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Advancing TGFβ-Resistant CAR-NK Cell Therapy for Acute Myeloid Leukemia

Award Number: R01CA315771
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Advancing TGFβ-Resistant CAR-NK Cell Therapy for Acute Myeloid Leukemia - Summary: Patients with relapsed/refractory (R/R) AML have poor outcomes and novel therapies are urgently needed. Although CAR engineering has changed the treatment paradigm for B-cell malignancies and multiple myeloma, its use in AML faces challenges due to risks of marrow aplasia, and heterogeneous antigen expression predisposing to leukemia escape. AML blasts, however, are susceptible to natural killer (NK) cell killing as they express stress ligands recognized by NK cell activating receptors. Thus, CAR-NK cells could potentially address some of the challenges related to antigen escape and tumor heterogeneity through their innate ability to recognize and kill AML cells combined with their engineered specificity against tumor antigens. Our group has validated the safety and efficacy of cord blood (CB) derived CAR19/IL-15 NK cells in a first-in-human clinical trial in patients with R/R B-cell malignancies (NEJM 2020; Nature Medicine 2024). Building on these data, we now propose a clinical trial targeting CD70 in AML. Unlike other AML targets, CD70 is not expressed on normal HSCs, minimizing the risk of cytopenias. Our engineered NK cells, express a truncated human CD27 (the natural receptor for CD70), a CD28 costimulatory domain, a CD3æ signaling domain, IL-15, and an inducible caspase-9 (iC9) safety switch (collectively referred to as iC9/CAR27-28æ/IL-15 NK cells). Moreover, given our recent data showing the critical role that TGF-â plays in AML to rewire NK cells epigenetically towards a dysfunctional state (Science Translational Medicine 2024), we have introduced CRISPR gene editing of the TGFBR2 to protect our NK cells from this immunosuppression. Our TGFBR2 KO iC9/CAR27-28æ/IL-15 NK cells have shown potent antitumor activity against AML preclinically. Our therapeutic approach also includes an innovative lymphodepleting chemotherapy regimen that combines the hypomethylating agent decitabine with standard fludarabine and cyclophosphamide, designed to enhance CAR-NK cell efficacy by upregulating CD70 expression. The clinical protocol has been approved by IRB and FDA (protocol #2024-1967, IND31339) and the trial is open and accruing at our center. Additionally, we have developed a robust genome-wide CRISPR screening platform to identify novel regulators of CAR-NK cell function and mechanisms of resistance in AML. Insights from these studies will inform the development of next-generation CAR-NK cells, optimized to overcome immune evasion strategies and improve patient outcomes. The overarching goal of this research is to develop novel, highly effective cellbased therapies for AML using CB-derived NK cells, further improving their clinical potential through genetic engineering to enhance specificity and potency. In Aim 1 we will conduct a Phase I/II clinical trial to evaluate the safety and efficacy of TGFBR2 KO iC9/CAR27-28æ/IL-15 NK cells in patients with CD70+ AML. In Aim 2 we will perform innovative correlative studies. In Aim 3, we will perform genome-wide CRISPR screens in both our iC9/CAR27-28æ/IL-15 NK cells and AML cell lines to uncover novel mechanisms of resistance and identify actionable targets for next-generation CAR-NK cell therapies. Lead candidates identified through these screens will be validated in vivo using animal models, which are necessary to evaluate CAR-NK cell trafficking, expansion, persistence and antileukemic activity within the complex leukemia and bone marrow microenvironment, features that cannot be adequately modeled in vitro. These studies will define mechanisms of therapeutic resistance and inform the rational design of next-generation CAR-NK cell therapies for AML.


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 = $387,156 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	8/10/2026	NEW	$387,156
														Subtotal = $387,156

Grand Total All Awards = $387,156

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Advancing TGFβ-Resistant CAR-NK Cell Therapy for Acute Myeloid Leukemia

Award Number: R01CA315771

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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