Immunoresponsive Cells with Protease-Regulated IL-18
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Solution Overview
Problem
Current strategies for engineering immunoresponsive cells to express pro-inflammatory cytokines like IL-18 for anti-tumor activity face challenges in safety and efficacy, particularly due to unregulated expression leading to toxicity and the need for cumbersome dual transduction procedures.
Innovation Solution
Development of immunoresponsive cells expressing a modified pro-cytokine of the IL-1 superfamily with a cleavage site recognized by a protease other than caspase-1, such as granzyme B, to regulate the activity of IL-18, IL-36α, and IL-36γ, allowing for controlled anti-tumor T cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunoresponsive cells are engineered to constitutively express mature IL-18 to enhance anti-tumor activity, then anti-tumor efficacy is improved, but toxicity to non-cancerous tissues increases
Solution Approach 1:
The patent applies preliminary action by expressing a modified pro-cytokine precursor form in the immunoresponsive cells rather than the mature active form. The pro-cytokine contains a proteolytic cleavage site that is pre-prepared for future activation, but remains inactive until triggered by specific proteases in the tumor microenvironment. This allows the cell to carry the anti-tumor capability without immediately executing it, thereby avoiding constitutive toxicity while maintaining the potential for enhanced anti-tumor activity when needed.
Solution Approach 2:
The patent changes the parameter of cytokine maturation state from mature/active to pro-precursor/inactive form. By modifying the cytokine expression parameter to produce an inactive pro-form that requires proteolytic cleavage for activation, the system transforms the harmful constitutive activity into a controlled, condition-dependent activity. This parameter change allows the cytokine to remain biologically inactive in normal tissues while being activatable in the tumor microenvironment where proteases are present.
2Object-affected harmful factors
If a dual transduction procedure is used to achieve regulated IL-18 expression, then safety is improved, but device complexity increases
Solution Approach 1:
The patent merges the functions of multiple transduction steps into a single transduction event. Instead of requiring separate viral vectors or transduction procedures to deliver both the CAR/TCR and the regulated cytokine expression components, the invention combines these into one integrated genetic modification. The single transduction introduces a modified pro-cytokine expression construct that inherently contains the regulation mechanism through its proteolytic cleavage site, eliminating the need for complex multi-step transduction while maintaining safety through regulated activation.
3Object-affected harmful factors
If native IL-18 is expressed without a conventional signal sequence to avoid toxicity, then safety is improved, but the cytokine cannot be properly secreted or activated
Solution Approach 1:
The patent introduces an intermediary proteolytic cleavage site as a mediator between the pro-cytokine precursor form and the mature active cytokine. This cleavage site acts as a controlled activation mechanism that is recognized by specific proteases in the tumor microenvironment. The intermediary cleavage site enables the transition from inactive pro-form to active mature form only under specific conditions, allowing proper secretion and activation without constitutive toxicity. The proteolytic cleavage serves as the intermediary step that bridges the gap between safety (inactive form) and functionality (active form).
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enhances T cell responses and anti-tumor activity while minimizing toxicity to non-cancerous tissues by spatiotemporally restricting cytokine activity, potentially overcoming the limitations of existing methods.
Implementation Method 1
Some IL-1 superfamily members are synthesized in precursor forms that require proteolytic cleavage in order to demonstrate biological activity. Examples of cytokines with anti-tumour activity that are regulated in this fashion include IL-1β, IL-18 and IL-36 α-γ.
Data Source
AI summary
Provided herein are immunoresponsive cells having IL-1 superfamily activities with spatiotemporal restriction. The immunoresponsive cells can further express a protease for regulating the IL-1 superfamily activities, and a chimeric antigen receptor (CAR) or a parallel CAR. Also provided herein are methods of preparing the immunoresponsive cells and methods of directing T cell mediated immune response using the immunoresponsive cells.