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Personal tumor neoantigens for immunity against chronic lymphocytic leukemia

Award Number: R01CA155010
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2011
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Personal tumor neoantigens for immunity against chronic lymphocytic leukemia - Project Summary Personal neoantigens have been conceptualized as optimal tumor antigens but their broad applicability across cancers has been limited by the variability in mutational burden across tumors. Recent clinical experiences in targeting neoantigens, such as by vaccination, in high and moderate mutation-rate tumors (e.g. melanoma, glioblastoma) have been promising, but such promise for low mutation burden cancers remains under evaluation. Chronic lymphocytic leukemia (CLL) is an example of such a low mutation burden malignancy where improved tumor antigen identification could open new therapeutic opportunities. Indeed, although a growing armamentarium of clinically active therapies is now available for CLL (i.e. targeted inhibitors, CAR-T cells, CPB), CLL remains largely incurable. While inherently immunogenic, as highlighted by evidence of spontaneous regression and its responsiveness to the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic cell transplantation (allo-HCT), CLL patients demonstrate inconsistent ability to mount antigen-specific immunity. Notably, we have achieved several exciting technologic advances over the last 5 years that impact antigen discovery, including: (i) new understanding of the cancer genome and transcriptome, advanced by new sequencing technologies, yielding potential alternative sources of cancer neoantigens; (ii) establishment of a scalable approach to rapidly validate peptide-MHC interactions, providing essential experimental feedback to our prediction efforts; (iii) improvements in the sensitivity, throughput and analysis of immunopeptidome data; (iv) expanded computational infrastructure to rapidly incorporate findings into prediction models for HLA class I. In this application, we hypothesize that novel classes of neoantigens are discoverable in CLL and that antigen-specific interactions arising from recognition of these alternative neoantigens could contribute to leukemia control. We propose an integrative strategy for the discovery and validation of novel neoantigen species. This commences with detection analyses of alterations that could encode these alternative CLL neoantigens through long-read and ribosomal sequencing, that can be used to inform improvements on the analysis pipelines. It then proceeds with validation using new high throughput binding assays, immunopeptidome detection and T cell response assessments (Aim 1). Our strategy further involves systematic improvement of our class I prediction tools through generation of experimental data from which we can iteratively correct and refine the epitope predictions. We furthermore incorporate the feature of peptide-MHC stability, which has been increasingly identified as relevant in peptide-MHC immunogenicity (Aim 2). Finally, we propose to confirm the functional relevance of alternative tumor neoantigens through their evaluation in the context of variation in natural history of CLL in a newly-assembled cohort of >1000 molecularly characterized samples, and within the setting of therapeutic response following whole CLL cell vaccination after alloHCT (Aim 3). We thus propose to expand the ‘universe’ of CLL neoantigens and to define their impact within informative clinically annotated CLL datasets.


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 = $759,203 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	14	2/14/2025	NON-COMPETING CONTINUATION	$683,283
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	14	5/22/2025	NON-COMPETING CONTINUATION	$75,920
														Subtotal = $759,203

Issue Date FY: 2024 ( Subtotal = $714,052 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	13	4/12/2024	NON-COMPETING CONTINUATION	$714,052
														Subtotal = $714,052

Issue Date FY: 2023 ( Subtotal = $751,633 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	12	4/12/2023	NON-COMPETING CONTINUATION	$751,633
														Subtotal = $751,633

Issue Date FY: 2022 ( Subtotal = $771,133 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	11	1/19/2022	COMPETING CONTINUATION	$771,133
2022	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	1/11/2022	NON-COMPETING CONTINUATION	$0
2022	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	10	5/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $771,133

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	5/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $675,300 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	5/4/2020	NON-COMPETING CONTINUATION	$675,300
														Subtotal = $675,300

Issue Date FY: 2019 ( Subtotal = $655,040 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	9	3/28/2019	NON-COMPETING CONTINUATION	$655,040
														Subtotal = $655,040

Issue Date FY: 2018 ( Subtotal = $675,300 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	8	4/3/2018	NON-COMPETING CONTINUATION	$675,300
														Subtotal = $675,300

Issue Date FY: 2017 ( Subtotal = $675,300 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	7	4/27/2017	NON-COMPETING CONTINUATION	$607,771
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	7	6/9/2017	NON-COMPETING CONTINUATION	$67,529
														Subtotal = $675,300

Issue Date FY: 2016 ( Subtotal = $675,300 )
2016	2016	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	6	3/29/2016	COMPETING CONTINUATION	$675,300
														Subtotal = $675,300

Issue Date FY: 2015 ( Subtotal = $795,625 )
2015	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	4/15/2015	NON-COMPETING CONTINUATION	$363,125
2015	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	5	4/20/2015	SUPPLEMENT FOR EXPANSION	$432,500
														Subtotal = $795,625

Issue Date FY: 2014 ( Subtotal = $640,563 )
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	4	9/24/2014	SUPPLEMENT FOR EXPANSION	$288,332
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	3/26/2014	NON-COMPETING CONTINUATION	$352,231
														Subtotal = $640,563

Issue Date FY: 2013 ( Subtotal = $341,338 )
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	5/2/2013	NON-COMPETING CONTINUATION	$85,335
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	3	6/28/2013	NON-COMPETING CONTINUATION	$256,003
														Subtotal = $341,338

Issue Date FY: 2012 ( Subtotal = $363,125 )
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	4/27/2012	NON-COMPETING CONTINUATION	$363,125
														Subtotal = $363,125

Issue Date FY: 2011 ( Subtotal = $363,125 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	6/1/2011	NEW	$363,125
														Subtotal = $363,125

Grand Total All Awards = $8,856,037

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Personal tumor neoantigens for immunity against chronic lymphocytic leukemia

Award Number: R01CA155010

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2011

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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