Project Details
Description
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy including immune
checkpoint blockade. Meanwhile, immunotherapy targeting the PD-1:PD-L1 pathway is inducing stunning
clinical outcomes in other advanced malignancies. Despite decades of cancer immunology research, the
underlying mechanisms governing immune surveillance in pancreas cancer are largely unknown. This is due,
in part, to a lack of animal models that permit the detection of tumor-specific T lymphocytes during disparate
clinical outcomes commonly observed in patients. We have filled this knowledge gap by creating novel animal
models that permit the interrogation or the rare tumor-antigen specific T cells over time. Based on our recent
discoveries, we are now uniquely poised to identify how to safely promote antigen-specific T cell-mediated
destruction of pancreas cancer, and our proposal will use these results to develop a novel preclinical
combination immune-based therapy to inform a clinical trial. Our compelling preliminary data support the
hypothesis that immune-mediated pancreas cancer eradication requires a combination of a 1) high affinity
tumor specific T cell, 2) modifying suppressive intratumoral myeloid cells, and 3) overcoming chronic
inflammatory signaling mediated by TNFα. We screened a series of immunotherapies and identified that
agonistic αCD40 or PD-L1 blockade has only transient antitumor activity whereas the combination leads to
tumor eradication in 63% of animals. PD-L1 blockade failed to reinvigorate intratumoral T cell functions and
instead changed the peripheral tumor-specific T cell repertoire and expands a unique peripheral T cell
subpopulation enriched for pro-survival genes and Ikzf2. In contrast, agonistic αCD40 promotes potent, yet
short-lived, cytolytic intratumoral T cells which correlates with a decrease in intratumoral myeloid cell IL-27
production. Finally, abrogating Tnfr1 expression by non-tumor/host cells overcomes tumor escape resulting in
100% of tumor eradication in αCD40+αPD-L1-treated animals. In Aim 1, we will identify the functional
significance of the altered TCR repertoire and the Ikzf2+ T cell subpopulation induced following PD-L1
blockade. In Aim 2, we will test if agonistic αCD40 promotes potent cytolytic effector T cells by abrogating
intratumoral myeloid cell production of IL-27 and/or CD8 T cell production of IL-10. In Aim 3, we will identify
how IFNγ and TNFα signaling on non-tumor/host cells lead to disparate outcomes following combination
immunotherapy of pancreas cancer and test a novel combinatorial immunotherapy that includes TNFα
blockade in combination with a CD40 agonist and a PD-1 inhibitor. The studies are designed to identify a
mechanistic basis for T cell dysfunction in pancreas cancer and to create a feasible clinical strategy to
overcome it with the goal to create a safe and effective immune-based treatment for pancreas cancer patients.
Status | Active |
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Effective start/end date | 3/1/21 → 2/28/25 |
Funding
- National Cancer Institute: $388,795.00
- National Cancer Institute: $423,354.00
- National Cancer Institute: $423,354.00
- National Cancer Institute: $431,094.00
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