Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Elucidating the Role of Cancer-Associated FGL1 in Tumor Immunity and Developing FGL1-Guided Anti-LAG-3 Cancer Immunotherapy

Award Number: R37CA273333
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/11/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

Group Awards By:

View Award Description

Elucidating the Role of Cancer-Associated FGL1 in Tumor Immunity and Developing FGL1-Guided Anti-LAG-3 Cancer Immunotherapy - Project Summary Resistance to anti-CTLA-4, PD-1/PD-L1 (PD) T cell-based immune checkpoint blockade (ICB) therapy in large subsets of cancer patients necessitates the search for other tumor-associated T cell immune checkpoints that critically affect tumor immunity. Lymphocyte activating gene 3 (LAG-3) is a T-cell inhibitory receptor and represents a promising target for cancer immunotherapy, as monoclonal antibodies (mAb) blocking LAG-3 with its known ligand, MHC-II, in combination with anti-PD-1 show modest but promising efficacy in recent clinical trials. The FDA recently accepted for priority review the biologics license application for LAG-3 blocking mAb relatlimab and anti-PD-1 nivolumab fixed-dose combination for treating melanoma. However, very few single- agent activities of these MHC-II blocking anti-LAG-3 mAbs were observed, and no useful biomarkers for patient stratification have been suggested thus far. Motivated by numerous studies suggesting that the immunosuppressive effect of LAG-3 is largely independent of MHC-II, we identified for the first time that fibrinogen-like protein 1 (FGL1) is a high affinity and major functional ligand for LAG-3 whose interaction interface is distinct from MHC-II. FGL1 is a hepatocyte-secreted protein that can be detected in circulation. We found that soluble FGL1 inhibits antigen-specific T cell activation in a LAG-3 dependent manner. FGL1 genetic ablation or antibody blockade in mice promotes anti-tumor immunity in established mouse tumors, even in FGL1 negative tumors, suggesting a functional role of host-derived FGL1. In contrast to its minimal expression in normal tissues except the liver, FGL1 is upregulated by cancer cells in multiple cancers, such as non-small cell lung cancer (NSCLC) and melanoma; however, the role of tumor-associated FGL1 in the control of tumor immunity is still unclear. The major anti-LAG-3 clinical programs currently focus on those blocking only the MHC-II/LAG-3 interaction, which do not elicit any single-agent activities. Thus, it is critical to mechanistically dissect the immunological function of the FGL1/LAG-3 axis in the tumor microenvironment to design better LAG-3 targeted approaches for clinical application. In this project and through two complementary aims, we will leverage our extensive experience and expertise in cancer immunology and immunotherapy to 1) determine the functional role of tumor-associated FGL1 in modulating tumor immunity, its cancer induction mechanism by oncogenic Kras mutations and functional biomarker value in predicting responses to immunotherapies; 2) develop FGL1-guided, next-generation anti-LAG-3 cancer immunotherapy. We will compare the anti-tumor efficacy of our in-house anti- human or mouse LAG-3 antibodies that differentially block either or both FGL1/MHC-II and map the LAG-3 binding interfaces of these antibodies via CryoEM and X-ray crystallographic studies. In sum, our proposed studies will significantly deepen our understanding of the newly defined FGL1/LAG-3 axis and foster new immunotherapy designs for treating human cancers.


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 = $571,458 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	5	6/26/2026	NON-COMPETING CONTINUATION	$571,458
														Subtotal = $571,458

Issue Date FY: 2025 ( Subtotal = $571,456 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	4	6/18/2025	NON-COMPETING CONTINUATION	$571,456
														Subtotal = $571,456

Issue Date FY: 2024 ( Subtotal = $542,889 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	6/27/2024	NON-COMPETING CONTINUATION	$542,889
														Subtotal = $542,889

Issue Date FY: 2023 ( Subtotal = $560,030 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	2	6/16/2023	NON-COMPETING CONTINUATION	$560,030
														Subtotal = $560,030

Issue Date FY: 2022 ( Subtotal = $588,833 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	1	7/11/2022	NEW	$588,833
														Subtotal = $588,833

Grand Total All Awards = $2,834,666

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Elucidating the Role of Cancer-Associated FGL1 in Tumor Immunity and Developing FGL1-Guided Anti-LAG-3 Cancer Immunotherapy

Award Number: R37CA273333

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/11/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer