An analysis of a first-in-human study of NEXI-001 donor-derived antigen-specific CD8+ T-cell treatment of relapsed AML after allogeneic hematopoietic cell transplantation (HCT).
Authors: Al Malki Monzr M. , Vasu Sumithira , Modi Dipenkumar , Afonso-Smith Suzanne D , Kim Sojung , Lu Emily , Marcucci Guido , Oelke Mathias , Knight Robert D. , Varela Juan Carlos 
Published: June 2023

7043 Background: NEXI-001 is a non-genetically engineered donor-derived cellular therapy product consisting of > 90% CD3+/CD4- T cells that includes significant numbers of CD8+ T cells that are of early memory subtypes and target 5 specific HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens that are commonly expressed on AML blasts and leukemic stem cells. Methods: AML patients who relapse after allogeneic HCT have a high unmet medical need. These patients have a poor prognosis (2-year survival rate < 10%) and few treatment options. Currently 11 patients have completed the 4-week dose-limiting toxicity (DLT) period in the 3+3 design of the dose-escalation stage of this NEXI-001 phase I trial. The following doses of NEXI-001 T cells were administered during the DLT period: Cohort 1, 4 patients received an infusion of 50M (million) to 100M T cells; Cohort 2, 4 patients received an infusion of 200M T cells; and Cohort 3, 3 patients received infusions of 200M T cells on Days 1, 8, and 15. Results: The NEXI-001 antigen-specific T cells were found to persist and expand in peripheral blood, traffic to bone marrow, and maintain a less differentiated immunophenotype in blood and bone marrow for ≥3 months. No DLTs have occurred. NEXI-001-related adverse events have included grade 2 cytokine release syndrome (2), grade 1 diarrhea (2), grade 2 orthostatic hypotension (1), and a grade 3 GvHD of the gut in week 3 of the first NEXI-001 cycle that resolved within 72 hours with corticosteroid treatment. Clinical activity consisting of the following have occurred in patients within each cohort; neutrophil and platelet count recovery resulting in decreased transfusions and decreases in blasts in peripheral blood and bone marrow. A patient who achieved an MRD- remission following bridging therapy and then was administered a single infusion of 200M NEXI-001 T cells has continued to remain in CR at 6 months of follow-up. A patient in Cohort 3 who relapsed after alloHCT with extramedullary disease manifested by a pleural effusion has achieved a 45% decrease of the symptomatic moderate effusion at baseline to an asymptomatic small effusion after the administration of three 200M NEXI-001 T cells on Days 1, 8, and 15 of the first 4-week cycle. The patient remains asymptomatic at 3 months of follow-up with no detectable AML blasts in peripheral blood or bone marrow and a stable small effusion. A PET scan of the chest showed no areas of increased uptake. Conclusions: Early results indicate that the antigen-specific NEXI-001 T cells have the potential to enhance GvL effects and is tolerated with easily manageable side effects. Greater clinical activity has been observed with increased doses of the NEXI-001 T cells. The trial remains ongoing, and the data support an Expansion Cohort of the study that will allow for a more complete assessment of clinical activity. Clinical trial information: NCT04284228 .