Project Term
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Yale University
New Haven, CT
United States
Project Summary
STAT5-driven B-ALL, T-LGL, and T-cell lymphomas exhibit poor outcomes and lack effective targeted therapies. We discovered that the PTPN1/2 inhibitor ABBV-CLS-484 (AC484), originally developed to enhance anti-tumor T-cell responses in solid tumors, unleashes STAT5-signaling and selectively kills STAT5-driven lymphoid malignancies. Unlike solid tumors, STAT5-driven B-ALL, T-LGL and T-cell lymphomas exhibit a unique dependency on their ability to curtail oncogenic STAT5-signaling. We propose that AC484 will exploit this vulnerability while also enhancing anti-leukemia T-cell responses. This dual mechanism may provide the first targeted strategy for STAT5-driven T-LGL and T-cell lymphomas, and synergize with immunotherapies such as blinatumomab (Fig. 2) and CD19 CAR T cells (Fig. 3) in B-ALL.
Lay Abstract
Background and Significance: Certain blood cancers—including B-cell acute lymphoblastic leukemia (B-ALL), T-cell large granular lymphocytic leukemia (T-LGL), and a subset of T-cell lymphomas—are driven by a protein called STAT5 that helps cancer cells grow and survive. Patients with these cancers often respond poorly to standard therapies. While CD19-targeted immunotherapies such as blinatumomab and CAR T-cells have improved outcomes in B-ALL, no targeted treatments currently exist for T-LGL or STAT5-driven T-cell lymphomas.
Discovery and Rationale: We studied a new drug, AC484, originally developed to boost immune T-cell responses in solid tumors. Early trials showed it was safe, but it did not directly kill solid tumor cells. In contrast, we found that certain blood cancers with abnormal enzymes—like B-ALL with BCR-ABL1 or JAK2 fusions and T-cell lymphomas with ALK or TYK2 fusions—were highly sensitive to AC484. Using gene-editing screens, we discovered that the drug’s effectiveness depends on STAT5 signaling: removing key STAT5-related genes made cancer cells resistant, whereas disabling negative regulators of STAT5 made them even more vulnerable. This revealed a “Goldilocks” requirement: these cancer cells need just the right level of STAT5 activity to survive, which AC484 disrupts.
Hypothesis: Because AC484 both disrupts cancer cell signaling and boosts immune T-cell activity, we propose that it could provide a dual benefit: directly killing leukemia and lymphoma cells while enhancing the immune system’s ability to attack them. This approach could provide the first targeted therapy for T-LGL and STAT5-driven T-cell lymphomas and may work in combination with immunotherapies like blinatumomab or CD19 CAR T cells in B-ALL.
Specific Aims: Aim 1: Test AC484 in combination with blinatumomab and CAR T cells in STAT5-driven B-ALL using humanized mouse models engineered to carry human CD19 and CD3 genes. These models allow us to study how AC484 enhances immune-based therapies in immunocompetent settings.
Aim 2: Exploit the vulnerability of STAT5-driven T-LGL and T-cell lymphomas using synthetic lethality. We will study relevant cell lines in the lab and evaluate AC484 in four patient-derived tumor models (three STAT5B-mutant T-cell lymphomas and one BCR-JAK2 T-LGL) to confirm both effectiveness and selectivity.
Given its favorable safety profile and oral bioavailability, this work will support the clinical development of AC484 as a first-in-class therapy for STAT5-driven B-ALL, T-LGL, and T-cell lymphomas, offering new hope for patients with these difficult-to-treat cancers.
Program