GTB-3550 TriKE™ for the Treatment of High-Risk Myelodysplastic Syndromes (MDS) and Refractory/Relapsed Acute Myeloid Leukemia (AML) Safely Drives Natural Killer (NK) Cell Proliferation At Initial Dose Cohorts

Introduction: Relapsed/refractory AML and MDS present a clinical challenge. Despite FDA approval of multiple new targeted agents, many patients lack actionable mutations and have exhausted conventional chemotherapeutic options. We have shown that NK cell infusions after lymphodepleting chemotherapy...

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Veröffentlicht in:Blood 2020-11, Vol.136 (Supplement 1), p.7-8
Hauptverfasser: Warlick, Erica D., Weisdorf, Daniel J., Vallera, Daniel A., Wangen, Rose, Lewis, Dixie, Knox, JoAnn, Schroeder, Martin, Felices, Martin, Miller, Jeffrey S.
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Sprache:eng
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Zusammenfassung:Introduction: Relapsed/refractory AML and MDS present a clinical challenge. Despite FDA approval of multiple new targeted agents, many patients lack actionable mutations and have exhausted conventional chemotherapeutic options. We have shown that NK cell infusions after lymphodepleting chemotherapy can induce remissions in relapsed/refractory AML. However, this cell-based therapy lacks antigen specificity. To address this, we developed GTB-3550 TriKE, a novel CD16/IL-15/CD33 Tri-Specific Killer Engager (TriKE). GTB-3550 TriKE is comprised of two single chain variable fragments (scFvs); one that binds CD16 on NK cells and one that binds CD33 on myeloid malignancies, plus an IL-15 linker bridging the CD16 and CD33 scFvs for sustained cell activation. Pre-clinical data shows specific NK cell activation and targeted cytolytic activity in xenogeneic AML mouse models. Methods: Patients with CD33+ malignancies (primary induction failure or relapsed AML with failure of one reinduction attempt or high risk MDS progressed on two lines of therapy) age 18 and older were eligible (NCT03214666) if they had adequate renal, hepatic, cardiac and lung function and absolute lymphocyte count (ALC) ≥ 200 cells/µL or absolute circulating CD56+/CD3- NK cell count >25 cells/µL within the 14 days prior to start of therapy. The primary endpoint is to identify the maximum tolerated dose (MTD) of GTB-3550 TriKE. Correlative objectives include the number, phenotype, activation status and function of NK cells and T cells. During phase 1, each patient received the GTB-3550 TriKE at 5-200 mcg/kg/day (in 6 cohorts) for 3 weeks (infusion block #1, #2, and #3) of 96 hours continuous infusion separated by a 72-hour rest. Two patients enrolled per dose cohort. Disease response assessed by bone marrow biopsy between Days 21-42. Results: Four patients have enrolled, two at 5 mcg/kg/day and two at 10 mcg/kg/day, and three have completed therapy. Two patients with stable disease and one had substantial disease progression in the setting of a FLT-3 ITD mutation (Figure 1A). The first patient at 5 mcg/kg/day had stable disease after course 1 and qualified for retreatment with a second course of 3 weeks of GTB-3550 TriKE due to improved platelet transfusion requirements. Of the four complete courses of treatment delivered, all were delivered on schedule without treatment interruptions. The previous MTD of continuous infusion rhIL-15 was 2 mcg/kg/day (Conlon et al, Clin. Ca Res.) with associated feve
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2020-136398