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Serum biomarkers to predict immune related adverse events and benefit from single agent pembrolizumab therapy in early stage triple negative breast cancer

Award Number: R01CA286128
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/14/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Serum biomarkers to predict immune related adverse events and benefit from single agent pembrolizumab therapy in early stage triple negative breast cancer - Abstract Breast cancer is the most diagnosed cancer and the second leading cause of cancer death in women in the USA. Immune checkpoint therapy (ICI) is revolutionizing the therapy of a number of malignancies, including triple negative breast cancer (TNBC). Therapeutic blockade of immune checkpoints, such as by anti-PD-1, removes the tumor-initiated suppression of the immune system and unleashes prolonged anti-tumor immunity. Despite the encouraging success, many patients develop severe and sometimes life-threating adverse effects, or many also fail to benefit from immunotherapy. Existing immune therapy response predictive markers have only modest positive predictive values and there are no clinically useful markers of toxicity. Our proposed study will focus on comprehensive evaluation of serological auto-antibodies (AAb) as potential predictors of immune related adverse event (irAE) and benefit from therapy. Serum based biomarkers exploit easy sample accessibility and directly measure immune responses. Our platform can be rapidly adopted for clinical use. Our study leverages collaboration between experts on immunoproteomics and biomarker discovery and physician scientists specializing in breast cancer. Our study will analyze more than 3000 longitudinal serum samples collected from 1,195 patients enrolled in a randomized phase III trial (SWOG S1418) that tests the efficacy of one year of single agent adjuvant pembrolizumab (anti-PD-1 antibody) therapy compared to observation in high risk TNBC. Serum samples were collected at baseline and at 13 and 55 weeks after starting therapy, all samples are annotated with detailed toxicity and outcome information that were collected during this FDA registration trial. We will employ two complementary high-throughput antibody profiling technologies including Nucleic Acid Programmable Protein Array (NAPPA) and Multiple In Solution Antibody Assay (MISPA) that we developed. NAPPA allows the detection of antibodies against tens of thousands freshly produced full length proteins in hundreds of samples while MISPA enables more precise quantification of hundreds of antibodies in thousands of samples and could be scaled for clinical use. Our approach involves (i) a discovery step using the NAPPA arrays that will interrogate serum samples for AAbs against 18,000 human proteins in the discovery cohort, (ii) a verification step of identified outcome-predictive AAb using the MISPA platform using the discovery samples to select the final set of candidate markers, (iii) and blinded validation of candidate AAb using MISPA on the held out validation set. Identification of biomarkers that can predict clinically-relevant immune-related adverse events or recurrence, and hence inefficacy of therapy, would help better estimate the risk benefit ratio of these very expensive and potentially toxic therapies. Predictors of adverse events could also influence patient monitoring and allow earlier therapeutic intervention. The lessons learned from this proposed study on TNBC will likely impact a broad spectrum of other cancers since adverse events are not cancer type dependent.


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: 2026 ( Subtotal = $632,461 )
2026	2026	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	3	5/7/2026	NON-COMPETING CONTINUATION	$632,461
														Subtotal = $632,461

Issue Date FY: 2025 ( Subtotal = $643,798 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	2	12/3/2024	NON-COMPETING CONTINUATION	$579,418
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Detection and Diagnosis Research	002	2	5/30/2025	NON-COMPETING CONTINUATION	$64,380
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Detection and Diagnosis Research	001	2	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $643,798

Issue Date FY: 2024 ( Subtotal = $671,146 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	1	12/18/2023	NEW	$671,146
														Subtotal = $671,146

Grand Total All Awards = $1,947,405

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Serum biomarkers to predict immune related adverse events and benefit from single agent pembrolizumab therapy in early stage triple negative breast cancer

Award Number: R01CA286128

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/14/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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