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Cassette exons in neoplastic pro-B-cells: implications for immunotherapy

Award Number: U01CA232563
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Cassette exons in neoplastic pro-B-cells: implications for immunotherapy - PROJECT SUMMARY/ABSTRACT Successful immunotherapies for childhood cancers typically target lineage-, rather than cancer-specific markers, B-cell specific CD19 being the prime example. These successes culminated in the recent FDA approval of bi-specific T-cell engagers and chimeric antigen receptor (CAR)-armed T-cells for B-cell acute lymphoblastic leukemia (B-ALL). However, relapses frequently occur in patients treated with CD19- directed immunotherapies, often due to epitope loss. While strategies based on dual antigen targeting are beginning to emerge, they are still based on targeting canonical B-cell markers, with the unavoidable side effect of total ablation of normal B-cells. The apparent paucity of tumor-specific targets in pediatric cancers (including leukemias) is likely to limit future immunotherapies. We hypothesize that alternative splicing could be both a mechanism of epitope loss and a rich source of a neo-antigens in B-ALL. Indeed, using computational and biochemical approaches, we have identified hundreds of local splicing variations (LSVs), mapping to transmembrane proteins (e.g., CD19 and CD22) with prominent extracellular domains (ectodomains). In fact, in our prior work we described a mechanism of acquired resistance to CART-19 based on selective loss of the CD19 ectodomain, primarily through exon 2 skipping. The two large Aims of this U01 are as follows. Aim 1: To identify programs and determinants of altered splicing of B-ALL cell surface antigens. Our overarching goal is to construct a dedicated “splicing code” for leukemic B-cells. Such a code will predict cis-acting genetic variants as well as trans-acting factors involved in alternative splicing and allow us to identify all alternatively spliced ectodomains. Then in Aim 2, we will investigate the effects of alternative splicing on B-ALL immunotherapy. Using CD22 as just one example, we will determine how truncated protein isoforms confer resistance to CD22-targeting immunotherapeutics, including antibody- drug conjugates such as inotuzumab ozogamicin, which was recently approved by FDA to treat relapsed or refractory B-ALL. We will also raise antibodies against peptides spanning novel exon junctions, generate antibody-drug conjugates, and test their efficacy against B-ALL cell lines and patient-derived xenografts. In summary, this leukemia-based U01 will create new computational and conceptual frameworks, which would be highly synergistic with Pediatric Immunotherapy Discovery & Development Network (PI-DDN) overall goals, including identification of antigenic epitopes that are uniquely expressed on childhood cancers and of cancer cell-intrinsic mechanisms of immune evasion.


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 = -$12 )
2025	2022	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	10/17/2024	SUPPLEMENT FOR EXPANSION	-$12
														Subtotal = -$12

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	1	7/13/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	7/13/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $420,362 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	3/21/2022	SUPPLEMENT FOR EXPANSION	$420,362
														Subtotal = $420,362

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	8/31/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $185,346 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	8/24/2020	SUPPLEMENT FOR EXPANSION	$185,346
														Subtotal = $185,346

Issue Date FY: 2018 ( Subtotal = $2,931,750 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/14/2018	NEW	$2,931,750
														Subtotal = $2,931,750

Grand Total All Awards = $3,537,446

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Cassette exons in neoplastic pro-B-cells: implications for immunotherapy

Award Number: U01CA232563

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/14/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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