Chimeric Hematopoietic Receptors for NK Cell Proliferation
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Solution Overview
Problem
Current NK cell-based immunotherapies for cancer rely on cytokines like IL-2 and IL-15, which enhance NK cell activity but also induce adverse effects such as capillary leak syndrome and expand regulatory T cells, limiting their efficacy and safety.
Innovation Solution
Genetic modification of NK cells to express chimeric polypeptides with hematopoietic growth factor receptors, such as c-MPL, IL2RB, IL21R, IL7R, IFNAR2, or IL12RB2, allowing for enhanced proliferation and cytotoxicity with reduced cytokine dependence, and administration of TPO or EPO agonists like eltrombopag to promote cell survival and tumor targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If cytokines like IL-2 and IL-15 are administered to enhance NK cell activity, then NK cell proliferation and cytotoxicity are improved, but adverse effects such as capillary leak syndrome and expansion of regulatory T cells occur
Solution Approach 1:
The patent extracts and removes the harmful effects (capillary leak syndrome and Treg expansion) while retaining the beneficial NK cell activation. This is achieved by replacing conventional cytokine administration with genetically modified NK cells that express cytokines autonomously, eliminating the need for exogenous cytokine therapy and its associated side effects.
Solution Approach 2:
The NK cells are genetically engineered to express cytokines (IL-2, IL-15, IL-21) and their receptors autonomously, enabling them to self-stimulate and self-regulate without external cytokine administration. This self-service capability allows the cells to maintain proliferation and cytotoxicity while avoiding the adverse effects of systemic cytokine therapy.
2Productivity
If high doses of IL-2 are administered to promote NK cell activation and proliferation, then NK cell cytotoxicity is enhanced, but regulatory T cells are expanded which suppress immune responses
Solution Approach 1:
The patent uses genetically modified NK cells as intermediaries that locally produce and respond to cytokines. These cells serve as self-contained units that can activate and proliferate without requiring high-dose systemic IL-2, thereby avoiding the unwanted expansion of suppressive Treg cells while maintaining effective NK cell cytotoxicity.
Solution Approach 2:
The cytokine production and response is localized to individual NK cells through genetic modification, rather than being systemic. This local quality allows each cell to autonomously regulate its activation state without affecting the broader immune environment in a way that would promote Treg expansion and immune suppression.
3Duration of action of stationary object
If exogenous cytokines are administered to improve NK cell persistence in vivo, then NK cell survival is enhanced, but cytokine-associated toxicities occur
Solution Approach 1:
The NK cells are engineered with autonomous cytokine expression capabilities, allowing them to sustain their own persistence and survival without requiring continuous exogenous cytokine administration. This self-service approach eliminates cytokine-associated toxicities while maintaining long-term in vivo persistence through endogenous cytokine production.
Data Source
AI summary
Modified natural killer (NK) or T cells expressing hematopoietic growth factor receptors are provided. In some aspects, the modified NK cells or T cells express a thrombopoietin receptor, an erythropoietin receptor, or a chimeric polypeptide including an extracellular domain of a thrombopoietin receptor, a transmembrane domain, and an intracellular domain including an interleukin-2 receptor beta intracellular signaling domain. Methods of treating a subject with cancer are also provided, including administering the modified NK cells or T cells to the subject in combination with a thrombopoietin receptor agonist or erythropoietin receptor agonist, and in some example, interleukin-2, particularly reduced or low-dose amounts of IL-2.