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Liquid biopsy-based toolkits for neoantigen and cognate TCR discovery for cancer immunotherapy

Award Number: R33CA256112
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Liquid biopsy-based toolkits for neoantigen and cognate TCR discovery for cancer immunotherapy - Project Summary/Abstract Neoantigens derived from tumor-specific mutations are a major driving force behind the current cancer immunotherapies. The interactions between neoantigens and antigen-specific T cells enable T cell recognition and tumor killing. Resolving neoantigens and antigen-reactive T cells normally requires fresh (or snap frozen) tumor materials from which the tumor tissue can be sequenced and tumor-infiltrating lymphocytes can be isolated and expanded. Unfortunately, the availability of fresh (or snap frozen) tumor tissue biopsies is a significant limiting factor for personalized immunotherapy. Sequencing quality of paraffin-embedded pathological specimen is often suboptimal for neoantigen discovery. Sequencing data of a small biopsy from a single tumor lesion may not be representative of the tumor's full clonal spectrum. More importantly, the molecular profile of tumors evolves dynamically over time. But repeated biopsy sampling is seldom feasible for patients with many cancers that require invasive biopsy procedures. Circulating tumor cells (CTCs) and match blood lymphocytes are good surrogates for neoantigen and cognate TCR discovery. They enable clinicians to repeatedly and non-invasively interrogate the mutational landscape and dynamic evolution of the anti-tumor immunity via serially collected blood samples. A major technical challenge here is to develop high-throughput, low sample volume, minimally invasive tools to resolve the neoantigen and cognate TCR dynamics and to match the TCR genes with specific neoantigens. We propose to develop a toolkit for liquid biopsy-based neoantigen and cognate TCR discovery through a strategic integration of a novel on-chip image cytometry platform and a highly modular nanoparticle-barcoded single-molecule peptide-MHC tetramer cell sorting assay. We will perform advanced development and rigorous validation of the toolkit in this proposed work. We will investigate the dynamic evolution of neoantigen and TCR repertoires during immune checkpoint blockade using serially collected blood samples from melanoma patients. Upon successful completion, it will deliver a simple and noninvasive approach for liquid biopsy-based neoantigen and cognate TCR discovery for patients whose surgical biopsies are not available or not attainable, with transformative potentials on personalized neoantigen vaccines and T-cell based immunotherapies. The neoantigen and cognate TCR dynamics will provide critical insights into the understanding of immunotherapy response and resistance.


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 = -$7,229 )
2026	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	3	1/8/2026	NON-COMPETING CONTINUATION	-$7,229
														Subtotal = -$7,229

Issue Date FY: 2023 ( Subtotal = $442,712 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	001	3	8/29/2023	NON-COMPETING CONTINUATION	$442,712
2023	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	2	5/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $442,712

Issue Date FY: 2022 ( Subtotal = $433,138 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	2	8/16/2022	NON-COMPETING CONTINUATION	$433,138
														Subtotal = $433,138

Issue Date FY: 2021 ( Subtotal = $462,881 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	1	9/2/2021	NEW	$462,881
														Subtotal = $462,881

Grand Total All Awards = $1,331,502

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Liquid biopsy-based toolkits for neoantigen and cognate TCR discovery for cancer immunotherapy

Award Number: R33CA256112

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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