Project 3

Information

  • Research Project
  • 10270395
  • ApplicationId
    10270395
  • Core Project Number
    P01CA254849
  • Full Project Number
    1P01CA254849-01A1
  • Serial Number
    254849
  • FOA Number
    PAR-20-077
  • Sub Project Id
    5978
  • Project Start Date
    9/16/2021 - 3 years ago
  • Project End Date
    7/31/2026 - a year from now
  • Program Officer Name
  • Budget Start Date
    7/1/2021 - 3 years ago
  • Budget End Date
    6/30/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    9/16/2021 - 3 years ago
Organizations

Project 3

ABSTRACT: PROJECT 3 Over the last several decades, it has become possible to isolate a patient?s own cells, engineer and expand them in the laboratory, and use them to treat an existing cancer. This technology has largely advanced to using primary human T cells genetically modified to express a tumor specific T cell receptor (TCR) or chimeric antigen receptor (CAR). This approach has demonstrated durable cures in some leukemias, but has had limited success in the treatment of solid tumors. This lack of efficacy is believed to be due to challenges faced by T cells in migrating into and within complex solid tumor microenvironments and multiple immunosuppressive modalities found there. As many of these challenges have been identified and mechanistically studied, we hypothesize that we can engineer CAR T cells capable of overcoming all challenges found in the solid tumor microenvironment, leading to durable cures for cancer patients with the worst prognosis. Recently, a number of groups have published high efficiency methods for engineering T cells using CRISPR/Cas9. Moreover, the use of recombinant adeno associated virus (rAAV) as a DNA donor molecule for homologous recombination (HR) combined with Cas9 has also demonstrated incredible rates of site-specific gene delivery in T cells. Although these approaches are highly effective, there are still drawbacks and issues to be resolved to improve capabilities and safety of gene editing cells for therapy. For instance, nuclease-based gene editing still relies on stochastic repair of genotoxic double strand breaks (DSBs) with little uniformity in the editing outcome. Fortunately, new technologies have emerged to gene edit DNA at single base pair resolution with high product purity and efficiency and without a targeted DSB, termed Cas9 base editors (BEs) and primer editors (PEs). We have demonstrated that this technology allows for highly efficient multiplex genome editing via programmable enzymatic single base changes without creating toxic DSBs, i.e. ?digital editing?. As this technology is relatively new, there is also opportunity to develop new and innovative genome editing strategies to develop fully digitally edited cells intended for therapeutic use in a cost effect, rapid, and accurate manner. Thus, our specific aims are as follows: 1) Further develop multiplex digital editing in murine and human T cells and explore novel uses for digital editing, 2) Deploy multiplex digital editing to install novel edits in order to enhance T cells migration into and within mechanically complex tumor microenvironment and also hardwire T cells to maintain a T resident memory phenotype, 3) Implement digital editing to develop ?off-the-shelf? T cells with enhanced solid tumor efficacy via digital knockout of all 3 NUR4A transcription factor family. In summary, by deploying digital editing, we will make gene editing of cells intended for therapeutic use more sophisticated, safe and lead to effective therapies against solid tumor tumors with mechanically complex and immunosuppressive tumor microenvironments.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    P01
  • Administering IC
    CA
  • Application Type
    1
  • Direct Cost Amount
    353964
  • Indirect Cost Amount
    194680
  • Total Cost
  • Sub Project Total Cost
    548644
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NCI:548644\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZCA1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    UNIVERSITY OF MINNESOTA
  • Organization Department
  • Organization DUNS
    555917996
  • Organization City
    MINNEAPOLIS
  • Organization State
    MN
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    554552070
  • Organization District
    UNITED STATES