CIK Cell Manufacturing With Oncolytic Virus for Cold Storage Viability
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Solution Overview
Problem
Current cancer therapies, such as CAR T-cell therapy and CIK cell therapy, are limited by the need for autologous cells, high manufacturing costs, and complex storage and shipping requirements, which hinder their widespread use and effectiveness in treating a broad range of cancer types.
Innovation Solution
A method for producing stabilized populations of cytokine-induced killer (CIK) cells by culturing them under specific conditions, infecting them with an oncolytic virus, and maintaining them at 2°C to 8°C for extended periods, which enhances their viability and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cells are cultured and expanded ex-vivo for therapy, then the therapeutic efficacy is improved, but the manufacturing complexity and cost increase
Solution Approach 1:
The patent modifies culture parameters including cytokine concentrations (IL-2, IFN-γ), pH levels (using bicarbonate-buffered media), and oxygen tension (culturing at reduced oxygen levels) to optimize CIK cell expansion and activation while simplifying the manufacturing process. These parameter changes enable robust cell production without requiring overly complex manufacturing protocols.
2Adaptability or versatility
If immune cells are stored and shipped to distant locations, then treatment accessibility is improved, but cell viability decreases
Solution Approach 1:
The patent employs parameter changes during storage and transport, specifically maintaining cells at controlled temperatures (2-8°C or room temperature in some embodiments), adjusting pH buffering capacity, and optimizing osmolarity. These modifications enable cells to maintain high viability during extended storage and shipping periods, making distant treatment locations accessible to patients.
Solution Approach 2:
The patent performs preliminary activation and expansion of CIK cells before storage and shipping. By pre-activating cells with cytokines and selecting for desired phenotypes (CD3+CD56+ cells) before transport, the cells are in a more stable, transport-resistant state that maintains viability during shipping to distant treatment centers.
3Reliability
If autologous cells are used for therapy, then patient-specific efficacy is improved, but manufacturing time and cost increase
Solution Approach 1:
The patent performs preliminary expansion and activation of CIK cells from patient-derived PBMCs before final formulation and infusion. By pre-expanding cells to high numbers and pre-activating them with cytokines, the actual treatment can be administered more quickly without sacrificing patient-specific efficacy. The preliminary actions are performed in advance to reduce on-site manufacturing time.
4Quantity of substance
If CIK cells are expanded with high cytokine concentrations, then cell proliferation is improved, but cell activation and phenotype stability worsen
Solution Approach 1:
The patent uses periodic addition of cytokines (IL-2, IFN-γ) during culture rather than continuous high concentrations. Cytokines are added at specific intervals and in controlled amounts, allowing cells to proliferate while preventing over-activation that would lead to phenotype instability. This periodic dosing strategy maintains CD3+CD56+ phenotype stability while achieving sufficient cell expansion.
Solution Approach 2:
The patent dynamically adjusts cytokine concentrations and culture conditions during expansion. By changing parameters such as cytokine dosage, pH, and oxygen levels at different culture stages, the system optimizes for proliferation early on while maintaining phenotype stability during later stages, resolving the contradiction between cell quantity and composition stability.
Data Source
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AI summary
Methods of infection, hold times and storage temperatures are provided to extend the viability and stabilize the phenotype of the cytolytic cells as a monotherapy and cytolytic cells containing an oncolytic virus capable of cell cycle arrest. Pre-infection of effector cells prior to storage at 4°C or room temperature resulted in sustained viability of expanded immune cells and a higher percentage of CD3+/CD56+ T cells including a higher percentage of those CD3+/CD56+ T cells expressing the NKG2D receptor. In some embodiments, viral infection of immune cells increases the expression of the NKG2C, D and E receptors and influence the migration, binding and cytolytic activity towards tumor cells representing synergy between the immune cell and oncolytic virus in attacking and lysing tumor cells.