Bispecific T-cell Engager Antibody Research Articles

Transcriptomic Features of Immune Exhaustion and Senescence Predict Outcomes and Define Checkpoint Blockade-Unresponsive Microenvironments in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Reinstating immunological control of AML is highly desirable to eradicate chemotherapy-resistant clones and provide long-term disease control. We recently identified bone marrow (BM) microenvironmental transcriptomic profiles that stratify patients with newly diagnosed AML into an immune-infiltrated and an immune-depleted subtype and that refine the accuracy of survival prediction beyond that afforded by current prognosticators (Vadakekolathu J et al., 2020). We have also shown that CD8 + T cells from patients with AML exhibit features of immune exhaustion and senescence (IES), including heightened expression of killer cell lectin-like receptor subfamily G member 1 (KLRG1) and B3GAT1 (encoding CD57) (Knaus H et al., 2018). Whether deranged T-cell functions affect the likelihood of responding to antitumor therapy, including immune checkpoint blockade (ICB), is an outstanding question in AML.In the current study, we analyzed 183 BM samples collected longitudinally at time of AML onset, response assessment and disease relapse from multiple cohorts of patients with AML treated with standard-of-care induction chemotherapy, and from 33 elderly AML patients with newly diagnosed or chemotherapy-refractory/relapsed AML treated with azacitidine, and the PD-1 checkpoint inhibitor pembrolizumab (NCT02845297). Primary patient specimens and associated clinical data were obtained via informed consent in accordance with the Declaration of Helsinki on research protocols approved by the Institutional Review Boards of the participating Institutions. RNA (150-200 ng) was extracted from BM aspirates and was processed on the nCounter FLEX analysis system (NanoString Technologies, Seattle, WA) using the PanCancer Immune profiling panel, as previously published (Vadakekolathu J et al., 2020). The correlation between transcriptomic features of IES, clinical characteristics, therapeutic response and patient outcome was validated using publicly available RNA-sequencing and NanoString data from 1,698 patients with AML, including samples from the TCGA-AML (n=147 cases), Beat-AML Master Trial (n=264 cases, of which 240 with survival data and 195 with chemotherapy response data) and Children's Oncology Group (COG)-TARGET AML series (n=145 cases).We initially showed that, compared with their non-senescent CD8 +CD57 -KLRG1 - counterpart, senescent CD8 +CD57 +KLRG1 + T cells are functionally impaired in terms of their ability to effect AML-blast killing mediated by an anti-CD33/CD3 bi-specific T-cell engager antibody construct (kindly provided by Amgen, USA; effector/target [E/T] ratio = 1:5). We then used gene set enrichment analysis (GSEA) to derive a transcriptomic signature of IES encompassing natural killer (NK)-cell and stem-like CD8 + T-cell markers, and showed that IES states correlate with lymphoid infiltration, adverse-risk molecular lesions (TP53 and RUNX1 mutations), experimental gene signatures of leukemia stemness (LSC17 score; Ng et al., 2016) and poor outcome in response to standard induction chemotherapy (Fig. 1A). In independent validation cohorts of children and adults with AML, the IES score was higher at baseline in patients with primary induction failure (following a standard 2 cycles of chemotherapy) compared with complete remission, increased in post-chemotherapy BM specimens, and predicted survival with greater accuracy than the ELN cytogenetic risk classifier (Fig. 1B). In the immunotherapy setting, high IES scores at baseline defined a checkpoint blockade-unresponsive AML tumor microenvironment and correlated with significantly shorter overall survival (9.1 versus 15.56 months in patients with high and low IES scores, respectively; HR = 3.32 (95% CI = 1.19-9.25); log-rank P = 0.021; Fig. 1C). Finally, the IES-related gene set also predicted for long-term outcomes and objective responses, based on RECIST criteria, to single-agent nivolumab or pembrolizumab, or combination anti-PD-1 + anti-CTLA-4, in 106 patients with melanoma (PRJEB23709 and GSE93157 series), a tumor type known to derive durable clinical benefit from ICB (Fig. 1D).Our findings encourage the pursuit of immune senescence reversal as a strategy to functionally reinvigorate T cells and could inform the delivery of ICB and other T cell-targeting immunotherapies to patients who are likely to benefit. [Display omitted] DisclosuresRadojcic: Syndax Pharmaceuticals: Research Funding; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Allakos: Membership on an entity's Board of Directors or advisory committees. Minden: Astellas: Consultancy. Tasian: Aleta Biotherapeutics: Consultancy; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Incyte Corporation: Research Funding.

Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement

T cell engaging bispecific antibody (TCB) is an effective immunotherapy for cancer treatment. Through co-targeting CD3 and tumor-associated antigen (TAA), TCB can redirect CD3+ T cells to eliminate tumor cells regardless of the specificity of T cell receptor. Tissue factor (TF) is a TAA that involved in tumor progression. Here, we designed and characterized a novel TCB targeting TF (TF-TCB) for the treatment of TF-positive tumors. In vitro, robust T cell activation, tumor cell lysis and T cell proliferation were induced by TF-TCB. The tumor cell lysis activity was dependent upon both CD3 and TF binding moieties of the TF-TCB, and was related to TF expression level of tumor cells. In vivo, in both tumor cell/human peripheral blood mononuclear cells (PBMC) co-grafting model and established tumor models with poor T cell infiltration, tumor growth was strongly inhibited by TF-TCB. T cell infiltration into tumors was induced during the treatment. Furthermore, efficacy of TF-TCB was further improved by combination with immune checkpoint inhibitors. For the first time, our results validated the feasibility of using TF as a target for TCB and highlighted the potential for TF-TCB to demonstrate efficacy in solid tumor treatment.

Evidence-Based Recommendations for Nurse Monitoring and Management of Immunotherapy-Induced Cytokine Release Syndrome: A Systematic Review from the Children's Oncology Group.

Children with B-precursor acute lymphoblastic leukemia and B-cell lymphoma, particularly those with relapsed or refractory disease, are increasingly enrolled on phase II and phase III clinical trials studying immunotherapies. These therapeutic agents may be associated with a high risk of cytokine release syndrome (CRS), and nurses lack standardized guidelines for monitoring and managing patients with CRS. Six studies and one clinical practice guideline were included in this systematic review that examined the evidence of CRS following administration of chimeric antigen receptor T-cell therapy or the bi-specific T-cell engager antibody, blinatumomab. Six nursing practice recommendations (five strong, one weak) were developed based on low or very low-quality evidence: three reflect preinfusion monitoring, one focuses on monitoring during and postinfusion, and three pertain to the nurse's role in CRS management.

Optimal Timing of Blinatumomab for the Treatment of B-Lymphoblastic Leukemia

Introduction Blinatumomab is a CD19-targeting bi-specific T-cell engager antibody construct developed for the treatment of CD19-expressing B-cell malignancies. After early impressive in vitro and in vivo pre-clinical results,1–3 blinatumomab was quickly incorporated into clinical investigations. After a phase I non-Hodgkin lymphoma (NHL) trial established a safe and effective dose, delivered via continuous intravenous (IV) infusion,4 trials exploring its use in B-lymphoblastic leukemia (B-ALL) soon followed. The results of these trials have been largely positive, though the extent of response and benefit appears to vary based on disease status and burden at the time of treatment. Thus, the optimal incorporation of blinatumomab into B-ALL therapy is still being refined.

T-cell Redirecting Therapies for the Treatment of B-cell Lymphomas: Recent Advances.

Simple SummaryB-cell non-Hodgkin lymphomas (NHL) include many diseases with distincts pathogenic mechanisms, prognoses and management. Most patients benefit generally from efficient therapies allowing cure or prolonged remission. However, when they are refractory or relapse after standard therapy, they harbor a poor prognosis. In last decades, numerous novel immunotherapies have been developed with the aim of redirecting T-cell specificity against tumor antigens. Latest data on CAR T-cells confirm their efficacy and their safety in this setting. In addition, trials with bispecific antibodies are also ongoing for these patients, with encouraging premiminary findings, whether before or after CAR T-cells treatment. Here, we review the main results of CAR T-cells and bispecific T-cell engagers studies in the B-cell non-Hodgkin lymphomas setting. These advances in immunotherapies have transformed diffuse large B-cell lymphomas prognosis and will process indolent NHL’s future. Results with such treatments could lead to a new standard of care for those patients who are often heavily pretreated.T-cell specificity can be redirected against tumor antigens either ex vivo using engineered chimeric antigen receptor (CAR) T-cells or in vivo by bridging natural T-cells and tumor cells with bispecific T-cell engager (TCE) antibodies. Currently, four CAR T-cells have been approved by the FDA for the treatment of B-cell lymphomas, including diffuse large B cell lymphomas (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). No TCE have yet been approved for the treatment of B-cell lymphomas. However, at least four of them are in clinical development and show promising activity. Here, we review the most recent advances of CAR T-cells and TCE in the treatment of B-cell lymphomas.

Changes in Leukemic Blasts CD19 Expression in Children with Relapsed/Refractory B-Cell Precursor ALL Treated with Blinatumomab

Blinatumomab is a bispecific T-cell engager (BiTE) antibody construct targeting CD3 and CD19, resulting in T-cell-mediated lysis of malignant B cells. Currently the main application of blinatumomab is the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although promising results were obtained therapy with blinatumomab fails in 30-60% of patients. CD19 downexpression is shown to be one of the possible mechanisms of tumor cells adaptation and subsequent escape from treatment. Moreover, loss of CD19 is a serious obstacle for flow cytometric minimal residual disease (MRD) assessment, necessary for control the leukemia response to therapy. The aim of the present study was to evaluate changes of CD19 expression in children with BCP-ALL treated with blinatumomab and possible monitoring of MRD using additional markers.Patients and methods. From December 2015 to July 201739 (18 F/21M) patients with median age of 8 years (8 mo-20 y) with relapsed/refractory (R/R) BCP-ALL completed at least one course of blinatumomab. 5 patients (13%) carried various types of KMT2A-gene rearrangements and in 3 (7,5%) children ETV6-RUNX1 fusion transcript was detected. MRD monitoring was performed by 8-color flow cytometry. After CD19-directed treatment CD22 and CD24 were added to conventional antibodies' combinations for MRD detection (as suggested by Cherian S. et al, Cytometry B. 2016) to avoid negative influence of potential CD19 loss on cytometric data analysis and interpretation. MRD-negativity was defined as undetectable at the sensitivity level of 0.01%.Results. 20 out of 39(51%) patients continue in complete continuous remission(CCR) after one or two blinatumomab courses, followed by alloHSCT.In 8 (40%) patients in CCR, MRD was never detected since completion of first blinatumomab course, and they were excluded from further analysis. In other 12 pts were found to be MRD-positive at least once after blinatumomab administration. Among them in 5 patients leukemic blasts were still CD19-positive and in 7 patients residual leukemic cells were CD19-negative.Among 19 out of 39 patients (49%) who were resistant to(n=7) or developed bone marrow relapse after blinatumomab (n=12), in 12 (63%) cases tumor cells at relapse were CD19-positive, whereas 5 children experienced CD19-negative relapse. Among them only CD19-positive MRD was detected in one case, only CD19-negative residual blasts - in two cases and in other two children both types of CD19 expression were found atdifferent time-points.Two additional patients, who had CD19-negative MRD, then developed relapse as a lineage “switch” from BCP-ALL to acute myeloid leukemia (AML). In these patients myeloid switch developed in a different ways: one patient carried KMT2A-AF4 fusion gene which is more or less typical for switching AL, the second patient with germline KMT2A hadvery small AML population at the time of relapse diagnosis. Thus in this case positive selection of myeloid subclone during the blinatumomab treatment could be the main pathway of AML development.Conclusions. In our group the remission rate after blinatumomab treatment was about 50%. In those children, who didn't respond and/or developed subsequent relapse, CD19 downexpression seems to be one of the significant pathways for tumor escape from blinatumomab - 26% of relapses were CD19-negative, and in 42% of all relapsed/resistant casesCD19-negative blasts were detected at least on MRD level. Rather frequent loss of CD19 could be a serious obstacle for flow cytometric MRD monitoring, but application of expanded antibodies panel and use of 10-12-color investigation allows residual blasts detection in nearly all cases. Other mechanisms of leukemia resistance including myeloid switch (even in KMT2A-germline patients) can cause blinatumomab failure. DisclosuresNo relevant conflicts of interest to declare.

The Efficacy and Toxicity of Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia: Russian Multicenter Experience

Introduction. The prognosis of patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), especially after allogeneic hematopoietic stem cell transplantation (allo-HSCT), is very poor. Therapeutic options for these pts are limited. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3. BiTE® therapy may help to overcome the resistance to chemotherapy (CT) with minimal toxicity, and may be a bridge to allo-HSCT.Patients and Methods. We analyzed data of 52 pts from 7 hematologic centers in Russian Federation with CD19 positive R/R ALL, who received BiTE®. The median age was 21 (range 1-53) years, 18 (35%) pts <18 yrs, 34 (65%) pts ≥18 yrs. The diagnosis was ALL B-I (EGIL) subtype in 15 pts, B-II - in 29, B-III - in 5 pts, B-IV - in 2 pts, and 1 patient had mixed phenotype leukemia (M5 (FAB) and B-ALL). Five (10%) pts had Philadelphia positive (Ph+) ALL. Primary refractory in 1 pts. In 19 pts it was the 1st relapse of ALL, in 17 - 2nd, in 15 - 3rd. In 47 pts it was isolated bone marrow relapse, in 5 pts - combined relapse (bone marrow and extramedullary sites). The bone marrow blast infiltration was <50% in 27 pts, >50% in 25 pts. Disease relapse was revealed after CT in 31 pts. Allo-HSCT after BiTE® therapy was performed 12 (39%) pts (4 - from related, 5 - from unrelated, 3 - from haploidentical donors). Twenty one pts received BiTE® due to relapse after allo-HSCT (6 - from related, 12 - from unrelated, 3 - from haploidentical donors). Six pts received 2nd allo-HSCT after BiTE® therapy. In 10 pts with posttransplant relapse donor lymphocyte infusion (DLI) was used in combination with BiTE®. Every patient received from 1 to 7 cycles (median 2) of BiTE®.Results. Complete remission (CR) was achieved in 31/52 (60%) pts: in 18/31 (58%) pts with ALL relapse after CT, in 13/21 (62%) pts - after allo-HSCT. In 22/31 (71%) pts with CR after BiTE® therapy minimal residual disease was negative. Pts with less than 50% blasts in bone-marrow at baseline experienced substantially higher response rates compared with patients with 50% blasts or higher (70% (19/27) vs 48% (12/25)). Response rates were similar although the number of relapse - 58% (11/19) in 1st relapse, 59% (10/17) in 2ndrelapse and 60% (9/15) in 3drelapse. Pts with posttransplant ALL relapse who received BiTE® in combination with DLI had higher response rate than pts, who received BiTE® as monotherapy: 70% (7/10) vs 54% (6/11) respectively. One-year OS was 50% (95% CI 25-75%). One-year DFS was 42% (95% CI 18-66%). Grade ≥3 hematological toxicity (neutropenia, thrombocytopenia) was observed in 14 (27%) pts, grade ≥3 liver toxicity - in 6 (12%) pts. Ten pts (19%) developed toxic neuropathy during the therapy. Cytokine release syndrome occurred in 5 (9%) pts. One pts after allo-HSCT (but not after DLI) developed grade I aGVHD. One pts after allo-HSCT developed grade II aGVHD after BiTE® in combination with DLI. There were no fatal treatment related toxicity. Nine (29%) pts who responded to BiTE® had relapse, 6 of them bone marrow and 3 extramedullary sites. Nine (29%) pts died: 5 pts - due to R/R ALL, 2 pts due to infection, 1 case of transplant related mortality and 1 pts due to second solid tumor (synovial sarcoma).Conclusion. The treatment of R/R ALL with BiTE® is effective and has acceptable toxicity. We demonstrated high efficacy in therapy of posttransplant ALL relapses, especially when BiTE® was combined with DLI, perhaps, due to additional immunological effect of the transplant. DisclosuresNo relevant conflicts of interest to declare.

Baseline Biomarkers Influencing Clinical Outcomes in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL) Treated with Blinatumomab Versus Standard-of-Care Chemotherapy (SOC) from a Randomized Phase 3 Study

Introduction: Blinatumomab, an anti-CD3/CD19 bispecific T-cell engager antibody construct, showed antileukemic activity and significantly longer overall survival (OS) vs SOC in adults with advanced Philadelphia chromosome-negative R/R ALL (median OS 7.7 vs 4.0 months; P=0.01) (N Engl J Med 2017;376:836−847). Here we aimed to identify baseline biomarkers that were prognostic (disease-related) or predictive (treatment-related) of clinical outcomes.Methods: Adults with R/R ALL (refractory to primary induction therapy or salvage therapy, first relapse <1 year, second or later relapse, or relapse after allogeneic hematopoietic cell transplantation [alloHCT]) were randomized to receive either blinatumomab or SOC. Blinatumomab was given by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 μg/d on d1‒7 of cycle 1 and 28 μg/d thereafter). Up to 4 additional maintenance cycles (4 wks on/8 wks off) were allowed for up to 1 year. Evaluated biomarkers included leukocytes, monocytes, lymphocytes, granulocytes, platelets, neutrophils, CD45+ CD3+ CD4+ T cells, CD45+ CD3+ CD8+ T cells, CD45+ CD3- CD19+ B cells, CD3- CD16+ CD56+ cells, bone marrow (BM) blasts, CD3+ T cells, CD19+ cells, and ratios of CD3+/CD19+ and CD3+%/BM blast%. A multivariate model was used to select potential biomarkers associated with treatment outcomes. Effect on outcome was determined if either the main effect or interaction term between the biomarker and treatment had a P value ≤0.3. Prognostic and predictive associations of baseline biomarkers with OS, hematologic response (complete remission [CR] or CR with full, partial, or incomplete hematologic recovery [CR/CRh/CRi]) within the first 12 wks, and minimal residual disease (MRD) response were assessed by Cox regression for OS and multivariate logistic regression for hematologic response and MRD response. Predictive biomarkers were identified using interaction tests with treatment group.Results: A total of 405 patients received blinatumomab (n=271) or SOC (n=134). Baseline characteristics including age, prior alloHCT, salvage status, granulocytes, platelets, and lymphocyte subpopulations (CD45+ CD3+ CD8+, CD45+ CD3- CD19+, and CD3+) were generally balanced between treatment arms. Associations of baseline biomarkers with clinical outcomes are presented in the table. Higher platelet counts were associated with decreased risk of death (HR 0.43; 95% CI 0.29-0.65) and increased CR (odds ratio [OR] 4.12; 95% CI 2.04-8.33) and CR/CRh/CRi (HR 1.64; 95% CI 0.90-2.99). Higher granulocyte counts were associated with decreased risk of death (HR 0.75; 95% CI 0.57-0.99), whereas total leukocyte counts were not (HR 1.04; 95% CI 0.70-1.54). Lower BM blast percentage was associated with increased CR (OR 0.90; 95% CI 0.82-0.97) and CR/CRh/CRi (OR 0.87; 95% CI 0.80-0.95) but not OS (HR 1.04; 95% CI 0.98-1.09). Higher CD3+ T cells were associated with increased MRD response (OR 1.75; 95% CI 0.99-3.08). Higher counts of CD45+ CD3- CD19+ cells increased the risk of death for blinatumomab patients (HR 1.19; 95% CI 1.09-1.29) but also was not associated with a survival advantage for SOC patients (HR 1.03; 95% CI 0.93-1.15). Higher CD45+ CD3+ CD8+ T cells were associated with increased CR (OR 1.39; 95% CI 1.18-1.65) and CR/CRh/CRi (OR 1.44; 95% CI 1.22-1.70) in patients treated with blinatumomab but did not correlate with increased hematologic response in SOC patients. Multiple logistic regression modeling for adverse events (AEs) of interest showed that BM blasts and lymphocyte markers (CD3+ and CD45+ CD3+ CD8+) were not associated with grade ≥3 neurologic events, infections, or cytokine release syndrome.Conclusions: Higher platelet and granulocyte counts, lower BM blasts, and higher numbers of CD3+ T cells were prognostic for improved OS, hematologic response, and MRD response, respectively, in patients with R/R ALL who received blinatumomab vs SOC. A higher frequency of CD45+ CD3+ CD8+ cells was predictive of increased hematologic response to blinatumomab, whereas a higher frequency of CD45+ CD3- CD19+ cells was predictive of decreased OS. BM blast percentage and lymphocyte markers were not associated with AEs of interest. Overall, these data demonstrate that responses to blinatumomab can be seen across a variety of subgroups, including those expressing specific baseline biomarkers. Further study is needed to identify subgroups most likely to benefit from blinatumomab. [Display omitted] DisclosuresWei:AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria. Ribera:Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Pfizer: Research Funding, Speakers Bureau; Amgen Inc.: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Larson:Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Research Funding. Ritchie:Amgen Inc.: Honoraria. Chen:Amgen Inc.: Employment, Other: Stock holder. Dos Santos:Amgen Inc.: Employment. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Kantarjian:Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding.

Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Blinatumomab in B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease: Initial Results of a Phase II Trial

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms.

In the past decade, the available treatments for patients with acute lymphoblastic leukemia (ALL) have rapidly expanded, in parallel with an increased understanding of the genomic features that impact the disease biology and clinical outcomes. With the development of the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin, the CD3-CD19 bispecific T-cell engager antibody blinatumomab, CD19 chimeric antigen receptor T-cell therapy, and the potent BCR-ABL1 tyrosine kinase inhibitor ponatinib, the outlook of ALL in both younger and older adults has substantially improved. The availability of highly effective drugs raised important questions concerning the optimal combination and sequence of these agents, their incorporation into frontline regimens, and the role of hematopoietic stem cell transplantation. In this review, we discuss the rapidly evolving paradigms in the treatment of ALL, highlighting both established and effective regimens, as well as promising new therapies that are being evaluated in ongoing clinical trials. We specifically focus on novel combination regimens in both the frontline and salvage settings that are leading to new standards of care in the treatment of ALL.

Maintenance Therapy with Blinatumomab in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL): Overall Survival in Adults Enrolled in a Phase 3 Open-Label Trial

IntroductionHematopoietic stem cell transplant (HSCT) after induction/consolidation therapy with standard chemotherapy or targeted therapies, such as blinatumomab or inotuzumab (Kantarjian H, et al. N Engl J Med . 2016;375:740-53), is considered the only treatment option with curative intent for patients with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (r/r Ph- B-precursor ALL). A recent randomized phase 3 study of blinatumomab, a bispecific T-cell engager antibody construct, in patients with r/r Ph- B-precursor ALL, included a maintenance treatment phase to allow patients in hematologic remission to continue blinatumomab (Kantarjian H, et al. N Engl J Med . 2017;376:836-847). In this exploratory analysis, we examined overall survival (OS) for patients who received blinatumomab maintenance therapy and compared outcomes with data pooled from patients who did not receive maintenance therapy in the phase 3 and phase 2 (Topp MS, et al. Lancet Oncol . 2015;16:57-66) blinatumomab trials.MethodsAdult patients (≥18 years) in this phase 3 trial were randomized to either blinatumomab or standard of care (SOC) chemotherapy. Patients randomized to blinatumomab received this treatment by continuous intravenous infusion (4 weeks on, 2 weeks off; 9 μg/day on days 1-7 of Cycle 1 and 28 μg/day thereafter) during induction and consolidation cycles. Patients could receive HSCT at any time after cycle 1. Patients who received blinatumomab, and had bone marrow blasts <5% after two induction and three consolidation cycles of blinatumomab, were eligible for blinatumomab maintenance, administered for up to an additional 12 months (4 weeks on therapy, 8 weeks off). Maintenance therapy was discontinued in case of transition to HSCT, investigator discretion, toxicity, relapse, or use of protocol-excluded medications. The cumulative probability of OS over time was estimated using the Simon-Makuch method and the effect of maintenance was analyzed using the Mantel-Byar method. OS was measured from the start of maintenance therapy for patients who were in remission until the start of Cycle 6 (for those who received maintenance) or at Day 211 (landmark date for those who did not receive maintenance). Data from the phase 3 study and an earlier phase 2 study in which maintenance was not offered were pooled to increase the sample size for this OS analysis.ResultsAs of the primary analysis cutoff, 119 of 271 (43.9%) patients receiving blinatumomab achieved a best response of CR/CRh/CRi within two treatment cycles, and 27 patients continued to the blinatumomab maintenance phase. Three patients completed the maintenance phase, 4 transitioned to HSCT, and one discontinued due to adverse events (AE). Twenty-one (77.8%) patients had a best response of CR during maintenance, 1 (3.7%) patient each had CRh or blast free hypoplastic or aplastic bone marrow, and 2 (7.4%) patients each had hematologic relapse or were not evaluable. The Mantel-Byar analysis demonstrated a relative OR for OS of 0.59 (95% CI, 0.20 - 1.73) P = 0.33 comparing maintenance vs. no maintenance (Figure), representing a 41% reduction in the risk of death associated with maintenance therapy, though not statistically significant. Among patients receiving blinatumomab who entered the maintenance phase, the incidence of adverse events of interest generally was less compared with the incidence during the induction or consolidation phases (Table).ConclusionsIn r/r ALL patients who achieved a hematologic response following blinatumomab induction/consolidation, high response rates with blinatumomab maintenance therapy (beyond cycle 5) were observed, with longer OS compared with patients receiving no maintenance. During maintenance with blinatumomab, no new safety concerns were identified. A lower incidence of adverse events of interest was seen during the maintenance phase, compared with events recorded during the induction/consolidation phases of this, and prior blinatumomab studies.Research supported by Amgen Inc. [Display omitted] DisclosuresRambaldi:Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy; Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses. Rigal-Huguet:Bristol Myers-Squibb, Novartis, Pfizer, Amgen, Incyte, Jazz Pharma: Consultancy; Bristol Myers-Squibb, Novartis, Pfizer, Amgen, Incyte, Jazz Pharma: Honoraria. Nie:Amgen: Employment, Equity Ownership. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Honoraria, Other: Travel, Research Funding; Regeneron: Consultancy, Honoraria, Research Funding; Celgene: Other: Travel; Roche: Consultancy, Research Funding; Macrogenics: Consultancy, Research Funding.

T-cell engager antibodies enable T cells to control HBV infection and to target HBsAg-positive hepatoma in mice

Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients. We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study invivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells. The 2T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. Invivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden. This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC. T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.

Recent updates on bispecific T-cell engager (BiTE) antibodies in relapsed and refractory multiple myeloma.

e20034 Background: Bispecific T-cell engager (BiTE) antibodies are currently being studied for various hematological malignancies including relapsed and refractory multiple myeloma (RRMM). BiTE antibodies that target CD3 on T cells and antigens GPRC5D, BCMA or FcRH5 on myeloma cells are being studied in RRMM patients (pts). Methods: A comprehensive literature search was done on Pubmed, Embase, and Cochrane. The data presented in various conferences (ASH, ASCO) were also included. Results: Six clinical trials are currently evaluating anti-BCMA, anti CD3 BiTE in RRMM. Madduri et al. reported ORR of 39% in 49 pts treated with REGN5458 an anti BCMA and CD3 BiTE antibody. Grafall et. al reported an ORR of 73% with Teclistamab at 1500µg/kg SC. Harrison et al. reported ORR of 83% in 9 pts treated with 9mg of AMG 701. Lesokhin et al. reported an ORR of 33% among 18 RRMM pts at all dose levels and ORR of 75%. at dose level of 215μg/kg weekly (n=4), and 360 μg/kg weekly (n=4). Rodriguez et al. reported an ORR of 80% among 15 RRMM pts treated with TNB-383B at the dose of 40-60mg IV every 3 weeks. Topp et al reported an ORR of 70% among 10 pts treated with AMG420/BI-836909 at MTD of 400µg/d. Chari et al reported results of Talquetamab which targets GPRC5D which showed an ORR of 66% in 55 evaluable pts. ORR at RP2D (405 µg/kg SC) was 69% in 19 pts treated at this dose. Cohen et al reported results on BFCR4350A, an anti FcRH5 BiTE which showed an ORR of 53% at dose ≥3.6/20mg Q3W. Cytokine release syndrome (CRS) is a serious side effect of BiTE antibodies and was reported in 39%, 64%, 65%, 61%, 45%, 38%, 54% and 76% in studies by Madduri et al, Grafall et al., Harrison et al., Lesokhin et al., Rodriguez et al., Topp et al., Chari et al., and Cohen et al., respectively. Most of the CRS cases were grade 1-2 and resolved either by themselves or required treatment with tocilizumab and steroids. Other most common side effects are reported in table. Conclusions: The most recent data on BiTE antibodies in RRMM has shown promising results with good tolerability. However, the trials are ongoing and a longer follow up is needed.[Table: see text]

IL-12 abrogates mechanisms of immune suppression by B-ALL

Abstract Despite major advance in therapeutic options for treating patients with acute lymphoblastic leukemia (ALL), including the use of immunotherapies, 15–20% of patients still succumb to disease. Given the high mortality rates, particularly in the context of immune-based therapies, there is still a knowledge gap regarding how leukemia cells evade immune surveillance. In published studies, we have shown that interleukin-12 (IL-12) secreted by B-leukemia cells stimulate T-cell mediated immunity. We found that recombinant IL-12 treated WT and Rag1−/− mice, which lack B- and T-cells but still have innate immune cells, had prolonged survival as compared to untreated mice. These results demonstrate that IL-12 increases the anti-leukemia immunosurveillance capacity of innate and adaptive immune cells. Mechanistically, we observed when T-cells were stimulated in ALL supernatant in vitro there is a reduction in the surface expression of the T-cell activation marker, CD44, and marker of degranulation, CD107b. Macrophages co-cultured with leukemia cells were also unable to significantly upregulate the activation markers, CD80 and CD86, compared to macrophages in media alone. We then explored combination therapeutics in vitro to override ALL immune suppression. Considering the potency of IL-12 alone and Blinatumomab, a bispecific T-cell engager (BiTE) antibody used to treat patients with relapsed and refractory disease, we determined how combining these therapies impacted B-ALL cytotoxicity when cultured with T-cells. Impressively, IL-12 augmented the efficacy of Blinatumomab resulting in more T-cell mediated killing of leukemia cells. Our results demonstrate the therapeutic potential of IL-12 as a treatment for ALL.

Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

BackgroundThe outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response.Case presentationPatient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR.ConclusionIn our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Efficacy and preclinical safety of ARB202, a potential first-in-class anti-CDH17/CD3 bispecific T-cell engager, for treatment of pancreatic and colorectal cancers.

405 Background: Globally, gastrointestinal (GI) cancers, which account for around 28% of all cancers, has increased constantly at a CAGR of 2% (2014-2019), while the treatment options remain limited and often ineffective. This is largely due to late diagnosis and lack of new tumor associated antigens for most of the GI malignancies. Cadherin-17, CDH17 (aka CA17), is being evaluated as a potential therapeutic target and molecular marker for GI cancers, of which aberrant expression of CDH17 was reported in 50-90% in tumor samples (including stomach, pancreas, liver/bile duct and colon) by multiple groups. The present study aims to develop a humanized CDH17-CD3 bispecific T-cell engager antibody, ARB202, to treat advanced pancreatic and metastatic colon cancers. Methods: The ARB202 bispecific was generated from anti-CDH17 monoclonal ARB102 as previously described (Lum Y et al, Mol. Pharm. 2020) by linking a CD3-binding scFv in the format of IgG4-scFv. Biophysical properties, efficacy and safety were evaluated. Efficacy was addressed in cytotoxicity assays, IL2-release assays and subcutaneous xenograft models using multiple GI tumor target lines. Preclinical safety profiles include Tissue cross-reactivity assays and GLP repeat-dose toxicity studies in NHP. Results: The ARB202 bispecific antibody was efficiently produced (yield ~1 g/L) and remained stable for at least 3 months under accelerated stress tests. Binding affinity (Kd [M]) of ARB202 to CDH17 and CD3 was at 10-10 and 10-9 respectively, with cellular affinities of 10-9 and 10-8. In vitro cytotoxicity assays demonstrate that ARB202-mediated tumor cell killing is CDH17-dependent and requires immune synapse formation with effector T cells. By contrast, normal cells and CDH17-negative cancer cells are resistant. Pancreatic AsPC1 xenograft model revealed an ARB202 (co-inoculated with human PBMC) dose-dependent inhibition of tumor growth. Human IL-2 release in mice blood samples was consistent with functional CDH17 and CD3 engagement. ARB202 PK profile in rodents and NHP was found to be excellent relative to other bispecifics and GLP toxicity studies showed no significant findings nor adverse effects. Conclusions: ARB202 bispecific antibody promises to be a first-in-class biologic, which may tackle approximately 50% of GI cancers that which have been reported CDH17 positive. First-in-human clinical study with advanced GI cancers is scheduled to start in Q1 2021.

Combinatorial targeting of multiple myeloma by complementing T cell engaging antibody fragments

Bispecific T cell engaging antibodies (BiTEs) address tumor associated antigens that are over-expressed on cancer but that can also be found on healthy tissues, causing substantial on-target/off-tumor toxicities. To overcome this hurdle, we recently introduced hemibodies, a pair of complementary antibody fragments that redirect T cells against cancer-defining antigen combinations. Here we show that hemibodies addressing CD38 and SLAMF7 recruit T cells for the exquisite elimination of dual antigen positive multiple myeloma cells while leaving single antigen positive bystanders unharmed. Moreover, CD38 and SLAMF7 targeting BiTEs, but not hemibodies induce massive cytokine release and T cell fratricide reactions, a major drawback of T cell recruiting strategies. Together, we provide evidence in vitro and in vivo that hemibodies can be developed for the effective and highly specific immunotherapy of multiple myeloma.

Human endoglin-CD3 bispecific T cell engager antibody induces anti-tumor effect in vivo.

Rationale: Endoglin, also known as CD105, is a homo-dimeric membrane glycoprotein required for angiogenesis and serves as a marker for cancer vasculature. In this study, we constructed a bispecific T-cell engager (BiTE) antibody that targets human endoglin and CD3 (hEND-CD3/BiTE). We examined BiTE binding to endoglin-expressing cells and its effects on the cytolytic activity of T cells and cancer development.Methods: The in vitro effects of hEND-CD3/BiTE, including binding to target cells, T-cell activation, proliferation, and cytotoxicity, were examined in endoglin-expressing 293T cells, human umbilical vascular endothelial cells, tumor-derived endothelial cells, and CD3+ T cells. An in vivo xenograft tumor model was established using A549 human lung cancer cells. The therapeutic efficacy of hEND-CD3/BiTE was assessed by monitoring tumor growth, angiogenesis, and mouse survival.Results: hEND-CD3/BiTE specifically bound to endoglin-expressing cells and CD3+ T cells in vitro and stimulated T-cell activation, proliferation, and Th1 cytokine secretion, and promoted T-cell-mediated cytolysis of endoglin-expressing cells. The hEND-CD3/BiTE in vivo caused minimal toxicity to major organs, reduced tumor neoangiogenesis, inhibited tumor growth, and significantly improved mouse survival.Conclusions: Our study demonstrated the therapeutic potential of hEND-CD3/BiTE and provided a novel approach to clinical cancer treatment.

Survival Trends over 18 Years of Patients with Multiple Myeloma Harboring Del(17p) and/or t(4;14): A Retrospective Real-World Study

Introduction . In multiple myeloma (MM), the presence of translocation t(4;14) and/or 17p deletion, found in around 10 to 15% of the patients, is considered as high-risk feature associated with adverse survival. Despite recent advances in the treatment of MM, t(4;14) and del(17p) are still associated with poor outcome. The aim of this study was to analyze the trends of survival in patients with newly diagnosed MM harboring t(4;14) and or 17p deletion over the past two decades. Methods . Patients from five French centers with newly-diagnosed MM from 2001 to 2019 and displaying del(17p) and/or t(4;14) were retrospectively included. Cytogenetics abnormalities were detected by interphase fluorescence in situ hybridization (FISH) and del(17p) positivity cut-off was 30%. New agents were defined as: pomalidomide, carfilzomib, ixazomib and anti-CD38 monoclonal antibodies. Results . 246 patients carrying either t(4;14) (n=106 patients), del(17p) (n=121 patients) or both (n=19 patients) were included. Median age was 64 years (range, 35-91). ISS and R-ISS score were 3 in 88 patients (36%). Eighty-seven patients (35%) were diagnosed in 2001-2010 period, and 159 (65%) in 2011-2019 period. Front-line autologous stem-cell transplantation (ASCT) was performed in 121 (49%) patients. Among transplant eligible patients, 112 patients (n=93%) received triplet induction, 78 patients (64%) a consolidation regimen and 15 patients (12%) a maintenance therapy. Double-ASCT was decided in 21 patients (17%). Among transplant ineligible patients, 61 patients (49%) received melphalan-based regimen in first line, 36 (29%) a bortezomib-based and 15 patients (14%) a lenalidomide-based regimen. At any line, 92 patients (37%) received at least one of the new agents with only 12 patients (5%) in frontline therapy. Median follow-up was 41 months (IQR: 21-69). Median overall survival (OS) was 58.4 months (IQR: 50.1-66.5) for the entire cohort, 55.5 months (IQR: 46.6-78.3) for del(17p), 62.5 months (IQR: 54.2-76.1) for t(4;14) and 48.6 months (18.1-not reached) for patients with both (p=0.2). Median of first progression-free survival (PFS1) was 25.6 months (IQR: 22.2-29.8), with no difference between del(17p), t(4;14) or both (p=0.57). Importantly, no improvement of median OS was observed in patients diagnosed between 2001-2010 in comparison with patients diagnosed between 2011-2019 (63.7 versus 53.2 months, p=0.32). In univariate and multivariate analysis: age (continuous and cut-off 71 years-old) and ASCT significantly were associated with risk of death (HR: 1.03, 1.09 and 0.45, respectively). Median OS of patients eligible to ASCT was 76.1 months (IQR: 62.5-90.3) vs 42.5 months (IQR: 36.8-54.6) for patients not eligible (HR 0.45, 95%CI 0.28-0.0.71; p&amp;lt;0.001). Double-ASCT did not improve significantly OS (75 vs 81.1 months ; p=0.41) and PFS1 (31.6 vs 47.8, p=0.30) compared with single-ASCT. Conclusion . This large multicenter real-world study confirms that patients with newly diagnosed MM carrying del(17p) and/or t(4;14) remain a therapeutic challenge with no significant overall survival improvement in the past decades despite the use of novel agents. The definition of high-risk MM patients is evolving with incorporation of new markers (i.e chromosome 1 abnormalities, PET-imaging). Minimal-residual disease achievement will also re-defined risk stratification. Nonetheless, the need for innovative approaches such as earlier strategies using new agents or immunotherapy (CAR-T cells, bispecific T-cell engager antibodies) may significantly improve outcomes. Figure captions Table 1. Clinical, biological characteristics, treatment and survival of the 246 included patients based on period of diagnosis. IQR: interquartile range; FISH: fluorescence in situ hybridization; ISS: international score system; LDH: lactate dehydrogenase; ASCT: autologous stem cell transplantation; len: lenalidomide; Poma: pomalidomide; Carfil: carfilzomib; Ixa: ixazomib; mAb: monoclonal antibodies; OS: overall survival Figure 1. Kaplan-Meier curves for overall survival for the 246 included patients based on period of diagnosis. Figure 1 Disclosures Moreau: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding.

Safety and Efficacy of Blinatumomab As Monotherapy Vs Combination Therapy in the Treatment of Relapsed/Refractory Adult ALL: A Systematic Review

Background: Acute lymphoblastic leukemia (ALL) is rare but aggressive. For refractory and relapsed ALL (R/R ALL), various treatment strategies are adopted, of which the use of blinatumomab has shown promising results in recent decades. Blinatumomab is a CD-19 directed CD3 bispecific T-cell engager antibody that has been approved by the FDA for the treatment of both adults and pediatric ALL. We report the efficacy and toxicity of blinatumomab in relapsed and refractory ALL adult patients. Materials/Methods: Following the PRISMA guideline, we performed a comprehensive literature search PubMed, Embase, Cochrane Library, Web of Science, and Clinicaltrials.gov. We used the following keywords, "acute lymphocytic leukemia" and "Blinatumomab" from the inception of data till 06/17/2020. We screened 1199 articles and included 7 trials and 6 retrospective studies. We excluded all case reports, case series, preclinical trials, review articles, and meta-analysis. We extracted the data for efficacy (complete response, relapse, overall survival, etc.) and safety (≥Grade 3 adverse events). Results: A total of 1393 patients with relapsed/refractory ALL were included. Monotherapy: In phase 3 TOWER trial, a total of 405 patients with heavily pretreated B-cell precursor ALL were randomized in a 2:1 ratio to either receive blinatumomab (n=271) or standard of care (SOC) (N=134). The mean age of both groups was 40.8 years and 41.1, respectively. The dose of blinatumomab (9-28 ug/d) was instituted to the intervention group, whereas the control group received investigator-chosen chemotherapy regimens. The CR/CRi rate for both groups was 95/267 (35.5 %) and 27/134 (31.34%), respectively (p&amp;lt;0.01). The median overall survival was 7.7 (5.6 to 9.6 months) vs. 4.0 (2.9 to 5.3 months); the hazard rate for death: 0.71 (95% CI 0.55-0.93) p=0.01 and MRD negativity was 76 % and 48 %, respectively. The most common grade 3 and 4 adverse events (AEs) were neutropenia 45.7%) vs. 61.94% and cytopenia 67.80% vs. 81.34% respectively. In 6 phase 1b/2 studies (N=469), the starting dose of blinatumomab was 5 µg /m2/d and subsequently increased to 30 µg/m2/d. The pooled CR/CRi for these studies was 180/469 (38.37%). The most common hematological grade ≥3 adverse events were neutropenia 89/448 (19.87%), anemia 45/422 (10.70%), and thrombocytopenia 41/422 (9.7%). A total of 509 patients were included in 5 observational studies. The overall CR/CRi reported was 129/509 (25.34%). Grade ≥3 neutropenia and thrombocytopenia were reported as 14/52(26.92%) in one study.CRS was reported in another study as 5/14 (35 %). Combination regimens: In a phase II trial of Blinatumomab when given with a TKI (Dastanib), CR/CRi achieved was 27/47 (56.3%). Blinatumomab related neurotoxicity was observed in 2/12 (16.67%) patients. A total of 38 patients were included in 3 observational studies involving Blinatumomab and TKIs. The overall CR/CRi reported was 25/30(83.33%). In a multicenter phase I/II trial blinatumomab when given with PD-1 inhibitor pembrolizumab (pembro) achieved a CR/CRi of 2/4 (50%). In a phase II study, Blinatumomab and PD-1 and CTLA-4 inhibitors were used in combination in 8 patients. The CR/CRi achieved was 4/5 (80%). Grade ≥3 non-hematological adverse events (AEs) were observed in 1/5 (20%) patients. Blinatumomab has been used in combination with Hyper-CVAD in a phase II study. The ORR and CR achieved have been 14/14 (100%) and 13/14 (93%) respectively. In a recent study, blinatumomab has been used along with miniHCVD + INO in 17 patients. The CR/CRi achieved was 13/17 (76.47%). Conclusion: Blinatumomab alone and in combination with TKIs, PD-1 inhibitors, CTLA-4 inhibitors,hyper-CVAD and miniHCVD + INO were well tolerated by adult patients with acute lymphocytic leukemia. Blinatumomab in combination therapy has shown superior efficacy in adult ALL patients as compared to blinatumomab monotherapy. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.