Membrane-Bound IL-15 and IL-21 for Persistent T Cell Therapy
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Solution Overview
Problem
Existing adoptive cell therapy methods face challenges with the in vivo persistence, survival, and anti-tumor activity of transferred T cells, particularly due to dose-limiting toxicity and the need for repeated administration, and there is a need for improved methods and products for producing cells for adoptive cell therapy and treating and/or preventing cancer.
Innovation Solution
The development of nucleic acids and polypeptides that encode interleukin-21 and IL-15 by a host cell, each bound to the cell membrane by a cell membrane anchor moiety, which comprise a nucleic acid sequence that provides high expression levels of both membrane-bound IL-15 and IL-21, enhancing anti-tumor efficacy and reducing systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble IL-15 is administered to enhance T cell proliferation and survival, then anti-tumor efficacy is improved, but dose-limiting toxicity and undesirable excessive cell growth occur
Solution Approach 1:
The invention extracts the harmful soluble form of IL-15 and removes it from the system by using a membrane-bound version. The IL-15 is tethered to the cell membrane via a transmembrane domain, preventing it from detaching and causing systemic toxicity while retaining its local immunostimulatory effects on T cells.
Solution Approach 2:
The invention introduces a transmembrane domain as an intermediary element that anchors IL-15 to the cell membrane. This intermediary structure allows IL-15 to exert its biological effects locally without becoming a free-floating soluble cytokine that causes systemic toxicity and uncontrolled cell growth.
2Duration of action of moving object
If high doses of cytokines are administered to improve T cell persistence and survival, then anti-tumor activity is enhanced, but the need for repeated administration and dose-limiting toxicity increase
Solution Approach 1:
The invention enables T cells to produce and display IL-15 on their own surface through the membrane-bound construct. This self-service approach allows T cells to autonomously maintain their own persistence and survival without requiring external administration of cytokines, eliminating the need for repeated dosing.
Solution Approach 2:
The membrane-bound IL-15 construct provides continuous local stimulation to T cells as long as the expressing cells are present in the tumor microenvironment. This continuous action maintains T cell persistence without interruption from repeated administrations, as the cytokine is continuously displayed on the cell surface.
3Object-generated harmful factors
If membrane-bound IL-15 is used to reduce systemic toxicity, then harmful effects are minimized, but expression levels and anti-tumor efficacy may be limited
Solution Approach 1:
The invention optimizes the linker region between IL-15 and the transmembrane domain to achieve the right balance. By adjusting linker length and composition, the construct achieves sufficient IL-15 expression levels for effective T cell stimulation while maintaining membrane anchoring that prevents systemic toxicity.
Data Source
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AI summary
Disclosed are nucleic acids and polypeptides which provide the co-expression of interleukin (IL)-21 and IL-15 by a host cell, each interleukin being bound to the cell membrane by a cell membrane anchor moiety. Also disclosed are related recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and methods of treating or preventing cancer.