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Imaging Acidosis and Immune Therapy in PDAC

Award Number: R01CA239219
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Imaging Acidosis and Immune Therapy in PDAC - Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal of all cancers and is largely resistant to all therapies, including immune therapies (IT). Despite this resistance, there are no fewer than 12 open clinical trials investigating treatment of PDAC with checkpoint blockade IT. There are multiple mechanisms that can account for this resistance, including the acidosis of PDAC tumors, which is due to high rates of glycolysis in combination with poor perfusion. Placement of activated T cells in acidic conditions profoundly inhibits their effector functions. We have shown that neutralization of tumor acidosis with oral NaHCO3 in murine models of PDAC can lead to dramatic improvements in response to checkpoint blockade. However, phase I/IIa clinical trials with bicarbonate failed to dose escalate. Thus, there is a compelling need to develop clinically viable alternatives to achieve the same result, viz. neutralization of tumor acidity in vivo in order to combine with IT. A therapy designed to directly neutralize tumor acidity is a clinically-tested CEACAM6-targeted urease (L- DOS47, Helix Biopharma). This cleaves endogenous urea into two NH4+ and one CO2, thus alkalinizing local pH, and this agent will be our primary focus in the proposed studies. We will use these approaches to test the hypothesis that neutralizing tumor acidity with L-DOS47 will be additive or synergistic with checkpoint blockade in mouse models of PDAC. Our preliminary data support these hypotheses, yet there are gaps in our knowledge that need to be filled prior to embarking on clinical trials combining L-DOS47 with immune therapy. Preliminary data have shown improved response to checkpoint blockade in combination with L-DOS47 in Panc02 tumors; an immune competent model of PDAC, and we plan to expand this to more biomedically relevant models in the current work. These will be addressed in 3 Aims: Aim 1 will determine the in situ pharmacodynamics (PD) of these agents using molecular imaging of 1.1) pH and 1.2) enzyme activity in order to optimize dosing schema to achieve acid neutralization. In Aim 2, we will combine these agents with checkpoint blockade (anti-PD1 and anti-PD-L1) to improve tumor control in mouse models of PDAC engineered to express CEACAM6 (Panc02, UN-KPC960/961). A secondary endpoint in this aim will be to develop imaging biomarkers of response that can be used prior to therapy to predict, and during therapy to monitor, response. Aim 3 will address the fundamental question of HOW an acidic pH induces T cell stasis. Preliminary data have shown that acidification of pHe induces a subtle, yet significant, drop in pHi, which may be responsible for subsequent T-cell stasis. We will also investigate whether there is a disruption of Ca2+ signaling dynamics, leading to altered NFAT distribution, and whether there is a differential sensitivity of T-cells to acidosis, compared with acid-adapted or acid-naïve cancer cells and fibroblasts. At the completion of this study, we will have developed a clinically translatable approach to improve IT in PDAC as well as an improved understanding of the mechanism underlying acid inhibition.


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: 2024 ( Subtotal = $649,329 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$34,175
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	5	1/31/2024	NON-COMPETING CONTINUATION	$615,154
														Subtotal = $649,329

Issue Date FY: 2023 ( Subtotal = $669,832 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	4	1/26/2023	NON-COMPETING CONTINUATION	$669,832
														Subtotal = $669,832

Issue Date FY: 2022 ( Subtotal = $669,832 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	002	3	8/26/2022	NON-COMPETING CONTINUATION	$0
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	001	3	6/23/2022	NON-COMPETING CONTINUATION	$54,677
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	3	1/13/2022	NON-COMPETING CONTINUATION	$615,155
														Subtotal = $669,832

Issue Date FY: 2021 ( Subtotal = $683,503 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	001	2	7/30/2021	NON-COMPETING CONTINUATION	$0
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	2	1/25/2021	NON-COMPETING CONTINUATION	$683,503
														Subtotal = $683,503

Issue Date FY: 2020 ( Subtotal = $683,503 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	1/24/2020	NEW	$683,503
														Subtotal = $683,503

Grand Total All Awards = $3,355,999

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Imaging Acidosis and Immune Therapy in PDAC

Award Number: R01CA239219

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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