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Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities

Award Number: R01CA251136
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/20/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities - The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncology has resulted in an increased incidence of a variety of immune-related adverse events (irAEs), some of which can have a lasting impact on the lives of our patients. The continued development of adjuvant immunotherapy protocols and more potent immunotherapy combinations such as the ipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs. Despite their growing prevalence, the underlying pathogenesis of individual irAEs is poorly understood and our therapeutic management of these conditions remains crude. Using a genetically engineered model of melanoma, we have found that anti-PD-1 antibody (ab) immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon lamina propria, closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitis and colitis, respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearing mice eliminates the development of these irAEs, suggesting the presence of a tumor-intrinsic pro- inflammatory mechanism. As part of this work, we have recently identified a tumor-intrinsic PD- L1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs including the lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knock- out of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasome suppresses the accumulation of neutrophils in these distant tissues. Based on these findings, we now hypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitor- associated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target for suppressing the development of these irAEs. To address this hypothesis, we have generated a transgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 in the development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will address a potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues and whether a small molecule inhibitor of NLRP3 would be a superior option over steroids for the management of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1 ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoing checkpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if genetic variations of NLRP3 may contribute to the development of these irAEs. Overall, this work will provide unique mechanistic insight into the development of irAEs and identify rational therapeutic strategies and predictive biomarkers for improving the management of patients undergoing immunotherapy.


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: 2027 ( Subtotal = $0 )
2027	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Treatment Research	000	6	10/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $392,031 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Treatment Research	000	6	1/6/2026	NON-COMPETING CONTINUATION	$352,827
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Treatment Research	001	6	4/27/2026	NON-COMPETING CONTINUATION	$39,204
														Subtotal = $392,031

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Treatment Research	001	5	6/3/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$263,831
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	002	4	6/24/2025	NON-COMPETING CONTINUATION	$0
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	4	6/3/2025	NON-COMPETING CONTINUATION	-$263,831
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $473,501 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	4	6/26/2024	NON-COMPETING CONTINUATION	$473,501
														Subtotal = $473,501

Issue Date FY: 2023 ( Subtotal = $297,705 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	3	7/20/2023	NON-COMPETING CONTINUATION	$297,705
														Subtotal = $297,705

Issue Date FY: 2022 ( Subtotal = $386,846 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	2	8/8/2022	NON-COMPETING CONTINUATION	$386,846
														Subtotal = $386,846

Issue Date FY: 2021 ( Subtotal = $396,432 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	1	7/20/2021	NEW	$396,432
														Subtotal = $396,432

Grand Total All Awards = $1,946,515

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Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities

Award Number: R01CA251136

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/20/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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