Phased CDK4/6 and Checkpoint Inhibitor Therapy for Immune Resistance
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Solution Overview
Problem
Current methods for predicting immune checkpoint inhibitor resistance in cancer are limited in their predictive power and are confounded by tumor composition, making it challenging to understand tumor immunity and resistance to immunotherapy.
Innovation Solution
Utilizing single-cell RNA-seq (scRNA-seq) and single-nuclei RNA-seq (sNuc-seq) to identify molecular signatures in malignant cells associated with immune evasion and resistance, and combining CDK4/6-inhibition with checkpoint inhibitors to modulate these signatures and enhance immunotherapy efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors are used to treat cancer, then immune response against cancer is enhanced and patient survival is prolonged, but immune checkpoint inhibitor resistance develops making treatment ineffective
Solution Approach 1:
The patent identifies and measures immune evasion gene signatures in malignant cells before initiating immunotherapy. By detecting these signatures upfront, the method enables preliminary stratification of patients who are likely to respond versus those who will develop resistance, allowing for pre-emptive combination therapy or alternative treatment strategies
Solution Approach 2:
The patent introduces CDK4/6 inhibitors as an intermediary agent that targets malignant cells directly to suppress immune evasion programs. This intermediary approach addresses the resistance mechanism by modifying the malignant cell's behavior rather than directly enhancing immune cell function, thereby overcoming the limitation of ICI monotherapy
2Quantity of substance
If bulk tumor sequencing methods are used to study tumor immunity, then overall tumor composition is analyzed, but the ability to dissect cancer-immune interplay and identify reliable response biomarkers is limited
Solution Approach 1:
The patent segments the tumor ecosystem into distinct cellular compartments by analyzing malignant cells separately from the bulk tumor. By focusing specifically on gene expression in malignant cells rather than averaging across all tumor cells, the method isolates the relevant immune evasion signals from confounding background noise
Solution Approach 2:
The patent applies local quality analysis by measuring specific immune evasion gene signatures in malignant cells with high precision. Rather than analyzing uniform bulk tumor properties, the method identifies localized molecular characteristics of cancer cells that directly determine immune response outcomes
3Measurement precision
If single-cell RNA-seq is used to map tumor ecosystem, then comprehensive cellular landscape is obtained, but the complexity of analyzing and applying these data for clinical prediction increases
Solution Approach 1:
The patent extracts the critical immune evasion gene signature from the comprehensive single-cell RNA-seq data set. By identifying and isolating the specific genes that drive immune evasion in malignant cells, the method distills complex high-dimensional data into a simplified clinical assay that maintains predictive power while reducing analytical complexity
Data Source
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AI summary
The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. The novel gene signatures predict overall survival in cancer and can be targeted therapeutically. Specifically, disclosed is a resistance program identified by a comprehensive single-cell profiling study in melanoma patients, which was validated in two large validation cohorts. Using a large-scale in silico prediction, CDK4/6 inhibitors were identified as a class of drugs that may reverse this resistance program. These predictions were validated in melanoma cell lines, patient-derived co-culture models, and melanoma in vivo models, which show that the combination of abemaciclib and immune checkpoint blockade (ICB) overcome intrinsic drug resistance. The present invention provides for detecting an immunotherapy resistance signature and modulating the signature with CDK4/6 inhibition. Also provided is a novel phased immunotherapy and CDK4/6 inhibitor combination therapy regimen.