Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL

Topp, Max S.; Gökbuget, Nicola; Zugmaier, Gerhard; Degenhard, Evelyn; Goebeler, Marie-Elisabeth; Klinger, Matthias; Neumann, Svenja; Horst, Heinz A.; Raff, Thorsten; Viardot, Andreas; Stelljes, Matthias; Schaich, Markus; Köhne-Volland, R; Brüggemann, Monika; Ottmann, Oliver G.; Burmeister, Thomas; Baeuerle, Patrick A.; Nagorsen, Dirk; Schmidt, Margit; Einsele, Hermann; Riethmüller, Gert; Kneba, Michael; Hoelzer, Dieter; Kufer, Peter; Bargou, Ralf C.

doi:10.1182/blood-2012-07-441030

Cited by 424 publications

(297 citation statements)

References 14 publications

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“…The primary endpoint, MRD‐negativity, was achieved in 16 of 20 (80%) evaluable subjects (one subject experienced a Grade 3 seizure and was not evaluable) 71. At a median follow‐up of 33 months, hematologic relapse‐free survival was 60% 72. Of note, 11 subjects on this trial did not receive subsequent allogeneic HSCT and six subjects remain alive in continuous remission.…”

Section: Clinical Experience With Blinatumomabmentioning

confidence: 93%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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Section: Clinical Experience With Blinatumomabmentioning

confidence: 93%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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“…The exquisite cytotoxic potential of T cells has thus far not been leveraged for treatment of AML, although it has been very successful for treating patients with NHL and ALL as exemplified by both blinatumomab (14,34,35), ) human AML cells were administered intravenously to female NOD/SCID mice and animals were allocated to treatment groups (n ¼ 5 or 10). In vitro expanded and activated human T cells were transplanted into the peritoneal cavity except for five animals that served as control on day 3.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Friedrich

Henn

Raum

et al. 2014

Molecular Cancer Therapeutics

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There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3e of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC 50 values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-g, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML. Mol Cancer Ther; 13(6); 1549-57. Ó2014 AACR.

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“…In studies of non-Hodgkin lymphoma and B-precursor acute lymphoblastic leukemia (B-ALL) patients, blinatumomab has been reported to induce a high rate of clinical benefit with an acceptable safety profile. [43][44][45][46][47][48][49] The blinatumomab data demonstrates clinical proof of principle for the platform technology. Clinical studies are ongoing in adult and pediatric patients with relapsed/refractory B-precursor ALL, adults with persistent minimal residual disease B-precursor ALL, and adults with relapsed diffuse large B cell lymphoma (DLBCL), (ClinicalTrials.gov identifiers NCT01471782, NCT01207388, NCT01466179, and NCT01741792).…”

Section: Introductionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL

Cited by 424 publications

References 14 publications

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

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