Abstract Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical
Background: Natural Killer (NK) cells are central to anti-tumor immunity, with the capacity to directly kill tumor cells by recognizing markers of cellular stress or abnormality. Through cytokine reprogramming, NK cells can gain memory-like features that augment their anti-tumor potential. WU-NK-101 is a non-engineered, cytokine-reprogrammed, expanded, and cryopreserved off-the-shelf NK cell product derived from peripheral blood mononuclear cells. WU-NK-101 demonstrates many features synonymous with memory NK cells, such as enhanced activity, proliferation, and persistence without the requirement of additional engineering strategies, overcoming limitations associated with conventional NK cell therapies. WU-NK-101 demonstrates potent in vitro and in vivo cytotoxicity against tumor cells, enhanced and adaptive metabolic fitness contributing to resilience within an adverse and immunosuppressive tumor microenviroment. Through large-scale feeder-cell-free expansion, WU-NK-101 enables multi-dose treatment of several patients from a single apheresis product (Mathyer M et al. SITC 2021). Multi-dosing may further augment anti-tumor activity leading to enhanced patient benefit without a substantial increase in patient risk.
Aims: This is a Phase 1, open-label, dose escalation, and cohort expansion study (NCT05470140) designed to characterize safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-leukemic activity of WU-NK-101 in R/R AML.
Methods: In the dose escalation phase, up to 18 patients will be treated in up to 3 dose levels (DL), starting with 300 x 106 for DL 1, 900 x 106 for DL2 and 1800 x 106 for DL3, with 1 potential de-escalation DL. Successive cohorts of 3 to 6 patients will be enrolled using a standard 3 + 3 design.
Once the maximum tolerated/administered dose is defined, 6 additional patients will be enrolled in the cohort expansion phase to further characterize the safety, tolerability, as well as determine the recommended Phase 2 dose of WU-NK-101.
Patients will receive a lymphodepleting chemotherapy regimen (cyclophosphamide 50 mg/kg and fludarabine 125mg/kg) starting on days -6 to -2 prior to receiving WU-NK-101. WU-NK-101 will be administered on Days 1, 8, and 15 in a 28-day cycle. All patients will be hospitalized for a minimum of 3 days following the first infusion of WU-NK-101 and will receive recombinant human interleukin-2 every other day of the cycle (1 million IU/m2 qod). Treatment will be limited to 1 cycle in dose escalation. In cohort expansion, patients achieving partial or complete remission may receive re-induction and/or consolidation, for a total of up to 4 cycles.
Eligible patients must have a confirmed diagnosis of primary or secondary AML. Patients with known central nervous system involvement are eligible if they have been treated and cerebrospinal fluid is clear for at least 2 weeks prior to enrollment. Patients with extramedullary disease are permitted if bone marrow blast count is >5%. Key exclusions are circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive therapies are allowed); uncontrolled or untreated bacterial or viral infections; uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG suggestive of acute ischemia or active conduction system abnormalities; and severe renal impairment.
Results: Summary/Conclusion:
Response assessment will take place on Day 28 (+/-3 days), by bone marrow aspirate and core biopsy, and response will be defined per 2022 European LeukemiaNet criteria. Response rate, duration of response, and mortality rate at 1 and 3 months will be evaluated.
Keywords: Clinical trial, Cellular therapy, NK cell, Acute myeloid leukemia