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PURPOSE The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti–PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

4084 Background: In a phase 1b trial (NCT03006926), L + P had promising antitumor activity as first-line (1L) therapy in uHCC. We present exploratory biomarker analyses of circulating angiogenic factors and cytokines/chemokines related to the mechanism of action of L + P (ie, pharmacodynamic [PD] biomarkers), as well as biomarker correlations with clinical outcomes in patients (pts) with uHCC, from this trial. Methods: Pts received lenvatinib 12 mg/d (bodyweight [BW] >60 kg) or 8 mg/d (BW < 60 kg) PO + pembrolizumab 200 mg IV Q3W. Tumors were assessed using mRECIST or RECIST v1.1 per independent imaging review. Peripheral blood samples were collected before administration of study drug at baseline, cycle (C) 2, day (D) 1, C3D1, C4D1, and off-treatment. 43 Biomarkers were assayed in serum from 100 1L uHCC pts (excluding 4 pts from the dose-limiting toxicity part of the trial with prior sorafenib). Of these 43, 31 biomarkers (for which ≤20% of samples had measurements above/below the quantification limit of the assay) were included in the analyses. Changes in biomarker levels from baseline were evaluated via 1-sample Wilcoxon signed-rank test. Associations were explored between changes in biomarker levels and maximum tumor shrinkage (MTS) via the Spearman’s rank correlation test, objective response (OR; complete response + partial response) via the Wilcoxon rank sum test, and PFS via Cox regression analysis and log rank test. Data cutoff date for clinical endpoints was 7 August 2020. Results: Levels of PD biomarkers related to angiogenic signaling (VEGF increase/ANG2 decrease), FGF signaling (increase in FGF23/FGF19), and IFNγ signaling (increase in IFNγ, CXCL9/10/11) were changed significantly (adjusted P< 0.05) with L + P (C2D1–C4D1; except for FGF19 at C3D1). Significant decreases of TIMP1 and increases of MCP1 were observed at C4D1 during treatment; these were associated with greater MTS. Greater decreases in TIMP1 and greater increases in MCP1 were observed in pts with OR vs others. Changes in levels of the PD biomarkers ANG2, IL10, and VEGFR2 were found to be associated with PFS by dichotomized analysis. With tertile 2 cutoff, median PFS for pts in the group with greater decreases of ANG2 was 13.9 months vs 9.6 months for pts in the group with lesser decreases of ANG2 (unadjusted P= 0.002; HR 2.65, 95% CI 1.39–5.08). Conclusions: These are the first exploratory biomarker analyses for the single-arm study of L + P in pts with uHCC. Changes in serum biomarkers associated with angiogenic-, FGF-, and IFNγ-signaling pathways indicated target engagement of L + P. Decreases in TIMP1 and increases in MCP1 were associated with MTS and OR. Associations were found between longer PFS and a greater decrease in levels of ANG2. Angiogenesis inhibition and modulation of cancer immune response were observed with L + P. Further validation from independent studies is warranted. Clinical trial information: NCT03006926.

4519 Background: LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT, approved for first line (1L) treatment of uHCC. PEMBRO, an anti-PD-1 monoclonal antibody, was granted accelerated approval for the treatment of patients (pts) with HCC after sorafenib therapy. We assessed the safety and efficacy of LEN + PEMBRO in uHCC. Methods: In this phase 1b trial (NCT03006926), pts received LEN 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW

Background LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. PEMBRO is an anti-PD-1 monoclonal antibody. LEN monotherapy is approved for first-line treatment of uHCC. PEMBRO monotherapy has shown significant efficacy in the second-line treatment of HCC. We report updated results from a phase 1b trial of LEN + PEMBRO in uHCC. Methods In this open-label, phase 1b study of LEN + PEMBRO in uHCC, 104 patients (pts) with BCLC stage B (not amenable for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS≤1 received LEN (body wt≥60kg: 12mg/day; Results Pts received LEN + PEMBRO (DLT-evaluation part, n=6; expansion part, n=61). At data cutoff (June 30, 2019), 34 (50.7%) pts remained on study treatment; median duration of follow-up was 11.7 months (95% CI, 7.8-17.6). Serious adverse events occurred in 42 (62.7%) pts; no new safety signals emerged. Updated safety data will be provided. ORR (including unconfirmed responses) was 44.8% (Table) and compared favorably with LEN arm of REFLECT trial (24.1%; Kudo M. Lancet. 2018). Median DOR was 18.7 months (95% CI, 6.9-NE). Conclusions LEN + PEMBRO showed promising antitumor activity and an acceptable safety profile in pts with uHCC. Blinded independent central review is in progress. A phase 3 trial (LEAP-002; NCT03713593) is ongoing to assess LEN + PEMBRO vs LEN alone as first-line therapy for pts with uHCC.Table747PTableResponse Parameter, n (%)LEN + PEMBRO (n=67)mRECIST Per Investigator ORR (CR + PR + unconfirmed PR or CR)a Best Overall Response CR. PRa Stable disease Progressive disease Unknown/not evaluable 30 (44.8) 4 (6.0) 26 (38.8) 25 (37.3) 6 (9.0) 6 (9.0) aIncludes unconfirmed partial responses (2 patients). CR, complete response; (m)RECIST, (modified) Response Evaluation Criteria In Solid Tumors [Lencioni et al. Semin Liver Dis. 2010;30:52-60]; ORR, objective response rate; PR, partial response. Clinical trial identification NCT03006926; Release date: December 30, 2016. Editorial acknowledgement Medical writing support was provided by April Suriano, PhD, of Oxford PharmaGenesis, Newtown, PA, USA and was funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure J. Llovet: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Celsion Corporation; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Merck; Advisory / Consultancy: Glycotest; Advisory / Consultancy: Navigant; Advisory / Consultancy: Leerink Swann LLC; Advisory / Consultancy: Midatech Ltd; Advisory / Consultancy: Fortess Biotech; Advisory / Consultancy: Sprink Pharmaceuticals; Advisory / Consultancy: Nucleix; Advisory / Consultancy: Can-Fite Biopharma. K.V. Shepard: Full / Part-time employment: Eisai Inc. R.S. Finn: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. M. Ikeda: Honoraria (self): Abbott, Bayer, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eisai, Lilly, Nobelpharma, Novartis, Otsuka, Taiho Pharmaceutical, Teijin Pharma, Yakult Honsha; Advisory / Consultancy: Bayer, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, MSD, NanoCarrier, Novartis, Shire, Teijin Pharma, Lilly; Research grant / Funding (self): ASLAN Pharmaceuticals, AstraZeneca, Baxalta/Shire, Bayer, Bristol-Myers Squibb, Chugai Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, NanoCarrier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takara Bio, Yakult Honsha. M. Sung: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis. A.D. Baron: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Genentech/Roche; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Merck. M. Kudo: Honoraria (self), Research grant / Funding (self): AbbVie; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Gilead Sciences; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Otsuka. T. Okusaka: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, Lilly Japan, Nippon Chemiphar, Nobelpharma, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon, Taiho Pharmaceutical, Teijin Pharma, Yakult; Advisory / Consultancy: Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Zeria Pharmaceutical; research funding from AstraZeneca, Baxter, Bayer, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, NanoCarrier, Nippon Boeh. M. Kobayashi: Speaker Bureau / Expert testimony: Eisai Inc. H. Kumada: Honoraria (self): AbbVie; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Gilead Sciences; Honoraria (self): MSD; Honoraria (self): Sumitomo; Honoraria (self): Dainippon. S. Kaneko: Honoraria (self): EA Pharma, MSD, Aska Pharma, Astellas Pharma, AbbVie, Eisai, Eidia, Otsuka, Gilead Sciences, Sysmex Corporation, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Taiho, Takeda, Chugai, Bayer, Bristol-Myers, Mylan EPD, Miyarisan, Mochida, Kowa, Mitsubis; Research grant / Funding (self): Gilead Sciences, AbbVie, Daiichi Sankyo, Astellas Pharma, Takeda, Nippon Boehringer Ingelheim, MSD, Ono Pharma, Pfizer, Shionogi, Teijin Pharma, Mitsubishi Tanabe, Zeria, Abbott Vascular Japan, Taisho Toyama, Novartis, Terumo Corporation, Taiho, Novo Nord. K. Mamontov: Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Medtronic; Honoraria (self): Roche. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: BTG; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Tarveda; Advisory / Consultancy: MSD. K. Mody: Full / Part-time employment: Eisai Inc. T. Kubota: Full / Part-time employment: Eisai Co., Ltd. K. Saito: Full / Part-time employment: Eisai Inc. A.B. Siegel: Full / Part-time employment: Merck. L. Dubrovsky: Full / Part-time employment: Merck. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.

TPS4152 Background: Len, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, is approved for first-line treatment of unresectable HCC (uHCC) based on the open-label phase 3 REFLECT study in which len showed noninferior overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time-to-progression (TTP) vs sorafenib. In the phase 2 KEYNOTE-224 study of pembro (a PD-1 inhibitor) as second-line treatment of advanced HCC, pembro showed meaningful clinical efficacy in pts previously treated with sorafenib, with median PFS 4.9 mo, median OS 12.9 mo, and a manageable safety profile. In results from the phase 1b KEYNOTE-524 trial, len+pembro was well-tolerated, with promising antitumor activity in pts with uHCC. LEAP-002 is a phase 3 study to evaluate the safety and efficacy of len+pembro vs len+placebo as first-line therapy for advanced HCC. Methods: Eligible pts are ≥18 y and have HCC confirmed by radiology, histology, or cytology; ECOG PS 0/1; BCLC stage C or stage B disease not amenable to locoregional therapy or curative treatment approach; CP class A liver score within 7 days before study; and ≥1 measurable lesion by RECIST v1.1. Pts with past or ongoing HCV infection and those with controlled HBV are eligible. 750 pts will be randomized 1:1 to receive len 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW 400 ng/mL; and ECOG PS 0/1. Primary end points are PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary end points are ORR, duration of response, disease control rate, and TTP per RECIST v1.1 by BICR, efficacy per modified RECIST, pharmacokinetics, and safety. Imaging assessments will be performed Q9W on study. AEs will be graded per CTCAE v4.0 and monitored up to 90 days after last dose. Clinical trial information: NCT03713593.

Background High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is used in many therapeutic protocols for pediatric intra- and extra-cranial solid tumors. HCT can be curative, but is associated with significant toxicity. Procedure Between January 2001 and June 2009, 92 solid tumor patients (age 6 months to 27 years) underwent 94 autologous apheresis procedures at Children's National Medical Center. Out of that group, 71 patients, who underwent 162 autologous HCT, were analyzed for transplant outcomes. Multiple variable modeling was used to identify independent variables related to transplant toxicity outcome measures, such as bacteremia, intensive care admission, and death. Other outcome measures (time to pre-apheresis peripheral blood CD34+ count, product yield, and time to engraftment) were also analyzed. Independent variables included patient-specific variables (age, weight, tumor type, chemotherapy administered, and primary vs. relapsed disease) and harvest or transplant-related variables (total white blood cell and CD34+ cell counts prior to transplant, and quantity of total nucleated cells and CD34+ cells infused during transplant). Results Transplant toxicity was significantly greater in younger patients (P = 0.001) and in neuroblastoma patients (P = 0.003). The time to neutrophil engraftment, controlling for weight, age, and chemotherapy, was positively related to absolute CD34+ cells/kg infused (P = 0.01). The time to CD34+ recovery pre-apheresis was affected by patient diagnosis (P = 0.05). Conclusions Younger patients had increased transplant toxicity, with infants

Purpose: To characterize the relationship between CD34+ collection efficiency and blood volumes processed in pediatric patients undergoing autologous peripheral blood stem cell (PBSC) collection. Methods: Retrospective 8-year (2001–2009) study of pediatric patients (n = 79) with neuroblastoma and central nervous system (CNS) tumors undergoing first day of autologous PBSC harvest using MNC program on the COBE Spectra (Caridian BCT, Lakewood, CO) was performed. Patients undergoing 0 to 2.9 BV (standard volume), 3 to 6 BV (large volume), and greater than 6 BV (ultra large volume) harvests were evaluated for CD34+ collection efficiency, diagnosis (neuroblastoma vs. nonneuroblastoma), disease type (primary vs. relapse), mobilization regimen, granulocyte colony stimulating factor (GCSF) dose, and apheresis complications. Results: CD34+ collection efficiencies (CE) for neuroblastoma patients were 67%, 50%, and 53% for standard (n = 14), large (n = 9), and ultra large (n = 5) volume harvests, respectively. Similarly, patients with nonneuroblastoma diagnoses had CD34+ CE of 63%, 55%, and 65% for low (n = 19), large (n = 27), and ultra large (n = 5) volume harvests, respectively. Weight, granulocyte colony stimulating factor (G-CSF) stimulation, type of mobilization, and apheresis complications (normalized by run time) were similar between the standard, large, and ultra large volume groups in patients with either neuroblastoma or nonneuroblastoma diagnoses. Conclusions: CD34+ collection efficiency in pediatric autologous PBSC collection on the first day of harvest does not decrease with higher numbers of blood volumes processed in patients with either neuroblastoma or nonneuroblastoma primary disease. These results indirectly indicate bone marrow CD34+ cell mobilization occurs with longer apheresis procedures in pediatric patients. J. Clin. Apheresis, 2011. © 2011 Wiley-Liss, Inc.

Bi-specific T cell engager antibody (BiTE) therapy has recently emerged as an effective immunotherapy by redirecting polyclonal T cell cytotoxicity against cell surface protein on tumor cells. We generated the first BiTE construct derived from a TCR-mimic monoclonal antibody (mAb), ESK1, specific for a peptide from an intracellular oncoprotein, WT1, in the context of HLA-A*02:01 molecules. Despite the low density peptide/HLA-A2 complex on the cell surface, ESK-BiTE was able to selectively activate and induce proliferation of cytolytic human T cells to kill multiple leukemias and cancers in vitro and in mice. Surprisingly, we also discovered that in an autologous setting, ESK-BiTE induced a robust secondary CD8 T cell response specific for antigens other than WT1, including HLA-A2-restricted her2-neu-derived peptide 369-377, in patients with her2- positive ovarian cancer. Therefore, the study demonstrated a new vaccinal mechanism for BiTE mAb action that could contribute to more effective long-term therapeutic activity of BiTE's and further broaden their reach to other tumor antigens not previously known or originally targeted. Citation Format: Tao Dao, Dmitry Pankov, Andrew Scott, Tatyana Korontsvit, Victoriya Zakhaleva, Manuel Direito de Morais Guerrerio, Yiyang Xu, Jingyi Xiang, Su Yan, Nicholas Veomett, Nicholas Veomett, Leonid Dubrovsky, Michael Curcio, Ekaterina Doubrovina, Cheng Liu, Richard J. O'Reilly, David A. Scheinberg. Potent therapeutic and immunological effects of the first T-BiTE derived from a TCR-mimic antibody targeting intracellular oncoprotein WT1. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A055.

Acute and chronic leukemias, including CD34+ CML stem cells, overexpress the Wilms tumor gene 1 (WT1) protein, making WT1 an attractive therapeutic target. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201, allowing it to target an undruggable, widely expressed, intracellular oncogene product. BV173 is an HLA-A0201+, human Ph+ ALL cell line that expresses WT1, and tagged by our lab with luciferase. We engineered a tyrosine kinase inhibitor (TKI) resistant BV173-R cell line by transducing BV173 with the resistant T315I Bcr-Abl plasmid. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. Tumor growth in vivo was assessed in NOD/SCID gamma (NSG) mice with bioluminescence imaging (BLI). RT-PCR was used to evaluate minimal residual disease in mice with negative BLI signal at the end of therapy. Imatinib, dasatinib, and ponatinib were used at up to maximally tolerated doses, given IP once daily. ESKM was administered at 100 µg twice weekly IP. ESKM mediated ADCC against both BV173 and BV173-R cell lines in vitro. In a BV173 engrafted human leukemia xenograft model, ESKM was more potent than imatinib, with median tumor growth reduction of 78% vs 52%. Combination of imatinib and ESKM therapy resulted in a 94% reduction in leukemic growth. High dose dasatinib (40 mg/kg daily) was more potent than ESKM, but discontinuation of therapy due to dasatinib toxicity resulted in relapse. Combination with ESKM therapy with dasatinib resulted in cure in 75% of mice, confirmed by bone marrow RT-PCR three weeks after termination of therapy. For mice cytoreduced with dasatinib followed by consolidation therapy with ESKM, delayed relapse was observed, but no cures. ESKM was highly superior to imatinib and dasatinib against the T315I BV173-R leukemia in vivo. Cures were not achieved with combination therapy of ESKM and either first or second generation TKIs against resistant T315I leukemia. Ponatinib at 10 mg/kg had higher efficacy than ESKM alone against BV173-R, but mice treated with combination of ESKM and ponatinib had superior tumor reduction. CONCLUSION: ESKM is an effective therapeutic antibody for sensitive and T315I Ph+ ALL. Resistant T315I Ph+ leukemic growth is inhibited more effectively by ESKM therapy compared to imatinib and dasatinib, and combination therapy with ESKM is superior to ponatinib. Supported by the Leukemia and Lymphoma Society, NIH R01CA55349, P01 23766 and T32CA62948-18. Disclosures: Yan: Eureka Therapeutics: Employment. Liu:Eureka Therapeutics: Employment, Equity Ownership.

3047 Background: Acute and chronic leukemias demonstrate significantly increased expression of the Wilms tumor gene 1 (WT1) product, including CD34+ CML stem cells, making WT1 an attractive therapeutic target. However, WT1 protein is intracellular and currently un-druggable. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201. Methods: BV173 is an HLA-A0201 positive Ph+ ALL cell line. It over-expresses WT1 and binds strongly to ESKM. We evaluated the in vitro and in vivo efficacy of ESKM in combination with TKIs. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. In vivo tumor growth was assessed in NSG mice bearing disseminated luciferase tagged BV173 with bioluminescence imaging and flow cytometry of the bone marrow after sacrifice. Imatinib was used at maximum tolerated doses for these mice as determined in pilot studies. Results: The addition of imatinib in vitro did not affect the ability of ESKM to perform ADCC. The BV173 engrafted NSG mice treated with ESKM with and without TKIs showed tumor regression one week after beginning therapy, clearing leukemia from the liver and spleen. Mice relapsed primarily in the bone marrow, with increasing luciferase signal after two weeks of therapy. Compared to untreated control animals, after 5 weeks of therapy, imatinib alone only reduced tumor growth by 45%; ESKM alone reduced growth by 81%, and the combination of ESKM and imatinib reduced growth by more than 95%. Flow cytometry of cells remaining after treatment showed binding of ESKM, suggesting escape was not due to down regulation of the epitope. Conclusions: In this mouse model of Ph+ ALL, ESKM antibody therapy is superior to imatinib and the combination of both modalities is additive. This antibody is efficacious in vitro and in vivo against WT1 overexpressing leukemias, in context of HLA-A0201. This combination holds promise as a therapy for leukemias in patients who are HLA-A0201 positive, with the potential of improved cytoreduction in patients with Ph+ leukemias.