Wednesday, July 23, 2025 7/23/2025

HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer

Award Number: R01CA269954
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer - Bladder cancer is the most expensive cancer per capita to treat in the US. Non-muscle invasive bladder cancer (NMIBC) which accounts for 70-75% of all newly diagnosed tumors and has only a single FDA approved first- line treatment option, Bacillus Calmette-Guérin (BCG). BCG has been the only approved first-line therapy for intermediate and high-risk NMIBC for more than 40 years. While BCG can induce durable responses, ~50% of patients have recurrence or progression of their disease. The current dosing of BCG is arbitrary with no data currently available to support the dosage, strain nor regimen. Furthermore, no clear mechanism of action behind BCG’s anti-neoplastic activity in NMIBC has been delineated. Better understanding of the immune response initiated by exposure to BCG and how such response is sustained over many repeated doses is essential to help improve its therapeutic action. Further, it may lead to discovery of predictive biomarkers and novel targets leading to advance care for patients, reduce the financial burden associated with the disease, and improve access to BCG. Our preliminary data have identified a significant Type-1 cytokine response to BCG in all patients inducing an activation and recruitment of IFN-g producing NKG2A+ natural killer (NK) cells and NKG2A+PD-1+ CD8 T cells to the tumor microenvironment (TME). Our preliminary analyses of post-BCG-treated specimens demonstrate IFN-g signaling as the most upregulated signature in BCG resistant specimens and strongly correlates with increased HLA-E and PD-L1 expression on the recurring tumors. Monalizumab (anti-NKG2A) is a novel therapeutic target and is currently in clinical trials across several cancer types. A role for NKG2A/HLA-E alone or in conjunction with PD-1/PD-L1 in regulating NK and CD8 T cells remains elusive with virtually nothing known in bladder cancer. Our hypothesis is that chronic activation from repeated exposures to BCG drives immune dysregulation followed by functional exhaustion in a significant proportion of patients, which then leads to disease recurrence or progression. The immune dysregulation in the TME is driven by NKG2A/PD-1 on CD8 T cells, NKG2A on NK cells and HLA-E and PD-L1 on tumor cells. To further validate our findings and better understand BCG mechanisms we will study the following aims: Aim 1: To analyze intratumoral NK cells and T cells and their interactions with tumors in response to BCG therapy. We will test the hypothesis that upregulated expression of HLA-E and PD-L1 on recurring tumors are directly in contact with infiltrating NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells. Aim 2: To longitudinally assess blood and tumor phenotypes and functions in response to BCG therapy. We will test the hypothesis that repeated exposures to BCG drives prolonged activation and dysregulation of NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells. Aim 3: To determine the effects of combination PD-L1 and NKG2A blockade on anti-tumor immunity. We will test the hypothesis that NKG2A+ NK and NKG2A+ PD-1+ CD8 T cells can be functionally restored through use of PD-L1 and NKG2A combination blockade.


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 = $667,174 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$600,457
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$66,717
														Subtotal = $667,174

Issue Date FY: 2024 ( Subtotal = $637,395 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	2	1/31/2024	NON-COMPETING CONTINUATION	$603,848
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$33,547
														Subtotal = $637,395

Issue Date FY: 2023 ( Subtotal = $686,087 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	1	2/1/2023	NEW	$686,087
														Subtotal = $686,087

Grand Total All Awards = $1,990,656

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HLA-E and NKG2A define a novel immune checkpoint axis in non-muscle-invasive bladder cancer

Award Number: R01CA269954

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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