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Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3 + 3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received one infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 26 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 million cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Biochemical abnormalities consistent with grade 2 hemophagocytic lymphohistiocytosis were seen in one patient (3.8%). Grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and one grade 2 acute graft-vs-host disease event occurred. Grade 5 events (11.5%) were due to fungal infection and multi-organ failure. The composite complete remission rate was 81.8% among 11/13 patients evaluable for response at the RP2D. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. ClinicalTrials.gov registration: NCT04984356., Competing Interests: Additional Declarations: Yes there is potential Competing Interest. Financial: Armin Ghobadi: Honorarium from Kite, a Gilead company; consultancy provided for Amgen, Atara, Bristol Myers Squibb, CRISPR therapeutics, Kite, Novartis, and Wugen; research funding from Amgen, Genentech, and Kite. Ibrahim Aldoss: Ad Board and consultant fees from Wugen, Amgen, KITE, Abbvie, Takeda; Research support: MacroGenics, Abbvie Shannon L. Maude: Clinical trial support from Novartis and Wugen; advisory and study steering committees for Novartis and Wugen; patent pending and licensed to Novartis Pharmaceuticals without royalty for PCT/US2017/044425: Combination Therapies of Car and PD-1 Inhibitors. Bhagirathbhai Dholaria: Institutional research funding, no direct payment: Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, NCI, Atara, Gilead, Molecular templates, BMS, AstraZeneca, Adicet. Consultation/Advisory board: Janssen, Pluri Biotech, BOXER CAPITAL, Ellipsis pharma, Lumanity, Autolus, Acrotech, ADC therapeutics, Gilead, Global health research, GSK, Roche Rawan Faramand: Advisory Board: Kite/Gilead; Autolus; Consultancy: Sanofi;Research Funding: Kite/Gilead; Novartis Andre Baruchel: Servier: symposia, travels; Jazz: advisory boards; Amgen: symposia; Servier: funding for academic clinical research protocol; Astra Zeneca: advisory board paid to institution Nicolas Boissel: Consultant for Novartis, Amgen, Bristol Myers Squibb, and Jazz Pharmaceuticals; and receives honoraria from Novartis, Amgen, Incyte, Servier, Bristol Myers Squibb, Jazz Pharmaceuticals, Celgene, Sanofi, and Pfizer. Brent Wood: Dr. Wood’s institution receives funding for contract laboratory testing from a number of biopharma companies including two that have products whose efficacy is being evaluated in T-ALL. However, there is no interaction between the services provided for each company. Dr. Wood also is a paid consultant on MRD testing for clinical trials for Amgen, but does not involve products for T-ALL. Haley Irons: Employment in Wugen Ben Capoccia: Employment in Wugen Deborah Masters: Employment and shares in Wugen Justo Gonzalez: Wugen employment Tony Wu: Employment and shares in Wugen Maria del Rosario: Employment and shares in Wugen Alexander Hamil: Employment and shares in Wugen Ouiam Bakkacha: Employment and shares in Wugen, MacroGenics stock John Muth: Employment and shares in Wugen Brett Ramsey: Employment and shares in Wugen Eileen McNulty: Employment and shares in Wugen Matthew L. Cooper: Equity, ownership, employment in Wugen Jan Baughman: Consultant to Wugen; MacroGenics stock Jan Davidson-Moncada: Employment and shares in Wugen John F. DiPersio: Consulting: Rivervest, Bluebird Bio, Vertex, HcBiosciences, SPARC; Equity-ownership WUGEN and Magenta; Research support: MacroGenics, Bioline, Incyte. Support: NCI R35 CA210084, Leukemia and Lymphoma Society SCOR Non-Financial: Armin Ghobadi: Wugen founders include members of Washington University physicians that are colleagues of Dr. Ghobadi. Ryan J. Mattison:Vice chair of the Acute Lymphoblastic Leukemia committee for the National Comprehensive Cancer Netork (NCCN) C. Michel Zwaan: Chair of Hem-iSMART study for T-cell ALL with support from Abbvie and Novartis

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956., (© 2021 by The American Society of Hematology.)