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Identifying the Mechanism of Resistance to Immunotherapy in Merkel Cell Carcinoma (for Zachary Reinstein)

Award Number: F30CA278298
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Identifying the Mechanism of Resistance to Immunotherapy in Merkel Cell Carcinoma (for Zachary Reinstein) - Project Summary/Abstract Merkel cell carcinoma (MCC) is the most aggressive and fatal cancer on a case-by-case basis with rapidly rising incidence. Approximately 80% of MCC cases are caused by Merkel cell polyomavirus, which expresses two viral oncogenes known as large T antigen and small T antigen that are required for clonal carcinogenesis. Notably, although MCC is highly aggressive, approximately 50% of patients treated with immune checkpoint blockade (ICB) respond to treatment. With approximately equal numbers of responsive patients to resistant patients and small, shared neoantigen repertoire, virus positive (VP) MCC serves as a model of T cell response in cancer. It is unknown why some patients respond to ICB while others resist treatment. A critical unmet need is to develop treatments for patients with primary or acquired resistant to ICB. To elucidate this mechanism and identify biomarkers of ICB response, we have collected the largest clinically annotated database of primary MCC samples treated with ICB. We have identified a subset of T cells that drive ICB response. In this project, we will elucidate the mechanism by which these cells mediate response to ICB. We will spatially and functionally identify which receptor-ligand interactions are most critical in triggering a response by these T cells. Next, we will identify specific T cell receptors that recognize tumor antigens. Finally, we will characterize anti-MCC T cells in the tumor microenvironment that are causing this response. These results will validate the prognostic potential of these cells and identify the mechanism by which it drives ICB response in VP MCC. My overall career goal is to become a successful, independent physician-scientist. The rigorous training plan proposed in this fellowship will allow me to achieve that goal by gaining research skills and knowledge in cellular immunology and bioinformatics. I will be mentored by Dr. Jaehyuk Choi, an expert physician-scientist in MCC, who has devised a training plan to develop all necessary research skills, communication skills and promote my professional development. This fellowship will broaden our understanding of MCC immunology and identify potential novel therapeutic strategies, as well as provide the necessary foundation for my future career as a physician-scientist.


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: 2025 ( Subtotal = $44,751 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	2	5/29/2025	NON-COMPETING CONTINUATION	$564
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	2	1/8/2025	NON-COMPETING CONTINUATION	$44,187
														Subtotal = $44,751

Issue Date FY: 2024 ( Subtotal = $44,187 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	001	1	1/23/2024	NEW	$0
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	000	1	1/23/2024	NEW	$42,907
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$1,280
														Subtotal = $44,187

Grand Total All Awards = $88,938

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Identifying the Mechanism of Resistance to Immunotherapy in Merkel Cell Carcinoma (for Zachary Reinstein)

Award Number: F30CA278298

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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