Cbl-b Deficient CD8+ T Cells for Anti-Tumor Immunity
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Solution Overview
Problem
Current approaches to inducing effective anti-tumor immune responses are hindered by the inability of CD8+ T cells to respond to tumors lacking costimulatory signals, often resulting in tolerance or anergy, due to mechanisms such as TGF-β inhibition and lack of effective recognition.
Innovation Solution
Reducing or eliminating Cbl-b activity in CD8+ T cells allows for activation and proliferation without co-receptor costimulation, enabling these cells to respond to tumors independently of CD28 signaling, using methods like inhibitory RNA delivery to target Cbl-b.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD8+ T cells are used to recognize tumor antigens, then tumor-specific immune response is initiated, but the T cells become anergic or tolerant when costimulatory signals are absent
Solution Approach 1:
The patent extracts and eliminates the harmful element Cbl-b from the T cell system. By specifically targeting and reducing Cbl-b expression in CD8+ T cells through RNA interference, the invention removes the molecular barrier that causes T cell anergy in the absence of costimulatory signals, thereby enabling reliable tumor-specific immune responses against tumors lacking B7 costimulatory ligands
Solution Approach 2:
The patent changes the molecular parameter of Cbl-b expression levels in CD8+ T cells. By reducing Cbl-b protein expression through inhibitory RNA delivery, the invention alters the signaling properties of T cells, transforming them from a state of anergy to a state capable of effective activation and proliferation in response to tumor antigens without requiring costimulatory signals
2Adaptability or versatility
If tumors do not express costimulatory ligands, then tumor immunogenicity is reduced, but T cell activation and proliferation are inhibited
Solution Approach 1:
Instead of attempting to force tumors to express costimulatory ligands (the conventional approach), the patent inverts the strategy by modifying the T cells themselves. By eliminating Cbl-b in T cells, the invention enables T cells to function effectively without costimulatory signals from tumors, thereby overcoming the limitation of low tumor immunogenicity and restoring T cell proliferation capability
Solution Approach 2:
The patent changes the signaling parameter of T cells by reducing Cbl-b expression. This molecular parameter change enables T cells to bypass the requirement for costimulatory signals, allowing them to proliferate and mount effective responses against tumors that do not express costimulatory ligands, thus resolving the contradiction between tumor immunogenicity and T cell productivity
3Ease of operation
If Cbl-b activity is reduced in CD8+ T cells, then activation without costimulation is enabled, but the mechanism of action becomes more complex
Solution Approach 1:
The patent introduces inhibitory RNA as an intermediary molecule to achieve Cbl-b reduction. This RNA mediator specifically targets Cbl-b mRNA for degradation, providing a controlled and specific method to reduce Cbl-b activity without directly manipulating the complex T cell activation machinery, thereby simplifying the overall approach while achieving the desired functional outcome
Solution Approach 2:
The patent replaces the complex mechanical signaling requirements (costimulatory signal pathways) with a molecular intervention approach. By using RNA interference to eliminate Cbl-b, the invention substitutes the need for complex costimulatory signaling mechanisms with a simpler molecular depletion strategy, enabling T cell activation through antigen recognition alone
Data Source
AI summary
The invention provides an isolated, purified population of human cells comprising CD8+ T cells with reduced Cbl-b activity. The invention provides uses of such cells in methods for inducing or enhancing an anti-tumor immune response in a subject. These methods comprise: (a) providing a cell population, from a subject or from another source, which comprises CD8+ T cells, (b) reducing Cbl-b activity in the CD8+ T-cells, (c) administering the cells of step (b) to the subject. The invention provides methods for making CD8+ T cells that do not require stimulation through a co-receptor in order for the cell to become activated or proliferated in response to contact via its T cell receptor. Such methods are based upon reducing function of Cbl-b. The invention also provides methods for identifying agents which affect Cbl-b expression or activity.