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R01CA264646

Project Grant

Overview

Grant Description
The Roles of EBV-Specific T Cells in Response to Checkpoint Blockade Immunotherapy of EBV-Driven Nasopharyngeal Carcinoma - Project Summary/Abstract

Nasopharyngeal Carcinoma (NPC) is an Epstein-Barr virus (EBV)-driven malignancy that is endemic to East and Southeast Asia. The overall 5-year survival rate for endemic NPC is only 51%, which represents an unmet clinical need. While NPC tumors are known to be infected with EBV and express PD-L1, little is known about the role of EBV-specific T cells in the control of NPC, and anti-PD-1 therapy has shown a low rate of efficacy (ORR ~20%).

The goal of this study is to better understand the role of EBV-specific T cell responses in NPC immunopathology and immunotherapeutic response. We will test the specific hypotheses that:

1. EBV-specific T cells contribute to tumor control elicited by combination anti-PD-1 and anti-CTLA-4 checkpoint blockade immunotherapy, and
2. That the phenotypic and clonal characteristics/dynamics of peripheral EBV-specific T cells can be useful as indicators of clinical outcomes for NPC patients.

To test these hypotheses, we will leverage our access to two Singaporean NPC patient cohorts:

Cohort 1: A 51-patient cohort of new-diagnosis NPC for which viably frozen PBMCs and archival FFPE tissues are available, and
Cohort 2: A 50-patient cohort participating in a phase II trial (NCT03097939 - National Cancer Centre Singapore) testing the combination of ipilimumab and nivolumab (IPI.+NIVO.) immunotherapy with longitudinally collected PBMCs and tissue biopsies.

Recently published preliminary analysis (AACR 2020) from this clinical trial shows that combined IPI.+NIVO. therapy is safe and achieved durable responses in recurrent and metastatic NPC patients and identified a negative association between circulating EBV-DNA levels and response. In addition, preliminary analysis of new-diagnosis NPC patient peripheral blood samples from Cohort 1 show associations between certain phenotypic profiles of CD8+ T cells and clinical parameters such as EBV-DNA levels.

Therefore, in Aim 1, we will investigate the clinical relevance of these preliminarily identified NPC-associated CD8+ T cell phenotypes. In addition to in-depth single-cell transcriptional, functional TCR sequence profiling of these cells, cellular imaging, transcriptional profiling, and bulk TCR sequencing of patient-matched tumor will allow discovery of novel associations between peripheral T cells and the tumor microenvironment.

In Aim 2, we will characterize EBV-specific T cell responses in the NPC periphery and tumor microenvironment during combination IPI.+NIVO. immunotherapy treatment to identify novel associations between the phenotypic profiles of EBV-specific T cells and immunotherapeutic response.

In Aim 3, we will investigate T cell clonal dynamics associated with treatment-induced changes to the NPC-specific immune response by comparing the TCR clonal diversity in peripheral blood and tumor biopsy samples from different stages of treatment.

Overall, characterization of EBV-specific T cell phenotypes in the NPC periphery and the tumor using multiple cutting-edge approaches will not only improve our understanding of the NPC immune landscape but also potentially identify clinically relevant EBV-specific T cell phenotypes that could be tested in future NPC immunotherapy trials.
Funding Goals
TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.
Grant Program (CFDA)
Place of Performance
Seattle, Washington 981094433 United States
Geographic Scope
Single Zip Code
Analysis Notes
Amendment Since initial award the total obligations have increased 379% from $634,760 to $3,042,380.
Fred Hutchinson Cancer Center was awarded EBV-Specific T Cell Responses in NPC Immunotherapy Project Grant R01CA264646 worth $3,042,380 from National Cancer Institute in August 2021 with work to be completed primarily in Seattle Washington United States. The grant has a duration of 5 years and was awarded through assistance program 93.395 Cancer Treatment Research. The Project Grant was awarded through grant opportunity NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).

Status
(Ongoing)

Last Modified 8/20/25

Period of Performance
8/1/21
Start Date
7/31/26
End Date
81.0% Complete

Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
100.0% Federal Funding
0.0% Non-Federal Funding

Activity Timeline

Interactive chart of timeline of amendments to R01CA264646

Transaction History

Modifications to R01CA264646

Additional Detail

Award ID FAIN
R01CA264646
SAI Number
R01CA264646-3243097607
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
TJFZLPP6NYL6
Awardee CAGE
50WB4
Performance District
WA-07
Senators
Maria Cantwell
Patty Murray

Budget Funding

Federal Account Budget Subfunction Object Class Total Percentage
National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) Health research and training Grants, subsidies, and contributions (41.0) $1,206,888 100%
Modified: 8/20/25