Preclinical development of an exhaustion-resistant CAR-T stem cell for cancer immunotherapy
Grant Award Details
Grant Type:
Grant Number:
DISC2-13212
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$1,420,200
Status:
Active
Grant Application Details
Application Title:
Preclinical development of an exhaustion-resistant CAR-T stem cell for cancer immunotherapy
Public Abstract:
Research Objective
The expected outcome is an exhaustion-resistant CAR-T cell, which persists long-term in a functional progenitor T cell state in the tumor microenvironment and can be used for cancer immunotherapy.
Impact
CAR-T cells are effective in B cell cancer, but less than 50% of patients experience long-term disease control. Exhaustion-resistant CARs may provide long-term benefit that extends to solid tumors.
Major Proposed Activities
The expected outcome is an exhaustion-resistant CAR-T cell, which persists long-term in a functional progenitor T cell state in the tumor microenvironment and can be used for cancer immunotherapy.
Impact
CAR-T cells are effective in B cell cancer, but less than 50% of patients experience long-term disease control. Exhaustion-resistant CARs may provide long-term benefit that extends to solid tumors.
Major Proposed Activities
- Establish and optimize a CRISPR-engineered CAR-T stem cell therapy that resists T cell exhaustion.
- Perform in vitro evaluation of TEx-resistant CAR-T cell tumor recognition and cytolysis, and progenitor cell state characterization, compared to conventional CAR-T cells.
- Perform in vivo evaluation of TEx-resistant CAR-T cell function and persistence in xenograft tumor models, compared to conventional CAR-T cells.
- Perform epigenomic characterization of T cell exhaustion in TEx-resistant CAR-T cell in tumor models, compared to conventional CAR-T cells.
Statement of Benefit to California:
A significant barrier to long-term efficacy of cancer immunotherapy is the development of T cell exhaustion, which limits T function in the tumor microenvironment. The proposed exhaustion-resistant CAR-T stem cell therapy candidate has the potential to benefit a large population of patients in California who suffer from a broad range of cancers that may be targeted by CAR-T cells, including solid tumors (lung, prostate, sarcoma, and skin) and blood cancers (leukemia, multiple myeloma, lymphoma).