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Augmenting Pancreatic Cancer Immunotherapy via TGFβ Pathway Inhibition

Award Number: F30CA236031
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/02/2019
PERIOD OF PERFORMANCE END DATE: 01/01/2024

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Augmenting Pancreatic Cancer Immunotherapy via TGFβ Pathway Inhibition - Project Summary/Abstract The evasion of immune-mediated cytotoxicity is a hallmark feature of tumorigenesis. To this end, therapeutic inhibition of the immune checkpoint Programmed Cell Death Protein 1 (PD-1) has shown considerable promise in the management of several malignancies. In pancreatic cancer, however, despite a strong association between expression of the PD-1 ligand (PD-L1) and poor survival, checkpoint inhibitors have shown limited efficacy as a monotherapy. Recent efforts have therefore focused on identifying additional factors in the tumor microenvironment that modulate PD-L1/PD1 expression in hopes of improving drug response. Our group has previously identified stromal-derived Transforming Growth Factor Beta (TGFβ) as a crucial repressor of anti- tumor immune function, particularly with respect to cytotoxic T lymphocytes. Despite these observations, pharmacologic inhibition of TGFβ signaling has also been ineffective in clinical trials. When examining a small cohort of pancreatic cancer patients, we found an inverse association between PD-L1 expression and that of SMAD4, a downstream target of TGFβ signals. In accordance with these observations, exogenous TGFβ1 repressed the acquisition of PD-L1 in vitro. Similarly, neoplastic mouse models with genetic ablation of TGFβ signaling developed increased PD-L1 expression in the pancreas, and failed to mount a full anti-tumor immune response. Using an established model of metastatic pancreatic cancer, we therefore administered pharmacologic inhibitors of PD-1 (Invivomab) and/or TGFBR1 (Galunisertib). While neither monotherapy had an effect, after two months, mice receiving both Invivomab and Galunisertib had no overt evidence of disease. Histologically, the pancreata of these mice had near complete regression of neoplasms, with abnormal tissues displaying increased lymphocyte infiltration, Granzyme deposition, and apoptosis. Combined, these data suggest that TGFβ pathway blockade augments immune checkpoint inhibition, and may be a reasonable approach to overcome drug resistance in the clinic. Given the substantial preclinical efficacy of this approach, it is essential to further understand the means through which TGFβ and PD-L1/PD-1 signals are regulated, as well as the merits to their inhibition in select patient populations. Through the experiments detailed in this proposal, we will gain valuable insight into these events in hopes of extending survival and reducing cancer- associated morbidity in PDAC patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$50,974 )
2025	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	5	11/27/2024	NON-COMPETING CONTINUATION	-$50,974
														Subtotal = -$50,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	001	5	6/6/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	5	12/21/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	001	4	5/24/2022	NON-COMPETING CONTINUATION	$716
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	4	1/6/2022	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	001	3	1/11/2021	NON-COMPETING CONTINUATION	$0
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	002	3	2/16/2021	NON-COMPETING CONTINUATION	$516
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	3	1/7/2021	NON-COMPETING CONTINUATION	$50,520
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $50,520 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	2	12/9/2019	NON-COMPETING CONTINUATION	$50,016
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	001	2	2/20/2020	NON-COMPETING CONTINUATION	$504
														Subtotal = $50,520

Issue Date FY: 2019 ( Subtotal = $50,016 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	000	1	12/3/2018	NEW	$50,016
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Research Manpower	001	1	12/3/2018	NEW	$0
														Subtotal = $50,016

Grand Total All Awards = $205,045

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Augmenting Pancreatic Cancer Immunotherapy via TGFβ Pathway Inhibition

Award Number: F30CA236031

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/02/2019

PERIOD OF PERFORMANCE END DATE: 01/01/2024

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