Improving engineered TCR-t cell therapy for solid tumors by targeting TCF1+ stem-like reservoirs in tumor-draining lymph nodes
Ended Project Grant Awarded Last action
- Award ID
- F31CA294918
- Recipient
-
Fred Hutchinson Cancer Center UEI TJFZLPP6NYL6
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $177,180
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date
- Place of performance
- Seattle, WA 98109, USA
Award details come from USAspending.gov.
Description
- Abstract
- Adoptive transfer of engineered t cells targeting tumor antigens is ineffective against most solid tumors, due in-part to poor persistence and the rapid onset of dysfunction. Recent studies of endogenous tumor- specific t cells (endog-t) have described a population of stem-like PD-1+TCF1+ progenitor exhausted t cells (tpex) that can self-renew and differentiate into effector-like t cells in the tumor. Tpex preferentially reside in tumor-draining lymph nodes (tdlns), where they are maintained through activation by dendritic cells (DCS). Importantly, tpex in tdlns are necessary for promoting persistent and functional t cell responses, as well as conferring response to PD-L1 blockade. However, IT is not clear whether engineered t cells form PD-1+TCF1+ populations in tdlns, and how this impacts their long-term persistence and function in the tumor. To test this, i adapted the clinically relevant KRASG12D-LSL/+; P53FL/FL murine model (KP) of lung adenocarcinoma to overexpress the model neoantigen ovalbumin (OVA) to compare OVA-specific engineered t cells (TCR-t) and endog-t cells. While the majority of endog-t cells in tdlns were PD-1+TCF1+, TCR-t cells were predominantly PD-1-TCF1+, markers associated with lack of activation and maintenance of a pre-exhausted central-memory phenotype. Consistent with these phenotypes, PD-L1 blockade failed to increase numbers of TCR-t cells and enhance tumor control in comparison to endog-t. Thus, i hypothesize that factors unique to TCR-t therapy, such as their in vitro pre-activation and/or infusion at a high cell number, promote their formation of PD-1-TCF1+ reservoirs in tdlns instead of PD-1+TCF1+. I also hypothesize that formation of PD-1- TCF1+ reservoirs in the tdln is actually an advantage for TCR-t therapy, since the PD-1-TCF1+ population may possess superior functional potential that can be mobilized through vaccination targeting DCS in the tdln. In this project, i seek to determine 1) why TCR-t cells form PD-1-TCF1+ reservoirs in tdlns instead of PD- 1+TCF1+ like what is described for endog-t, as well as 2) whether the PD-1-TCF1+ TCR-t cells in the tdln have stem-like characteristics and functional potential that can be unleashed with vaccination. In aim 1, i will use fluorescently-labeled tumors in the KP model, flow cytometry, and high-parameter fluorescence microscopy to determine how infusion of a large number of cells and/or in vitro pre-activation affect TCR-t cell formation of PD-1+TCF1+ populations in tdlns, and how this correlates with their localization near DCS. In aim 2, i will use RNA-SEQ, atac-SEQ, and EX vivo assays to describe the stem-ness and functional potential of the PD-1-TCF1+ TCR-t cells in the tdln compared to PD-1+TCF1+ endog-t. I will also evaluate whether a novel t cell vaccination approach targeting DCS in tdlns can activate PD-1-TCF1+ TCR-t cells to promote tumor control. Through this work, i will define the mechanisms by which TCR-t cells form TCF1+ stem-like reservoirs in tdlns and potentially identify a therapeutic strategy to enhance TCR-t efficacy by targeting these reservoirs that could be translated to the clinic to improve patient outcomes.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $44,718 | |
| Amendment | $0 | |
| Amendment | $44,154 | |
| Amendment | $0 | |
| Amendment | $44,154 | |
| Amendment | $0 | |
| Original award | $44,154 |
Quick answers
Who received award F31CA294918?
F31CA294918 was awarded to Fred Hutchinson Cancer Center by National Cancer Institute (National Institutes of Health) on December 19, 2024.
How much is award F31CA294918 worth?
$177,180 has been obligated on F31CA294918.
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