Michael A. Caligiuri

In this first-in-human open-label study, autologous FLT3 CAR-T cells were delivered to two patients with relapsed and refractory FLT3 ⁺ AML. Bone marrow examination revealed AML blasts with high but variable surface density of FLT3 expression. Following tumor cytoreduction and lymphodepletion, 1 × 10 ⁶ /kg of FLT3 CAR-T cells were administered, resulting in in vivo CAR-T cell expansion and grade 1 cytokine release syndrome in both patients. Both patients failed to achieve remission after CAR-T cell therapy, but bone marrow examination following therapy revealed the elimination of FLT3 ⁺ AML blasts, persistence of FLT3 ⁻ AML blasts, and early post-treatment preservation of normal CD34 ⁺ hematopoietic stem and progenitor cells (HSPCs) with variable FLT3 expression. Collectively, autologous FLT3 CAR-T cells can be safely administered and can eradicate FLT3⁺ blasts with minimal toxicity, without causing substantial damage to normal CD34⁺ HSPCs; however, they fail to induce leukemic remission due to the heterogeneity of FLT3 expression and the persistence of FLT3⁻ AML blasts.

Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34⁺CD38⁺ to CD34⁻CD38⁺ cells and blocks the differentiation of LSCs (CD34⁺CD38⁻) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34⁻CD38⁺ to CD34⁻CD38⁻ cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin⁻CD127⁺CD161⁻CRTH2⁻CD117⁻ (CD161⁻ ILC1s) that can be generated from umbilical cord blood CD34⁺ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.