Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab

Abstract

T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD ؉ B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/L within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

“…The observed lymphocyte redistribution (and transient expression of T cell activation markers) was similar to what has been reported for the BiTE® antibody construct blinatumomab. 12 , 23 In contrast with blinatumomab, which targets CD19, recurrence of peripheral T cells during solitomab treatment was delayed or absent in most patients during the first 50 hours of treatment in the first patients enrolled, possibly indicating T-cell migration from the peripheral blood to the solid tumor; however, this hypothesis require further investigation. Prolonged therapy with dexamethasone was necessary in patients with impacted lymphocyte levels.…”

“…Lymphocyte subpopulations were measured using density gradient-separated peripheral blood mononuclear cells prepared as previously described, 23 or whole peripheral blood collected at screening (for a subset of patients), at baseline (within 1 hour before infusion start), at various timepoints during the first two treatment cycles, and at the end of the treatment period. Lymphocyte subpopulations were analyzed by flow cytometric determination of cell surface markers to determine the relative cellular composition of blood samples using an eight-color FACSCanto™ II instrument (Becton Dickinson, Franklin Lakes, NJ, USA), a five-color FC500 instrument (Beckman Coulter, Brea, CA, USA), or a ten-color FACS NAVIOS instrument (Beckman Coulter).…”

A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19+tumor cells

“…Its molecular weight (»55 kDa) is below the glomerular filtration threshold, which results in a very short terminal elimination half-life (t 1/2 ) of slightly over 1 hour. 11 To maintain suitable drug concentrations, blinatumomab is administered by continuous infusion via pumps, which results in substantial inconvenience for patients and an increased possibility of treatment-related adverse events (e.g., infections at site of implanted port). Also, up to 70% of patients exhibit symptoms consistent with transient cytokine release.…”

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

“…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).…”