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The roles of EBV-specific T cells in response to checkpoint blockade immunotherapy of EBV-driven nasopharyngeal carcinoma

Award Number: R01CA264646
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 Ipilumimab and Nivolumimab (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 cells 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.


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: 2023 ( Subtotal = $603,444 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	4	7/27/2023	NON-COMPETING CONTINUATION	$603,444
														Subtotal = $603,444

Issue Date FY: 2022 ( Subtotal = $603,444 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	004	3	8/10/2022	NON-COMPETING CONTINUATION	$603,444
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	1	5/27/2022	NEW	-$279,150
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	2	5/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$279,150
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	003	2	7/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$38,517
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	002	1	7/28/2022	NEW	-$38,517
														Subtotal = $603,444

Issue Date FY: 2021 ( Subtotal = $634,760 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	1	7/27/2021	NEW	$634,760
														Subtotal = $634,760

Grand Total All Awards = $1,841,648

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The roles of EBV-specific T cells in response to checkpoint blockade immunotherapy of EBV-driven nasopharyngeal carcinoma

Award Number: R01CA264646

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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