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Elucidating the functional limitations of cDC1 in Glioblastoma to inform immunotherapeutic strategies.

Award Number: F31CA298582
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Elucidating the functional limitations of cDC1 in Glioblastoma to inform immunotherapeutic strategies. - PROJECT SUMMARY/ABSTRACT With a 5-year survival rate of merely 5%, glioblastoma (GBM) is the most common and aggressive primary central nervous system malignancy. Current treatments are both debilitating and ultimately ineffective, inevitably resulting in tumor recurrence due to diffusely spread cells that are treatment-resistant. Although immune cells can recognize and attack these treatment-resistant tumor cells, the GBM tumor microenvironment (TME) is severely immunosuppressive. Many subsets of antigen presenting cells (APCs) that educate, or “prime,” T cells are present within the GBM TME and exhibit signs of suppression and inactivation, yet there is a major gap in knowledge regarding the functional limitations of these APCs and how those limitations can be overcome to enhance immune surveillance in a CNS tumor setting. Specifically, a subset of APCs known as conventional type 1 dendritic cells (cDC1) are widely implicated in the initiation of antitumor responses, generally attributed to their distinctive capacity for cross-presentation and priming of cytotoxic CD8+ T cells. However, our preliminary data indicates that cDC1 are immature and poorly poised for T cell priming in the context of GBM—presenting a therapeutic opportunity for immunotherapies that can activate cDC1, such as CD40 and Toll-like receptor (TLR) agonists. Indeed, my preliminary studies demonstrate that concurrent CD40 and TLR agonism improves the survival of mice with established orthotopic GBM tumors through T cell-dependent tumor control when combined with immune checkpoint inhibitors even eradicating tumors in many of the treated mice. Multiple subsets of cells capable of antigen presentation express the receptors for these agonists, and it remains unknown how dual CD40 and TLR3 agonism alters their capacity to promote an effective anti-GBM T cell response. I hypothesize that the robust and durable tumor control initiated by dual CD40 and TLR3 agonism depends on enhanced immunostimulatory capacity of cDC1 during T cell priming, and that targeting CD40 agonism to the TME will overcome limitations to clinical translation. In Aim 1, I will test this hypothesis by elucidating how dual CD40 and TLR agonism alters the capacity of APCs to initiate T cell-dependent tumor growth control. In addition to testing the impact of dual CD40 and TLR agonism on APC activation and migration to the draining lymph nodes, I will evaluate the contribution of costimulatory molecules induced by CD40 stimulation and test the necessity of cDC1 for initiating robust tumor control. To address potential clinical limitations, Aim 2 will leverage CD40 agonist antibodies conjugated to tumor-specific L19 antibodies to target CD40 agonists to the GBM TME. Specifically, I will identify a safe and effective dose of conjugated L19-CD40 antibodies and examine the impact of focused ultrasound-mediated blood-brain barrier opening on the distribution of these L19-CD40 conjugates throughout the GBM TME. This proposal will provide mechanistic and translational insight into APC-targeted immunotherapies that could be used to enhance current immunotherapeutic approaches and ultimately improve the outcomes of patients with GBM.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $39,692 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Research Manpower	000	1	5/13/2026	NEW	$39,692
														Subtotal = $39,692

Grand Total All Awards = $39,692

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Elucidating the functional limitations of cDC1 in Glioblastoma to inform immunotherapeutic strategies.

Award Number: F31CA298582

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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