444 GTB-3550 tri-specific killer engager TriKE™ drives NK cells expansion and cytotoxicity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients

Background Treatment for relapsed/refractory [r/r] AML and high risk MDS is dismal NK cell infusions (with IL-2 or IL-15) after lymphodepleting chemotherapy can result in 30–40% remission. However, cells lack antigen specificity require cytokine expansion. We have developed a novel tri-specific molecule, 1 termed GTB-3550 TriKE, comprised of IL-15 surrounded by two single chain variable fragments (scFvs), one against CD16 on CD33 blasts. Methods Supported pre-clinical data, adults with CD33+ malignancies (r/r MDS) are eligible ( NCT03214666 ). Correlative objectives include the number, phenotype (Flow CyTOF), function before therapy. Results Twelve patients completed therapy at doses 5–150 mcg/kg/day without dose limiting toxicity. Out 11 post treatment disease assessment, 3 had blasts decreases 33, 61 63% cohorts 25, 50, 100 mcg/Kg/day, respectively. One patient (150 mcg/Kg/day) was found to multilineage leukemia significant population CD19+/CD33- not affected but demonstrated 50% decrease on-target CD19-/CD33+ blasts.Correlative studies show dose-dependent activity across cohorts, primarily robust expansion loss (figure 1A). Expansion specific preferential Ki-67 expression day 22 study 1B). Using detection as measure serum, we find short half-life predicted no evidence drug accumulation 1C). Despite rapid clearance, mononuclear further activation demonstrate enhanced cytotoxicity HL-60 targets days 8, 15, initial treatment, last 1D). To better predict factors responsiveness, responder non-responder blood (d22) incubated (no added) degranulation (CD107a) measured 1E). indicate that responders higher degranulating than non-responders. explore further, carried out 42-antigen CyTOF analysis. Differential analysis (DEA) mature (CD56+CD16+) showed increased maturation marker CD57 receptor NKG2D, while showing decreased inhibitory KIR 1F). Abstract 444 Figure Correlate outline potent, specific, Conclusions Our Phase I demonstrates TriKE safety, endogenous clinical signal activity. Immune monitoring suggests schedule maximize vivo repeat courses will enhance Trial Registration References Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, et al. IL15 Trispecific Killer Engagers (TriKE) Make Natural Cells Specific Targets While Also Inducing Persistence, In Vivo Expansion, Enhanced Function. Clinical cancer research: an official journal American Association Cancer Research 2016; (14):3440–50. Ethics Approval The protocol consent procedures were approved University Minnesota Institutional Review Board (HSC # STUDY00000881). FDA under BB-IND 136205. All donors gave informed prospective data collection accordance Declaration Helsinki.