without compromising the functional quality of the infused cells.
2Reliability
If conventional TIL expansion method is used, then TILs can be produced, but tumor specificity is variable and efficacy is reduced
Solution Approach 1:
The patent modifies the culture medium composition by incorporating 4-1BB agonist and OX40 ligand, which specifically enhances the proliferation and survival of tumor-reactive T cells. This parameter change increases both the tumor specificity and expansion efficiency of TILs, resolving the contradiction between reliability and productivity.
3Ease of operation
If tumor fragment culture is performed to obtain TILs, then adoptive cell therapy can be provided, but the process is complex and requires multiple steps
Solution Approach 1:
The patent develops a universal culture medium formulation containing IL-2, 4-1BB agonist, and OX40 ligand that can be applied across different tumor types and patient samples. This multi-functional medium simplifies the culture process by providing a standardized protocol that enhances TIL expansion and tumor specificity simultaneously, reducing operational complexity while improving therapy accessibility.
Data Source
AI summary
Disclosed herein is a method for ex vivo expanding tumor-infiltrating lymphocytes for use in adoptive cell therapy (ACT). The method involves culturing tumor fragments from the subject in a culture medium containing IL-2 and a 41BB agonist in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor-reactivity and specificity. Also disclosed is a method for treating a tumor in a subject that involves treating the subject with nonmyeloablative lymphodepleting chemotherapy, and administering tumor-infiltrating lymphocytes expanded by the disclosed methods.