Non-viral reprogramming of the endogenous TCRα locus to direct stem memory T cells against shared neoantigens in malignant gliomas
Grant Award Details
Grant Type:
Grant Number:
DISC2-11036
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Cell Line Generation:
Award Value:
$900,000
Status:
Closed
Progress Reports
Reporting Period:
Year 3/NCE
Grant Application Details
Application Title:
Non-viral reprogramming of the endogenous TCRα locus to direct stem memory T cells against shared neoantigens in malignant gliomas
Public Abstract:
Research Objective
We will develop a non-viral gene editing technology to replace the endogenous TCRα locus of stem memory T cells with transgene TCRs that are specific to brain cancer neoantigens.
Impact
Gliomas are lethal tumors often affecting children and young adults. Therapy using Tscm directed to attack truncal neoantigens in these tumors may provide long-lasting protective immunity.
Major Proposed Activities
We will develop a non-viral gene editing technology to replace the endogenous TCRα locus of stem memory T cells with transgene TCRs that are specific to brain cancer neoantigens.
Impact
Gliomas are lethal tumors often affecting children and young adults. Therapy using Tscm directed to attack truncal neoantigens in these tumors may provide long-lasting protective immunity.
Major Proposed Activities
- Establish and optimize the TCR replacement in CD8+ or CD4+ Tscm with H3.3K27M-specific or IDH1(R132H)-specific TCRs, respectively.
- In vitro evaluation of TCR-replaced Tscm for their functional avidity in comparison to Tscm engineered with the conventional retroviral TCR vector and CRISPR-knock out of endogenous (e)TCR.
- In vivo evaluation of TCR-replaced Tscm cells for anti-glioma effects in comparison with Tscm engineered with the conventional retroviral TCR vector and CRISPR-knock out of eTCR.
Statement of Benefit to California:
In children, brain tumors are the leading cause of cancer-related mortality and morbidity. Furthermore, IDH1-mutant gliomas tend to occur in young adults. Our institution is one of the largest brain tumor centers in the world, developing a number of innovative clinical trials and treating patients primarily from CA. The proposed study will establish a strong basis to develop a novel, safe and effective stem memory T cell therapy for patients with malignant brain tumors, including ones in CA.