Divergent response to radio-immunotherapy in hnscc and pdac is mediated by regulatory t cells

Active Project Grant Awarded Last action

Award ID
F31DE033887
Recipient
Awarding agency
Obligated
$276,108

Award facts

Assistance listing
93.121 Oral Diseases and Disorders Research
Completion date 62% complete
Place of performance
St. Louis, MO 63110, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Head and neck squamous cell carcinoma (hnscc) and pancreatic adenocarcinoma (pdac) differ in many of the genetic drivers, low responsiveness to immunotherapy remains a commonality shared between both. Resistance to therapy remains an issue and while the field awaits results from numerous ongoing clinical trials, the mechanistic underpinnings that contribute to response VS. Progression remain poorly understood. Our lab has shown that radiation therapy (RT) and PD1-IL2V, an immunocytokine that selectively delivers IL2 to PD-1 expressing cells via the intermediate affinity IL-2RSS, promotes increased infiltration, activation, and cytotoxicity of CD8 t cells and natural killer (NK) cells in preclinical orthotopic models of hnscc and pdac. Although the effect is substantial and results in significant tumor regression and abrogation of metastasis, the effect is transient, and tumors reoccur in the majority of mice. We therefore sought to investigate additional immunotherapies that can be added to further sustain the anti-tumor immune response induced by RT + PD1- IL2V. OX40 is a secondary costimulatory receptor which is expressed on activated t cells and provides survival signals which are critical to maintain long term immune responses. OX40 agonism has been shown to synergize well with immune checkpoint blockade (ICB), effectively boosting anti-tumor immunity in multiple tumor models. OX40 therefore represented a suitable candidate for combinatorial therapy along with PD1-IL2V and RT. Upon the addition of AOX40, we observed a striking dichotomy in the responses between preclinical models of hnscc and pdac. AOX40 promotes further efficacy of RT + PD1-IL2V and drives tumor eradication in hnscc, whereas survival is significantly decreased in pdac compared to RT + PD1-IL2V. Regulatory t cells (tregs), have been established as critical mediators of response in both hnscc and pdac, and interestingly, the depletion of tregs RE-establishes to therapy. Delving deeper into this disparity, we observed that pdac tumor microenvironment (TME) have an increased abundance of the cytokine IL-33 and is enriched with tregs expressing the IL-33 receptor ST2, a distinctly suppressive subset which is associated with tumor progression. We therefore hypothesize that OX40 agonism drives accelerated tumor progression in pdac by preferentially activating ST2 expressing tregs in the pdac TME. Aim 1 will focus on the effect that deletion of OX40 from tregs has on therapeutic outcomes in the context of RT + PD1-IL2V + AOX40. In aim 2, we will explore the tumor and TME intrinsic factors that can influence the dichotomous response to our combined radio-immunotherapy. We expect that this proposal will provide a mechanistic understanding of the parameters that determine response VS. Progression.

Transactions

Action Obligated Date
Amendment $46,668
Amendment $0
Amendment -$10,310
Amendment -$48,974
Amendment $48,974
Amendment $48,974
Amendment $47,694
Amendment $0
Amendment $47,694
Amendment $47,694
Amendment $0
Amendment $0
Original award $47,694
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Quick answers

Who received award F31DE033887?

F31DE033887 was awarded to The Washington University by National Institute of Dental and Craniofacial Research (National Institutes of Health) on August 13, 2024.

How much is award F31DE033887 worth?

$276,108 has been obligated on F31DE033887.

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