Immunotherapy targeting mutant nucleophosmin-1 on acute myeloid leukemia

Engineering T-lymphocytes with receptors for mutant nucleophosmin-1 to target acute myeloid leukemia

Acute Myeloid Leukemia (AML) is the most common type of (aggressive) acute leukemia in adults. Diagnosis of AML is an immediate indication to start high dose chemotherapy which may be followed by allogeneic hematopoietic stem cell transplantation. Although most patients initially respond, the disease returns within three years in approximately 50% of patients, which drastically worsens the prognosis.  

Nucleophosmin-1 is mutated in 30% of AML patients. At the LUMC, various mutant nucleophosmin-1 (dNPM1) structures have been found on the cell surface of AML. For one structure, a T-lymphocyte was isolated that was able to bind to dNPM1 with a specific receptor. The genetic information for this T-cell receptor (TCR) can be used to engineer and redirect patient T-lymphocytes to target AML.  

In Europe, 18,000 people are diagnosed with AML each year. The identified TCR recognizes dNPM1 in HLA-A*02:01. Approximately 30% of AML patients carry dNPM1 and 50% of Europeans are HLA-A*02:01 positive, accounting for an annual number of 2,700 (15%) patients that are eligible for dNPM1-A2 TCR-T cell therapy.  

LUMC and MILTENYI collaborate to develop dNPM1-A2 TCR-T cell immunotherapy as effective cancer therapy for severely ill patients with AML. The aim is to start a clinical study at the LUMC in 2023.  

A protocol was established to produce dNPM1-A2 TCR-T cells on MILTENYI’s MACS Prodigy platform which allows fast, standardized and automated manufacturing in a closed system. The TCR-T cells were shown to target AML in mice engrafted with human AML. In addition, a detailed preclinical safety evaluation was performed, which showed no evidence that dNPM1-A2 TCR-T cells will cause severe side effects. Finally, two new receptors were identified recognizing dNPM1 in HLA-A*03:01 or HLA-A*11:01, together expressed in 35-40% of Europeans. The two receptors are currently under investigation for their potential clinical use to treat patients with AML. 

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Summary
LUMC and MILTENYI collaborated to develop immunotherapy with patient T-lymphocytes that are engineered to target mutant nucleohosmin-1 on acute myeloid leukemia. The aim is to use T-lymphocytes for mutant nucleophosmin-1 as effective immunotherapy for severely ill patients with acute myeloid leukemia in a clinical study at the LUMC in 2023.
Technology Readiness Level (TRL)
7 - 9
Time period
36 months
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