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Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer

Award Number: R21CA263424
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer - ABSTRACT Blockade of the immune checkpoint PD-1/PD-L1 has increased overall and progression-free survival in various cancers. However, only a restricted number of patients show clinical benefits. Understanding the mechanisms by which anti-PD-1 antibodies modulate exhausted CD8+ T cells is mandatory to improve this approach. In this context, the role played by inflammation in T cell exhaustion and tumor immunotherapy is controversial. Observations on various mouse models and on human melanoma cohorts support the notion that activation of innate immune players such as inflammasomes, may play a key role in anti-PD-1 therapy. However, we need to identify molecular targets to trigger inflammasome activation potentially leading to improved anti-PD-1 therapy. TMEM176B is an intracellular cation channel strongly expressed by conventional type 2 dendritic cells (cDC2) that inhibits inflammasome activation through ionic mechanisms. Boritinib, a potent TMEM176B inhibitor, induced tumor growth control and reinforced the antitumor activity of anti-PD-1 antibodies in a Tmem176b, inflammasome and CD8+ T cell-dependent manner in lymphoma, melanoma, lung and colon mouse cancer models. However, the mechanism underlying CD8+ T cell reinforcement remains unknown. This project aims at characterizing the mechanisms by which Boritinib improves anti-PD-1 therapy, setting the ground for the clinical evaluation of the compound. Our published and unpublished results led us to propose that inflammasome activation triggered by Boritinib therapy may modulate subsets of exhausted CD8+ T cells, through a mechanism involving Th17 cells. We will carry out a research program involving functional in vivo studies and bioinformatics analysis based on three specific aims. In Specific Aim 1 we wish to confirm and complement our unpublished results suggesting that Boritinib modulates CD8+ T cell exhaustion. In specific aim 2 we will then assess whether Th17 cells are Boritinib/inflammasome-triggered effectors leading to modulation of exhausted CD8+ T cells. In Specific Aim 3 we will study the impact of timing when combining both therapies. We speculate that the timing at which anti-PD-1 therapy and inflammasome modulation occur might determine the fate of exhausted CD8+ T cells and, perhaps, the clinical outcome of immunotherapeutic modalities. On this basis, future research will then complete ongoing preclinical pharmacological characterization of Boritinib before engaging a clinical study of the compound. This knowledge may position Boritinib as a potential candidate to be a first-in-class drug in immuno- oncology.


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 = $0 )
2024	2022	ARDAN PHARMA S.A.S.	AVENIDA BELGRANO 758	SUNCHALES	SANTA FE			ARG	Cancer Treatment Research	000	2	4/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $120,219 )
2022	2022	ARDAN PHARMA S.A.S.	AVENIDA CORDOBA 1776, PISO 4	CIUDAD DE BUENOS AIRES				ARG	Cancer Treatment Research	000	2	9/13/2022	NON-COMPETING CONTINUATION	$120,219
														Subtotal = $120,219

Issue Date FY: 2021 ( Subtotal = $155,024 )
2021	2021	ARDAN PHARMA S.A.S.	AVENIDA CORDOBA 1776, PISO 4	CIUDAD DE BUENOS AIRES				ARG	Cancer Treatment Research	000	1	8/23/2021	NEW	$155,024
														Subtotal = $155,024

Grand Total All Awards = $275,243

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Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer

Award Number: R21CA263424

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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