Summary
This research project aims to engineer T cells to overcome inhibitory signals within the ovarian tumor microenvironment, thereby enhancing the efficacy of adoptive cell therapy against ovarian cancer while mitigating systemic toxicities.
Engineering T cells to overcome inhibitory receptor signals that limit the efficacy of adoptive cell therapy against ovarian cancer
US · IL
National Institutes of Health
grant
open
#nih-5K22CA266737-03
What they want
The project will investigate transcriptomic and functional changes in engineered T cells and the ovarian tumor microenvironment (TME) following immune checkpoint blockade. This will be conducted using preclinical mouse models (Aim 1) and a novel human slice culture system (Aim 2). The core objective is to utilize T cell engineering to knock down endogenous inhibitory receptor expression in tumor-specific T cells, with the goal of improving anti-tumor function without the immune-related toxicities observed with systemic combination checkpoint blockade. Findings are expected to inform the development of clinically-relevant T cell engineering strategies for various solid malignancies.
Deliverables
- Transcriptomic data on engineered T cells and ovarian TME after checkpoint blockade
- Functional data on engineered T cells and ovarian TME after checkpoint blockade
- Engineered tumor-specific T cells with knocked-down inhibitory receptor expression
- Data demonstrating improved anti-tumor function and reduced toxicity from engineered T cells
- Findings to inform development of clinically-relevant T cell engineering strategies
Technical requirements
- T cell engineering techniques (e.g., for knocking down inhibitory receptor expression)
- Preclinical mouse models (e.g., disseminated ID8 tumor model)
- Novel human slice culture system
- Transcriptomic analysis
- Functional assays (e.g., cytokine production measurement)
- Use of anti-PD-1, anti-Tim-3, and/or anti-Lag-3 checkpoint-blocking antibodies
- Targeting of antigen mesothelin (Msln)
