The development of antigen-specific t cells with epigenetic priming for ovarian cancer

Active Project Grant Awarded Last action

Award ID
F31CA318737
Recipient
Awarding agency
Obligated
$83,758

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date 0% complete
Originally
Place of performance
Washington, DC 20052, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy due to its highly immunosuppressive tumor environment (TME), responsible for the poor response of OC patients to existing therapies. While immunotherapies are promising, t cell therapies have demonstrated limited clinical success due to exhaustion in this aggressive tumor microenvironment, and the low mutational burden of OC limits the number of antigens available for targeting. Expanding t cells for specificity to multiple tumor antigens has demonstrated success in vitro, although multiantigen-specific t cell products for OC demonstrate limited persistence and have not been assessed in vivo in the context of the immunosuppressive TME. Epigenetic therapies such as DNA methyltransferase inhibitors (dnmtis) are often employed in OC, which remove repressive methylation marks at the promoters of gene bodies in tumor cells to stimulate a type i interferon response and recruit host immune cells. Epigenetic reprogramming of immune cells is less explored, but priming t cells with dnmtis has shown to downregulate inhibitory molecule expression and upregulate memory-associated genes. Thus, epigenetic priming may reverse OC-specific t cell exhaustion by promoting a memory phenotype, although this has not been explored, and the immune response to such products has not been investigated. I hypothesize that epigenetic priming will potentiate anti-tumor activity and limit exhaustion of OC-specific t cells to promote a pro-inflammatory TME. In aim 1, i will expand human donor t cells for specificity to multiple OC antigens using an established method that generates tumor lysate with heightened immunogenicity. This allows for greater antigen uptake and presentation by dendritic cells for t cell stimulation. Previous work from my lab has demonstrated this method generates human OC-specific t cells, although the effects of epigenetic priming on these t cell products have not been explored. I hypothesize that epigenetic priming will reverse exhaustion and increase anti-tumor activity of human OC-specific t cells by promoting a memory t cell phenotype. In aim 2, i will translate the above methods into a murine setting for assessment of dnmti-primed OC-specific t cells in the tumor microenvironment. I will generate murine multiantigen- specific t cells and investigate the role of epigenetic priming in altering their anti-tumor activity and phenotype. Murine OC- specific t cells will be assessed in vivo using a fully autologous, syngeneic C57BL/6 murine model, allowing me to probe the functionality of epigenetically primed t cells in the context of the TME. I hypothesize that epigenetically primed OC-specific t cells will have greater persistence in vivo and promote a pro-inflammatory immune response in the TME. Completion of these aims will uncover the therapeutic potential of epigenetic reprogramming to enhance adoptive t cell therapies for ovarian cancer.

Transactions

Action Obligated Date
Amendment $0
Original award $41,879

Quick answers

Who received award F31CA318737?

F31CA318737 was awarded to George Washington University (The) by National Cancer Institute (National Institutes of Health) on February 13, 2027.

How much is award F31CA318737 worth?

$83,758 has been obligated on F31CA318737.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login