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Multiplex Epitope Editing to Enable Novel Immunotherapies for Acute Myeloid Leukemia

Award Number: R01CA286036
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Multiplex Epitope Editing to Enable Novel Immunotherapies for Acute Myeloid Leukemia - PROJECT SUMMARY While immunotherapies have proved compelling efficacy against other leukemias, their application for acute myeloid leukemia (AML) is still hampered by the absence of tumor-restricted targets. The most suitable AML targets are shared with healthy hematopoietic stem/progenitor cells (HSPCs) or mature myeloid cells, leading to on-target/off-tumor toxicity and impairment of hematopoietic reconstitution. To address this issue, we hypothesized that epitope-engineering of donor HSPCs used for conventional bone marrow transplantation can endow hematopoietic lineages with selective resistance to CAR-T or monoclonal antibodies (mAb), without affecting protein function or regulation. This strategy allows targeting genes essential for leukemia survival regardless of shared expression on HSPCs, thus reducing the risk of tumor immune escape by antigen downregulation/loss. We have already identified single amino-acid (aa) changes that abrogate the binding of therapeutic mAb targeting FLT3, CD123, and KIT and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation capacity. We confirmed the in vivo resistance of epitope-edited hematopoiesis to CAR-T treatment and the concomitant eradication of patient-derived AML xenografts (Casirati et al., Nature 2023). Here, we will capitalize on these achievements and exploit state-of-the-art genetic engineering tools and in vivo modeling with the objectives to i) generate and functionally validate “stealth” FLT3, KIT, and IL3RA genes by multiplex base-editing; ii) identify the best- performing CAR configuration for multi-Ag targeting on AML samples and iii) validate resistance of edited HSPC to new immunotherapies directed against these targets. This project will provide fundamental advancement of new and more effective immunotherapy approaches for AML that should additionally have broad applicability to several other hematopoietic malignancies.


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 = $721,888 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	6/12/2025	NON-COMPETING CONTINUATION	$721,888
														Subtotal = $721,888

Issue Date FY: 2024 ( Subtotal = $780,389 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	7/3/2024	NEW	$780,389
														Subtotal = $780,389

Grand Total All Awards = $1,502,277

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Multiplex Epitope Editing to Enable Novel Immunotherapies for Acute Myeloid Leukemia

Award Number: R01CA286036

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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