Splicing Modulating Agents Induce Neoantigens for Immunotherapy
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Solution Overview
Problem
Current immunotherapy modalities for cancer treatment are limited in effectiveness, with only about 20% of patients experiencing long-term survival, and there is a need to expand the range of cancer types and patients who benefit from immunotherapy, as existing splicing modulators cannot specifically target aberrant splicing events to induce neoantigens that activate immune responses against tumor cells.
Innovation Solution
A method involving splicing modulating agents, such as nucleic acid sequences or oligonucleotides, that induce aberrant splicing events in target cells to produce neoantigens, activating immune responses by targeting specific nucleic acid sequences involved in splicing events, thereby enhancing immunotherapy's effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapy modalities are used, then immune response is activated, but only limited percentage of patients (around 20%) experience long-term survival
Solution Approach 1:
The invention targets specific local abnormalities in tumor cells - aberrant splicing events - rather than attempting to activate a general immune response. By inducing neoantigens through targeted splicing modulation of specific genes (e.g., TYR, hnRNPAB) in tumor cells, the therapy creates localized immunogenic changes that are specific to the tumor's splicing defects, thereby improving effectiveness while maintaining adaptability across different cancer types with similar splicing abnormalities.
Solution Approach 2:
The invention changes the molecular parameters of tumor cells by inducing aberrant splicing events that alter protein sequences and create neoantigens. Using splicing modulating agents (antisense oligonucleotides, small molecules) to change splicing patterns of specific genes transforms the immunological properties of tumor cells, making them more recognizable to the immune system and expanding the range of patients who benefit from immunotherapy.
2Manufacturing precision
If splicing modulating agents are used to induce aberrant splicing, then neoantigens are produced, but existing agents cannot specifically target aberrant splicing events
Solution Approach 1:
The invention segments the splicing modulation approach by targeting specific genes and splicing events individually rather than using broad-spectrum modulators. By designing splicing modulating agents that specifically target aberrant splicing in particular genes (e.g., TYR exon skipping, hnRNPAB intron retention), the invention achieves high specificity while making the therapy adaptable to different cancer types with different splicing abnormalities, thus resolving the contradiction between precision and availability.
Solution Approach 2:
The invention creates a universal platform for splicing modulation that can be applied across different cancer types and target different genes. The methodology of identifying aberrant splicing events and designing corresponding splicing modulating agents can be universally applied to any gene with detectable splicing abnormalities, making the approach both specific to individual targets and universally applicable across diverse cancers.
3Strength
If the immune system is activated against tumor cells, then anti-tumor response is enhanced, but tumor cells have developed ways to bypass immune checkpoints
Solution Approach 1:
The invention converts the tumor's attempt to evade immune detection into a benefit by exploiting the fact that tumors already have altered protein expression patterns through aberrant splicing. Instead of trying to overcome immune checkpoint suppression, the invention creates entirely new immunogenic targets (neoantigens) from the tumor's own splicing abnormalities, transforming the tumor's pathological changes into beneficial immunogenic features that activate strong anti-tumor responses.
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
The approach effectively induces the production of neoantigens in tumor cells, activating immune responses and potentially increasing the percentage of patients benefiting from immunotherapy, thereby improving treatment outcomes for a wider range of cancer types.
Implementation Method 1
A method involving splicing modulating agents, such as nucleic acid sequences or oligonucleotides, that induce aberrant splicing events in target cells to produce neoantigens
Data Source
AI summary
The invention relates to methods, compositions, and splicing modulating agents comprising nucleic acid sequences, specifically, antisense oligonucleotides and gene editing compounds. The splicing modulating agents of the invention are used in methods for producing neoantigens in subjects suffering from neoplastic disorders, by the induction of aberrant splicing events. The modulators of the invention are further used by the invention in enhancing immunotherapy.