Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies
NCI - National Cancer Institute
About This Grant
ABSTRACT Adoptive cell therapies (ACT) with chimeric antigen receptors (CAR) hold promise to treat cancer, yet several challenges must be overcome to achieve this goal. Clinical evidence attributes treatment failure and resistance to the lack of functional T-cell persistence, antigen escape, and a suppressive tumor microenvironment replete with inhibitory but not co-stimulatory molecules. Investigating response and relapse mechanisms and effectively targeting tumor resistance mediators are urgently needed to improve current ACT. Our analysis of clinical CAR-T products revealed intrinsic PD-L1 (int-PD-L1) expression on the T cells and trogocytic acquisition of tumor-derived PD-L1 (extrinsic; ext-PD-L1). However, the functional role of PD-L1 on CAR-T remains unknown. We hypothesize that both int-PD-L1 and ext-PD-L1 limit CAR-T activity, and that rewiring PD-L1 and CD80 signaling with synthetic receptors will boost antitumor efficacy across ACT platforms. Aim 1 will determine how int-PD-L1 regulates CAR-T under optimal and suboptimal antigen stimulation; Aim 2 will define the impact of trogocytic ext-PD-L1 transfer on CAR-T function using in vitro assays and in vivo leukemia and melanoma models. To enhance T-cell persistence and function, we developed 80BB, a synthetic dual-costimulatory receptor fusing the CD80 ectodomain to the 4-1BB endodomain. 80BB delivers CD28 and 4- 1BB signals and functions as a CTLA-4 switch receptor, driving tumor control across diverse ACT platforms. Although CD80 interaction with CD28 and CTLA-4 underlies these benefits, CD80 also binds PD-L1, yet 80BB did not protect CAR-T from PD-L1/PD-1-mediated inhibition. We therefore engineered a novel 80BB-based platform that retains CD80 interaction with CD28 and CTLA-4 while redirecting PD-L1 engagement, to overcome PD-L1-mediated suppression. Aim 3 will determine mechanisms of action and therapeutic benefit of this novel synthetic costimulatory receptor in B-cell malignancy and solid-tumor models. Our multidisciplinary approach combines basic immunology with translational immunoengineering to overcome ACT barriers. We aim to advance next-generation engineered T-cells and expand the scope of ACT, improving the survival and quality of life of cancer patients.
Grant Summary
Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies is a NCI - National Cancer Institute grant providing up to $716K for university, nonprofit, healthcare org. Applications are due 2031-04-30 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $716K
2031-04-30
- 1Confirm your organization is eligible for Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies from NCI - National Cancer Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NCI - National Cancer Institute before the deadline.
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Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies: Frequently Asked Questions
Who is eligible for the Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies?
Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies is offered by NCI - National Cancer Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies provide?
Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies provides up to $716K per award from NCI - National Cancer Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies deadline?
Applications for Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies are due 2031-04-30 (open). Because deadlines can change, verify the date with the funder, NCI - National Cancer Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies?
To apply for Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCI - National Cancer Institute.