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Tissue-based biomarkers of anti-PD-1-based therapy in metastatic renal cell carcinoma

Award Number: R01CA266424
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Tissue-based biomarkers of anti-PD-1-based therapy in metastatic renal cell carcinoma - PROJECT SUMMARY Immunotherapy, particularly immune checkpoint inhibitors (ICI), has shown considerable success in the treatment of advanced renal cell carcinoma (RCC), leading to durable responses in a subset of patients. However, most patients do not derive long-term clinical benefit from existing immune therapies. Moving forward, our team has prioritized identifying the determinants of ICI response in RCC, including the antigenic targets, T cell phenotypes, and microenvironment features that ultimately dictate the effectiveness of tumor- specific immunity. Human endogenous retroviruses (ERVs) are often aberrantly expressed in numerous disease states, including malignancy, and can lead to activation of both innate immunity (through sensing by the RIG-I/MDA-5 and cGAS-STING pathways) and adaptive immunity (by providing antigenic targets for tumor-specific CD8+ T cells). The expression of ERVE-4 has been associated with response to ICI monotherapy (i.e. anti-PD-1) in an analysis of a phase III randomized controlled trial in RCC, and an ERV-derived peptide (from ERVE-4) was identified as a target epitope in a long-term RCC responder to allogeneic stem cell transplant. Beyond recognition of tumor antigens, effective anti-tumor immunity requires a tumor microenvironment that permits infiltrating CD8+ T cells to carry out their effector function. A high level of tumor infiltration by antigen- experienced, non-exhausted CD8+ T cells has been associated with improved response to ICI monotherapy in clinical trials of RCC. However, resistance to ICI monotherapy is still common, in part owing to the immunosuppressive effects of infiltrating Treg and myeloid cells, and consequently combination (and not single agent) therapies with PD-1 blockade as a backbone are now the standard-of-care treatment for advanced RCC. It is therefore critical to understand the role of ERV expression, T cell phenotype, and the immune microenvironment in the context of clinically relevant contemporary ICI-based combination therapies. We hypothesize that aberrant expression of ERVs is associated with improved response to ICI combination therapy with ipilimumab and nivolumab, and that characterization of T cell phenotypes and the composition and states of other infiltrating immune cells in the RCC microenvironment will improve our understanding of the determinants of ICI response. By leveraging our unique access to clinically relevant large- scale clinical trial specimens of single-agent ICI and ICI-based combination therapy in RCC, as well as our collaborative team of physicians, translational researchers, and experimental biologists, we aim to systemically assess the association of ERV expression and ICI response and to determine other immune microenvironment features that ultimately influence response to current RCC immunotherapies. Our multidisciplinary team brings together a collective expertise in RCC biology, pathology, and tumor immunoregulation who are dedicated to bringing meaningful results that will optimize clinical outcomes for patients with RCC.


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 = $713,011 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	5	6/16/2026	NON-COMPETING CONTINUATION	$713,011
														Subtotal = $713,011

Issue Date FY: 2025 ( Subtotal = $713,011 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	4	6/2/2025	NON-COMPETING CONTINUATION	$713,011
														Subtotal = $713,011

Issue Date FY: 2024 ( Subtotal = $677,362 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	3	5/24/2024	NON-COMPETING CONTINUATION	$677,362
														Subtotal = $677,362

Issue Date FY: 2023 ( Subtotal = $698,751 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	2	5/24/2023	NON-COMPETING CONTINUATION	$698,751
														Subtotal = $698,751

Issue Date FY: 2022 ( Subtotal = $752,010 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	1	6/14/2022	NEW	$752,010
														Subtotal = $752,010

Grand Total All Awards = $3,554,145

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Tissue-based biomarkers of anti-PD-1-based therapy in metastatic renal cell carcinoma

Award Number: R01CA266424

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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