Nucleated Cell Constriction Loading for Mutant Ras T Cell Activation
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Solution Overview
Problem
Current therapies for K-Ras mutant cancers, including immunotherapies, have failed to induce effective immune responses against mutated Ras antigens, making K-Ras a 'undruggable' target despite its prevalence in various human cancers.
Innovation Solution
Administering nucleated cells, such as PBMCs, that are modified to intracellularly incorporate mutated Ras antigens, using a cell-deforming constriction process to facilitate antigen delivery, optionally with adjuvants like CpG oligodeoxynucleotide, to stimulate a robust immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapy methods are used to target mutated Ras antigens, then the treatment approach can be administered, but the immune response induced is insufficient to effectively target and destroy cancer cells
Solution Approach 1:
The patent applies preliminary action by pre-loading dendritic cells with mutated Ras antigens ex vivo before administering them to patients. This allows the dendritic cells to be primed with the specific antigen in a controlled laboratory setting, ensuring they can effectively present the antigen to T cells upon administration, thereby overcoming the insufficiency of conventional immunotherapy methods.
Solution Approach 2:
The patent uses dendritic cells as an intermediary between the mutated Ras antigen and the T cell response. The dendritic cells act as professional antigen-presenting cells that bridge the gap between the tumor antigen and the immune system, facilitating robust T cell activation and response that cannot be achieved by direct antigen administration alone.
2Adaptability or versatility
If K-Ras is targeted as a therapeutic focus, then treatment development can proceed, but the target has been considered undruggable despite its importance in cancer malignancy
Solution Approach 1:
The patent replaces direct pharmacological targeting of K-Ras (mechanical/chemical approach) with an immunological approach using dendritic cell vaccination. Instead of attempting to directly inhibit the K-Ras protein with drugs, the invention uses the immune system's natural mechanisms to recognize and attack cancer cells expressing mutated Ras, thereby overcoming the 'undruggable' nature of the target.
Solution Approach 2:
The patent introduces the immune system as an intermediary between the K-Ras mutation and cancer cell destruction. Rather than directly targeting the biochemical function of K-Ras, the invention uses dendritic cells and T cells as mediators to recognize tumor-associated antigens and mount an immune response, bypassing the need for direct K-Ras inhibition.
3Ease of operation
If current active immunotherapy protocols are used, then vaccination strategies can be implemented, but they have failed to induce effective endogenous T cell responses against mutated Ras
Solution Approach 1:
The patent applies preliminary action by performing ex vivo loading of dendritic cells with mutated Ras antigens before in vivo administration. This preliminary preparation step allows optimization of antigen presentation capability in a controlled environment, ensuring that the dendritic cells are properly primed to induce effective T cell responses when administered to patients, thereby overcoming the failures of previous vaccination strategies.
Solution Approach 2:
The patent uses dendritic cells as a specialized intermediary to bridge the vaccination strategy and T cell response induction. These professional antigen-presenting cells are uniquely equipped to process and present tumor antigens to T cells, making them more effective than generic vaccination approaches and enabling reliable T cell response induction against mutated Ras.
Data Source
AI summary
The present application provides nucleated cells comprising a mutated Ras antigen (such as a mutated K-Ras antigen), methods of manufacturing such nucleated cells comprising the mutated Ras antigen, and methods of using such modified nucleated cells (e.g., immune cells) for stimulating an immune response, treating, and/or vaccinating an individual with a cancer associated with Ras mutation.