CD4+ICOS+PD-1+CXCR5+ T Cell Enrichment for Tumor Reactivity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current immunotherapy and adoptive T-cell transfer methods for cancer treatment have variable response rates and low frequencies of tumor-reactive T cells, necessitating improved methods to enhance efficacy and characterize CD4 T cells involved in anti-tumor responses.
Innovation Solution
The use of CD4+ICOS+PD-1+CXCR5+ T cells, enriched through specific culture conditions and expanded with cytokines like IL-2, IL-15, and IL-21, and administered with checkpoint inhibitors, to treat tumors, along with methods to assess treatment efficacy by measuring CD4+ICOS+PD-1+CXCR5+ T cell presence and response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive T-cell transfer is used to treat cancer, then therapeutic response is achieved, but the frequency of tumor-reactive T cells remains low
Solution Approach 1:
The patent segments the T-cell population by identifying and isolating a specific subset (CD4+ ICOS+ PD-1+ CXCR5+) that has demonstrated tumor-reactive activity. This segmentation allows for enrichment of the therapeutically relevant cell population while excluding non-responsive cells, thereby increasing the frequency of tumor-reactive T cells in the adoptive transfer product.
Solution Approach 2:
The patent employs parameter changes by using specific surface marker expression profiles (ICOS+, PD-1+, CXCR5+) to identify and isolate the desired T-cell subset. These phenotypic parameters serve as selection criteria to enrich for tumor-reactive cells, transforming a heterogeneous T-cell population into a concentrated product of responsive cells.
2Reliability
If conventional ACT methods are used, then treatment is administered, but response rates vary significantly
Solution Approach 1:
The patent incorporates feedback mechanisms by using checkpoint inhibitor treatment as a selection process. Patients who respond to checkpoint inhibition (demonstrating functional anti-tumor T-cell activity) are then selected for adoptive transfer, creating a feedback loop that identifies and amplifies the most effective cellular components for treatment.
Solution Approach 2:
The patent applies preliminary action by administering checkpoint inhibitors before adoptive transfer to pre-select and activate tumor-reactive T cells in vivo. This preliminary treatment primes the immune system and enriches for responsive cells that will be subsequently expanded and transferred, improving the likelihood of treatment success.
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
Enhances the immune response against tumors by increasing the frequency of tumor-reactive CD4+ICOS+PD-1+CXCR5+ T cells, improving treatment efficacy and allowing for personalized treatment approaches based on patient response.
Implementation Method 1
expanding tumor-reactive T cells ex vivo using methods known to those of skill in the art, such as, but not limited to, stimulating the T cells with interleukin (IL)-2, IL-15, and/or IL-21
Data Source
AI summary
Methods are disclosed for treating a subject with a tumor. These methods include administering to the subject a therapeutically effective amount of CD4+ICOS+PD-1+CXCR5+ T cells. Methods also are disclosed for isolating a nucleic acid encoding a T cell receptor (TCR) that specifically binds a tumor cell antigen. These methods include isolating CD4+ICOS+PD-1+CXCR5+ T cells from a sample from a subject with a tumor expressing the tumor cell antigen, and cloning a nucleic acid molecule encoding a TCR from the CD4+ICOS+PD-1+CXCR5+ T cells. In addition, methods are disclosed for expanding CD4+ICOS+PD-1+CXCR5+ T cells. In additional embodiments, methods are disclosed for determining if a subject with a tumor will respond to a checkpoint inhibitor. The methods include detecting the presence of CD4+ICOS+PD-1+CXCR5+ T cells in a biological sample from a subject. Compositions of use in these methods are also disclosed.