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Identification of pathways to mitigate Immune-Related Adverse Events with Cancer Immunotherapy

Award Number: U01AR077511
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT: The emergence of immune checkpoint inhibitors (CPIs) has significantly improved outcomes for patients with a variety of malignancies. By blocking the inhibitory signaling pathways of T cells, CPIs are associated with a diverse spectrum of immune-related adverse events (irAEs). Immune-related cutaneous adverse events (ircAE) are the most frequent AE and may result in CPI dose interruption or discontinuation. Current guidelines recommend corticosteroids for the management of irAEs including those affecting skin. Yet ~25% of ircAEs are steroid unresponsive, and their use has revealed a negative effect on survival, underscoring the need for early identification of corticosteroid unresponsiveness and rational therapies. Although the underlying pathogenic mechanism of irAEs remain elusive, autoimmune and autoinflammatory reactions have a putative role in their development and maintenance. Thus, understanding the pathogenic events underlying irAEs are critical to their prevention and treatment. The underlying mechanisms of irAEs remain a significant knowledge gap that we will address in this proposal. Our Central Hypothesis is that patients with ircAEs have unique endotypes associated with polarized immune responses in the skin and blood, which results in corticosteroid responsive and unresponsiveness reactions that may require intervention with targeted immune pathway blockade. In addition, we hypothesize that specific ircAE skin manifestations are associated with unique immune dermatologic responses. Cutaneous irAEs give us a unique opportunity to understand the immune reaction in the involved end organ and systemically. We will test our central hypothesis through; Aim 1: Define and correlate ircAE phenotypes with their immune reaction endotype and response to toxicity- directed therapy. In this aim we hypothesize that ircAEs are associated with distinct, polarized immune endotypes that correlate with specific cutaneous phenotypes and predict response to available interventions (corticosteroids, biologics targeting inflammatory pathways). Aim 2: Identify skin and circulating lipid biomarkers which occur during and after ircAEs. This aim tests the hypothesis that distinct ircAE clinical phenotypes and their endotypes will manifest unique changes in the skin structural and circulatory signaling lipidome and suggest novel therapeutic strategies to mitigate ircAEs. Aim 3: Determine mechanisms associated with corticosteroid unresponsiveness in patients with ircAE. This aim tests the hypothesis that steroid unresponsiveness can be defined by understanding the major mechanistic pathways involved, and ultimately allow targeted therapy to resolve the ircAE. In this translational approach to understanding ircAEs, our goal is to define in patients, the mechanisms involved in ircAEs, activated polarized pathways, and advance our understanding of translational immunology as well as lead to actionable interventions to mitigate these devastating AEs that can limit cancer therapy.


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 = $608,731 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/1/2024	NON-COMPETING CONTINUATION	$608,731
														Subtotal = $608,731

Issue Date FY: 2023 ( Subtotal = $613,843 )
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/10/2023	NON-COMPETING CONTINUATION	$613,843
														Subtotal = $613,843

Issue Date FY: 2022 ( Subtotal = $610,938 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/17/2022	NON-COMPETING CONTINUATION	$555,395
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/17/2022	NON-COMPETING CONTINUATION	$55,543
														Subtotal = $610,938

Issue Date FY: 2021 ( Subtotal = $604,257 )
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/21/2021	NON-COMPETING CONTINUATION	$622,945
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	7/6/2021	NON-COMPETING CONTINUATION	-$18,688
														Subtotal = $604,257

Issue Date FY: 2020 ( Subtotal = $638,608 )
2020	2020	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/12/2020	NEW	$638,608
														Subtotal = $638,608

Grand Total All Awards = $3,076,377

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Identification of pathways to mitigate Immune-Related Adverse Events with Cancer Immunotherapy

Award Number: U01AR077511

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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