Chimeric Receptor Oligomerization for Controlled Immune Activation
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Solution Overview
Problem
Current cell therapies, such as CAR T cell therapy, face limitations in efficacy against solid tumors, uncontrollable immune activation leading to side effects, reliance on single signaling pathways, and inability to engineer innate immune cells, restricting their application to specific disease indications.
Innovation Solution
Development of a chimeric transmembrane receptor polypeptide that oligomerizes upon recognizing an extramembrane signal, activating multiple intramembrane signal pathways, allowing for controlled immune cell activation and expansion of therapeutic applications to include solid tumors, infectious diseases, and autoimmune conditions by utilizing both adaptive and innate immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR or TCR engineered T cells are used to treat solid tumors, then liquid cancers can be effectively treated, but efficacy against solid tumors remains very limited
Solution Approach 1:
The patent describes engineered immune cells equipped with multiple different CARs or TCRs that recognize different antigens, enabling a single cell product to treat multiple disease indications including both liquid cancers and solid tumors. This multi-functional approach allows the therapy to adapt to various tumor types and antigen targets.
Solution Approach 2:
The invention combines multiple signaling pathways (co-stimulatory, inhibitory, and cytokine signaling) within a single engineered immune cell construct. This composite signaling architecture integrates multiple functional elements to overcome the limitations of single-pathway approaches and enhance efficacy across different disease indications.
2Ease of operation
If engineered immune cells are activated autonomously by disease signals, then immune activation occurs without physician control, but this leads to cytokine release syndrome and severe side effects
Solution Approach 1:
The patent incorporates inducible signaling systems where an intermediary molecule or signal is required to activate the engineered immune cells. This intermediary control mechanism allows physicians to regulate immune activation timing and intensity, preventing uncontrolled autonomous activation and associated side effects like cytokine release syndrome.
Solution Approach 2:
The engineered immune cells feature dynamically controllable signaling pathways that can be activated or deactivated based on external inputs. This dynamic control enables flexible regulation of immune cell activity, allowing the system to respond appropriately to disease signals while preventing harmful overactivation.
3Device complexity
If only one specific signaling pathway is activated in engineered T cells, then the system is simpler to design, but multiple signaling pathways are needed for differential immune responses
Solution Approach 1:
The patent divides the signaling system into separate modular components including distinct co-stimulatory pathways, inhibitory pathways, and cytokine signaling modules. Each pathway can be independently designed and regulated, allowing complex immune response modulation while maintaining manageable design complexity through modular architecture.
4Ease of manufacture
If only adaptive immune cells (T cells) are used for therapy, then T cell engineering is well-established, but there are no tools to engineer innate immune cells for new disease areas
Solution Approach 1:
The patent describes universal engineering tools and signaling pathways that can be applied to both adaptive immune cells (T cells) and innate immune cells (macrophages, dendritic cells, neutrophils). This universal approach enables the expansion of cell therapy into new disease areas including infectious diseases, wound healing, aging, and autoimmunity by utilizing diverse immune cell types with the same engineering platform.
Data Source
AI summary
Provided herein are chimeric transmembrane receptor polypeptides configured to oligomerize upon recognition of an extramembrane signal. The receptors include an extramembrane domain, a transmembrane domain, and an intramembrane domain configured to induce activation of one or more intramembrane signal pathways upon oligomerization of the receptor. The provided receptors are particularly useful for engineered cell therapies. Also provided are systems and host cells including the disclosed receptors, and methods for using the disclosed materials.