Grant Details
Description
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.
Status | Finished |
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Effective start/end date | 09/5/21 → 08/31/24 |
Funding
- National Cancer Institute: $433,138.00
- National Cancer Institute: $442,712.00
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