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Targeting VLDLR to prevent both GvHD and leukemia relapse

Award Number: R01AI198352
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Targeting VLDLR to prevent both GvHD and leukemia relapse - ABSTRACT The therapeutic benefits of allogeneic hematopoietic cell transplantation (allo-HCT) are primarily derived from a graft-versus-leukemia (GvL) effect that is mediated by T cells which also cause graft-versus-host disease (GvHD). The disparate effects of GvHD and GvL are difficult to separate, and strategies directed against GvHD often adversely affect survival by reducing the beneficial GvL effect. As a result, overall mortality rates from leukemia relapse after allo-HCT have actually increased over the past 40 years. Thus, GvHD and leukemia relapse are the two most significant barriers to the success of allo-HCT. Therefore, finding a means to prevent both GvHD and leukemia relapse is a significant unmet need and major clinical goal. Although several groups, including ours, have proposed therapeutic strategies to reduce GvHD without abrogating GvL in animal models and human patients, no one has clearly identified the optimal therapeutic targets to selectively inhibit GvHD over GvL. More importantly, the mechanisms by which allogeneic donor T cells differentially modulate GvHD and GvL remain unknown. This gap in our mechanistic understanding hinders our ability to separate GvHD from GvL. Accordingly, using an unbiased genome-wide CRISPR/Cas9 guide RNA library screen and gene set enrichment analysis (GSEA), we have identified and prioritized very-low-density lipoprotein receptor (VLDLR) as a novel therapeutic target to separate GvHD from GvL. Our animal studies with VLDLR knock-out (KO) T cells suggest that targeting VLDLR is a promising approach to prevent both GvHD and leukemia relapse. Thus, we hypothesize that pharmacologic inhibition of VLDLR may separate GvHD from GvL. We will test this hypothesis in Specific Aim 1, using two distinct and independent mouse models of allo-HCT. We will also define the cellular mechanisms underlying the separation of GvHD from GvL by genetic/pharmacologic blockade of VLDLR. In Specific Aim 2, we will elucidate the molecular mechanisms by which VLDLR blockade selectively reduces GvHD over GvL. We have made three critical observations relating to T cells from VLDLR KO mice compared to those from wild-type (WT) mice: 1) increased frequencies of regulatory T cells, 2) reduced CD4 T cell proliferation when stimulated with allogeneic antigen presenting cells (APCs), but not with leukemic cells, and 3) normal CD8 T cell responses against both allogeneic APCs and leukemic cells. These findings may explain why VLDLR KO T cells selectively reduce GvHD over GvL. Our RNA-seq and GSEA studies of VLDLR KO vs. WT T cells stimulated with allogeneic APCs have identified Klrc1 as a top candidate, which encodes immune modulatory NKG2A. Of note, Klrc1 is upregulated only in VLDLR KO CD4 T cells, not CD8. Thus, we hypothesize that blocking VLDLR prevents GvHD and leukemia relapse by upregulating Klrc1 in CD4 T cells. Our innovative findings can potentially be practice-changing, resulting in a first-in-human clinical trial targeting VLDLR to modulate GvHD/GvL since the amino acid sequence identity between murine and human VLDLR is 97%. Thus, our studies have a substantial impact on the fields of allo-HCT and transplant immunology.


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 = $388,750 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	5/19/2026	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $388,750

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Targeting VLDLR to prevent both GvHD and leukemia relapse

Award Number: R01AI198352

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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