Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody

Abstract

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non-Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell-engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Tumor doubling time in patients with ALL was assumed to be 33 days based on literature report, 20 and the derived k g was 0.00126 1/hr. The effect of T cell proliferation was not considered in the current simulation since it was reported that, on average, blinatumomab caused approximately a two-fold expansion of T cells in patients, 41 which would only lead to minor changes in τ. CD19 expression level on B cells was assigned at 20,000 receptors per cell based on literature report, 42 and this value was 2- to 5-fold lower than that of B cell lines used in vitro cytotoxicity assays (20,000 vs. 40,000 – 100,000 receptors per cell). 22,33,43–45 The blood and bone marrow blinatumomab concentration-response curves predicted by the TBE model are shown in Figure 5.…”

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.…”

“…Proof of concept was shown early with blinatumomab in the setting of hematologic malignancies; 12 , 14 , 15 however, information on the applicability of BiTE® antibody constructs to the solid tumor setting remains very limited. 18 We report here the final results of the first-in-human phase 1 study of solitomab, a BiTE® antibody construct immunotherapy against EpCAM, in solid tumors.…”

“…In comparison to checkpoint inhibitors, BiTE® antibody constructs 12 induce an MHC-independent T-cell response, thereby circumventing specific immune escape mechanisms. 13 Blinatumomab was the first BiTE® antibody construct to be clinically evaluated, focusing on hematologic malignancies.…”

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

“…Continuous intravenous infusion (cIV) was tested in a subsequent phase 1 trial (MT103‐104), again among subjects with indolent NHL ( Figure 3, Table 2),54, 55 to mitigate toxicity and maintain exposures needed to sustain responses; it was hypothesized that intermittent dosing led to high C max and that the drug‐free period potentiated T‐cell cytokine release. The dose–exposure relationship was linear from 5–90 μg/m 2 /d, stable plasma blinatumomab levels were achieved rapidly with continuous infusion, and rapid clearance consistent with previous observations was observed 56.…”