Tumor Stromal Gene Profiling for PD-1 Immunotherapy Selection
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Solution Overview
Problem
Existing cancer immunotherapies, such as those targeting the PD-1/PD-L1 pathway, vary in effectiveness due to unique patient characteristics, necessitating targeted therapeutic strategies to identify patients likely to respond positively.
Innovation Solution
A method involving the identification of a low stromal signature score through measuring the expression of a panel of stroma-related genes in a tumor sample, followed by administration of anti-PD-1 or anti-PD-L1 antibodies, where the gene panel includes genes like CDH1, CDH2, MMP2, ITGA1, ITGA2, ITGA3, ITGA5, ITGA7, ITGA11, TGFB1, and TGFB1, to enhance treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-PD-1 or anti-PD-L1 antibody treatment is administered to all cancer patients, then some patients may benefit from immune checkpoint inhibition, but many patients will not respond due to heterogeneous tumor microenvironments and patient characteristics
Solution Approach 1:
The patent applies local quality by identifying specific subgroups of patients based on their tumor stromal characteristics. Instead of treating all patients uniformly, the method evaluates the stromal signature score of each patient's tumor and selectively administers anti-PD-1 or anti-PD-L1 antibody treatment only to those with low stromal signature scores, who are more likely to respond to the therapy.
Solution Approach 2:
The patent implements preliminary action by performing stromal signature score assessment before administering immunotherapy. This pre-treatment evaluation involves measuring the expression levels of multiple stromal-related genes to determine whether the patient's tumor microenvironment is favorable for checkpoint inhibitor response, thereby preventing ineffective treatment administration.
2Measurement precision
If a panel of multiple stromal-related genes is measured to determine stromal signature score, then patient stratification accuracy is improved, but test complexity and cost increase
Solution Approach 1:
The patent applies universality by developing a multi-gene panel assay that can simultaneously evaluate multiple stromal-related genes (such as collagen genes, fibroblast activation genes, and extracellular matrix remodeling genes) in a single test. This multi-functional approach allows comprehensive assessment of the tumor stromal microenvironment while streamlining the testing process compared to individual gene analyses.
Data Source
AI summary
The disclosure provides a method for treating a subject afflicted with a tumor comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof, wherein the subject is identified as having a low stromal gene signature score. In some aspects, the low stromal gene signature score is determined by measuring the expression of a panel of stromal genes in a tumor sample obtained from the subject, wherein the stromal gene panel comprises at least four genes selected from CDH1, CDH2, MMP1, MMP2, ITGA1, ITGA2, ITGA3, ITGA5, ITGA7, ITGA11, TGFB1, and TGFB1; at least four genes selected from TGFB1, TGFBR2, ACTA2, COL4A1, TAGLN, SH3PXD2A, TWIST1, ZEB1, and ZEB2; or MMP2 and MMP9.