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Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

Award Number: R01CA272772
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer - Lung cancer kills more people than any other type of cancer, including more than 130,000 people each year in the United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers) and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy (i.e., monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatin or carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studies, chemotherapy has some effects that are expected to enhance the efficacy of immunotherapies, whether chemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not well understood at present. Based on our preliminary data, we propose to investigate how cisplatin, a chemotherapy commonly used to treat NSCLC, creates an immunosuppressive tumor microenvironment (TME) that limits the anti-tumor activity of anti-PD-1 immunotherapy. Specifically, we hypothesize the following steps: (a) cisplatin induces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme on the surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production of extracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits the activation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo- immunotherapy. Furthermore, we propose a novel therapeutic strategy for overcoming this adenosine-mediated immunosuppression and sensitizing tumors to chemo-immunotherapy, whereby co-treatment with recombinant polyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressive adenosine into immunostimulatory inosine. In Specific Aim 1 of this project, we will test our predictions about the key cellular and molecular players in this pathway, including cisplatin-induced PGE2 secretion, CD73 expression on M-MDSC, adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivo systems that provide a faithful representation of human NSCLC, including an orthotopic murine lung cancer model and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2, we will test the effectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increase the anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mouse models of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patients who have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completion of these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse and therapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that is FDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that can be quickly translated into improved NSCLC treatment regimens.


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 = $317,740 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	000	3	3/20/2025	NON-COMPETING CONTINUATION	$317,740
														Subtotal = $317,740

Issue Date FY: 2024 ( Subtotal = $335,530 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	000	2	3/12/2024	NON-COMPETING CONTINUATION	$317,870
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$17,660
														Subtotal = $335,530

Issue Date FY: 2023 ( Subtotal = $353,329 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Treatment Research	000	1	3/24/2023	NEW	$353,329
														Subtotal = $353,329

Grand Total All Awards = $1,006,599

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Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

Award Number: R01CA272772

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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