Mechanism of Action Magnifier – 2016 Desk Reference
Blinatumomab: a Bispecific CD19-Directed CD3 T-Cell Engager
Blinatumomab (derived from “B-lineage–specific antitumor mouse monoclonal antibody”) is a bispecific CD19-directed CD3 T-cell engaging antibody that binds to1-3:
- CD19 (expressed on the surface of cells of B-lineage origin)
- CD3 (expressed on the surface of T cells).
More than 90% of cases of B-cell precursor acute lymphoblastic leukemia (ALL) express CD19 in more than 20% of malignant cells, the intensity of expression being sufficient to make this therapy suitable in ALL.4
Blinatumomab activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells (Figure).1,3 The nonimmunogenic linker protein that binds the anti-CD19 and anti-CD3 antibodies enables a great degree of rotational flexibility, which allows for close proximity of malignant CD19-positive B cells to CD3-positive T cells, favoring direct lysis.4
Furthermore, blinatumomab-activated T cells are capable of serial killing of the CD19-positive target cells. One hypothesis for this serial lysis lies in the preferential binding of CD19 compared with CD3, which potentially allows the T cells to be released from the target cells, enabling them to bind to additional target B cells. The T-cell proliferation and the serial killing of CD19-positive B cells induced by blinatumomab explain why this monoclonal antibody is also effective in patients with a limited number of T cells due to prior intensive therapy or early after hematopoietic stem cell transplantation.5-9
Thus, blinatumomab mediates1:
- The formation of a synapse between the T cell and the tumor cell
- Upregulation of cell adhesion molecules
- Production of cytolytic proteins
- Release of inflammatory cytokines
- Proliferation of T cells, which result in redirected lysis of CD19-positive cells.
On December 3, 2014, the FDA granted accelerated approval for blinatumomab for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).10 The approval was based on the achievement of durable complete remission (CR) and response with a reduction in minimal residual disease (MRD) to less than 10–4 in a multicenter single-arm study (Protocol MT103-211, or the ’211 study) that enrolled 185 patients with R/R ALL.11,12 Results showed that 32% (95% CI, 26%-40%) of patients with R/R ALL attained a CR with 2 cycles of treatment with single-agent blinatumomab, and the response was durable (median, 6.7 months; range, 0.46-16.5 months). Furthermore, 31% (95% CI, 25%-39%) of patients in the study had a CR with or without complete hematological recovery but with reduction in MRD to <10–4. Safety was evaluated in 212 patients with R/R ALL treated with blinatumomab. The most common adverse reactions (≥20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). A neurologic toxicity occurred in approximately 50% of patients and was a frequent reason for interruption of therapy. Blinatumomab activates endogenous T cells when bound to the CD19-expressing target cell, and activation of the immune system results in release of inflammatory cytokines. Cytokine release syndrome, including life-threatening or fatal events, was reported in 11% of the patients.
- Blincyto [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
- Ribera JM, Ferrer A, Ribera J, et al. Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia. Onco Targets Ther. 2015;8:1567-1574.
- Wu J, Fu J, Zhang M, et al. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:104.
- Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma. 2011;52:1098-1107.
- Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119:6226–6233.
- Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941-4944.
- Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol. 2013;5(suppl 1):5-11.
- Rathi C, Meibohm B. Clinical pharmacology of bispecific antibody constructs. J Clin Pharmacol. 2015;55(suppl 3):S21-S28.
- Ruella M, Gill S. How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia. Expert Opin Biol Ther. 2015;15:761-766.
- Przepiorka D, Ko CW, Deisseroth A, et al. FDA approval: blinatumomab. Clin Cancer Res. 2015;21:4035-4039.
- US Food and Drug Administration. Blinatumomab. www.fda.gov/Drugs/Informa tionOnDrugs/ApprovedDrugs/ucm425597.htm. Accessed November 21, 2015.
- Onyx Pharmaceuticals. Amgen presents data from pivotal phase 2 study of BLINCYTO™ (blinatumomab) immunotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. www.onyx.com/view.cfm/727/amgen-presents-data-from-pivotal-phase-2-study-of-blincyto-blinatumomab-immunotherapy-in-patients-with-relapsedrefractory-acute-lymphoblastic-leukemia. Accessed November 21, 2015.
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In my medical oncology practice at Johns Hopkins, I see approximately 4 patients with nonmetastatic NSCLC per week. Most of these patients are referrals from either pulmonary medicine or thoracic surgery. A patient with early stage disease initially sees a pulmonologist for diagnosis and may then be referred to a thoracic surgeon. The thoracic surgeon may refer the patient to us in medical oncology if there is an indication to enroll the patient in a clinical trial or for systemic therapy. In a community oncology practice, patients tend to go to surgery first and are then referred to the medical oncologist for adjuvant chemotherapy. In academic centers, it is more common for patients to be seen in a multidisciplinary setting.