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Tracking Peripheral T-Cell Repertoire Changes for Preoperative and Early Ovarian Cancer Diagnosis

Award Number: R01CA258524
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Tracking Peripheral T-Cell Repertoire Changes for Preoperative and Early Ovarian Cancer Diagnosis - Project Summary Ovarian cancer is the most lethal female cancer. When the disease can be diagnosed at early stage, there is striking survival improvement (five year survival ≥ 90%), compared to late stages (≤ 40%). However, currently no early detection method for ovarian cancer has enough accuracy, and most tumors already progressed to advanced stages at diagnosis. Furthermore, over 70% of the adnexal masses detected on preoperative imaging are found to be benign after pelvic surgery. Current clinical tests rely on serum CA-125 and sonograms to diagnose the ovarian adnexal masses. However, CA-125 is elevated by many common benign conditions; and ultrasound imaging of ovary frequently misses small but malignant lesions. As a result, surgical removal of the lesion and histologic evaluation remains the only gold standard for diagnosis. These limitations dictate an urgent clinical need of a better preoperative diagnostic method with high detection accuracy, to lower the mortality rate, reduce unnecessary surgeries and preserve the life choices for many patients, especially young women at reproductive age planning for pregnancies. Here, we propose a completely different route to detect ovarian cancer signals from the blood T cell repertoire. This is feasible because the T lymphocytes recognize tumor antigens at initial stages, proliferate and alter the peripheral T cell repertoire. Therefore, detection of cancer-associated T cells (CAT) in the blood provides an exciting novel opportunity for non-invasive cancer diagnosis. However, no prior studies have achieved this goal because it is difficult to identify CAT in high-throughput, as most of the cancer antigens remain unknown. To prepare for this task, we developed the software TRUST and iSMART, to obtain antigen-specific TCRs from cancer datasets. These tools have enabled us to produce a large training set of CATs, which allowed us to identify diagnostic TCRs for the ovarian cancer patients. Following this result, we further developed DeepCAT, for pan-cancer prediction using blood TCR sequencing data, and demonstrated over 99% specificity and 86% sensitivity in a pilot study to predict ovarian cancer patients (n=14) from healthy donors (n=176). To develop this approach into a novel ovarian cancer specific biomarker, we have established a biorepository to prospectively collect specimens from patients with benign or malignant ovarian lesions and from healthy donors of similar age span, with related clinical information. In Aim 1, we will generate TCR sequencing data of the new patient samples to develop a novel, TCR-based ovarian cancer predictor using machine learning method. In Aim 2, we will combine this approach with existing clinical tests to obtain a multi-modality biomarker, and independently test it using the samples from the Uterine Lavage cohort led by Dr. Steven Skates. These Aims will be delivered by the PIs and co-investigators with complementary expertise covering gynecological oncology, clinical cohort recruitment, biostatistics, artificial intelligence, immunology and ovarian cancer biomarker development.


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 = $837,856 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	2/12/2025	NON-COMPETING CONTINUATION	$754,071
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$83,785
														Subtotal = $837,856

Issue Date FY: 2024 ( Subtotal = $804,864 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	004	4	2/2/2024	NON-COMPETING CONTINUATION	$593,871
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	006	4	8/2/2024	NON-COMPETING CONTINUATION	$178,000
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	005	4	4/16/2024	NON-COMPETING CONTINUATION	$32,993
2024	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	2	11/15/2023	NON-COMPETING CONTINUATION	-$1
2024	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	003	3	1/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	002	3	11/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$92,438
2024	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	1	11/15/2023	NEW	-$92,437
														Subtotal = $804,864

Issue Date FY: 2023 ( Subtotal = $647,583 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	002	3	9/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$647,582
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	2	9/21/2023	NON-COMPETING CONTINUATION	-$627,706
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$627,707
														Subtotal = $647,583

Issue Date FY: 2022 ( Subtotal = $656,516 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	000	1	12/20/2021	NEW	$656,516
														Subtotal = $656,516

Grand Total All Awards = $2,946,819

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Tracking Peripheral T-Cell Repertoire Changes for Preoperative and Early Ovarian Cancer Diagnosis

Award Number: R01CA258524

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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