Simultaneous targeting of tumor and stroma cells to enhance solid tumor car-t cell therapy
Ended Project Grant Awarded Last action
- Award ID
- R43CA254820
- Recipient
-
Luminary Therapeutics, Inc. UEI MNKBAEZHWJS1
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,195,890
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Originally
- Funding
-
- $796,231.80 Federal
- $399,658.00 Non-federal
- Place of performance
- Minneapolis, MN 55414, USA
Award details come from USAspending.gov.
Description
- Abstract
- The use of t cells engineered to express specific chimeric antigen receptors (cars) to treat cancer has generated durable cures for many types of cancer and resulted in the first FDA approved car-t cell therapy to treat childhood acute lymphoblastic leukemia in 2017. Despite this success, car-t immunotherapies have been much less effective at targeting solid tumors. Part of this limited success stems from the solid tumor microenvironment, which forms a physical barrier to immune cell infiltration and produces soluble factors that downregulate t cell activity and accelerate t cell exhaustion. While immunotherapies targeting solid tumors are initially effective, the tumor microenvironment's inhibition of t cells prevents these treatments from producing durable responses. In this application, we propose a novel car-t cell therapy aimed to improve outcomes for patients with advanced stage pancreatic cancer by overcoming the deficiencies that plague current car-t cell therapies. To this end, we will engineer t cells to express multiple cars, enabling these cells to target tumor cells and cells in the immune-suppressive tumor microenvironment. Specifically, we will leverage the non-viral, TC buster DNA transposon system to insert a large multicistronic genetic construct containing multiple cars and a selection marker into t cells. Using this platform, we will generate t cells with cars targeting mesothelin (msln), a protein expressed by 80-85% of pancreatic cancer tumors, and fibroblast activation protein (FAP), a marker of cancer associated fibroblasts in the tumor microenvironment. We will then select a pure population of t cells expressing msln- and FAP-cars and determine the activity and specificity of these cells in vitro. We expect that engineered t cells will generate a specific and robust response, eliciting cytotoxic functions only against cells expressing their target antigen. We will then determine the efficacy of engineered t cells in vivo using a xenograft mouse model to generate msln and FAP positive pancreatic carcinomas followed by adoptive transfer of t cells. We expect immunotherapeutic delivery of bispecific t cells expressing FAP-cars and msln- cars will elicit a robust and long-lasting t cell response against msln+/FAP+ solid tumors resulting in tumor shrinkage and increased survival. Furthermore, we expect the development of a flexible, efficient, and reliable process to generate bispecific t cells with a single, non-viral gene delivery approach will facilitate the emergence of novel therapies to overcome many issues facing engineered t cell therapy today, including antigen escape and target specificity.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | -$3,084 | $0 | |
| Amendment | $399,658 | $0 | |
| Original award | $399,658 | $399,658 |
Quick answers
Who received award R43CA254820?
R43CA254820 was awarded to Luminary Therapeutics, Inc. by National Cancer Institute (National Institutes of Health) on August 1, 2021.
How much is award R43CA254820 worth?
$1,195,890 has been obligated on R43CA254820: $796,232 in federal funding and $399,658 in non-federal funding.
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