DRibbles for Tumor-Reactive T Cell Expansion
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Solution Overview
Problem
Current cancer immunotherapy methods fail to induce a large expansion and persistence of tumor-reactive cytolytic T cells, and are hindered by the inability to effectively cross-present short-lived tumor antigens due to rapid degradation by proteasomes, limiting their effectiveness in mediating tumor regression.
Innovation Solution
The use of defective ribosomal products (DRiPs) accumulated and secreted as DRibbles through proteasome inhibition and autophagy induction, which are then presented by antigen-presenting cells to stimulate a robust immune response, including the administration of DRibbles or DRibble-loaded dendritic cells to enhance tumor-specific T cell expansion and persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If proteasome inhibitors are used to accumulate DRiPs, then immunogenicity is improved, but protein degradation is inhibited causing cellular accumulation of defective ribosomal products
Solution Approach 1:
The patent converts the harmful accumulation of defective ribosomal products (DRiPs) caused by proteasome inhibition into a beneficial immunogenic stimulus. By blocking proteasome-mediated degradation, the invention causes DRiPs to accumulate and form blebs that are secreted extracellularly, creating a novel vaccine approach where the side effect becomes the therapeutic mechanism
Solution Approach 2:
The patent introduces autophagy as an intermediary mechanism that bridges proteasome inhibition and DRibble secretion. Autophagy serves as the cellular pathway that processes accumulated DRiPs and facilitates their extrusion as secreted blebs, enabling the conversion of intracellular accumulation into extracellular immunogenic particles
2Productivity
If proteasome function is inhibited to produce DRibbles, then tumor-reactive T cell expansion is improved, but normal protein degradation pathways are disrupted
Solution Approach 1:
The patent applies local quality by making the proteasome inhibition effect localized to specific cellular compartments and contexts. Rather than globally disrupting all protein degradation, the approach creates localized accumulation of DRiPs in specific subcellular regions that then form and secreted as discrete blebs, confining the degradation disruption to where it is needed for immunogenicity
Solution Approach 2:
The patent changes the parameter of proteasome activity from fully functional to partially inhibited, creating an optimal window where enough degradation function remains to maintain cellular health while sufficient inhibition occurs to generate immunogenic DRibbles. This parameter optimization resolves the contradiction between inhibition efficacy and cellular function
3Reliability
If autophagy is induced to secrete DRibbles, then cross-presentation to CTL is improved, but cellular homeostasis is disrupted
Solution Approach 1:
The patent employs partial action by inducing autophagy to a controlled extent that is sufficient to promote DRibble secretion and cross-presentation but does not completely override cellular homeostatic mechanisms. This partial induction allows the system to benefit from enhanced antigen presentation while maintaining adequate cellular function and stability
Data Source
AI summary
Methods are disclosed for producing defective ribosomal products (DRiPs) in blebs (DRibbles) by contacting cells with a proteasome inhibitor, and in some examples also an autophagy inducer, thereby producing treated cells. DRibbles can be used to load antigen presenting cells (APCs), thereby allowing the APCs to present the DRiPs and antigenic fragments thereof. Immunogenic compositions that include treated cells, isolated DRibbles, or DRibble-loaded APCs are also disclosed. Methods are also provided for using treated cells, isolated DRibbles, or DRibble-loaded APCs to stimulate an immune response, for example in a subject. For example, DRibbles obtained from a tumor cell can be used to stimulate an immune response against the same type of tumor cells in the subject. In another example, DRibbles obtained from a pathogen-infected cell or cell engineered to express one or more antigens of a pathogen can be used to stimulate an immune response against the pathogen in the subject.