Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 × anti-CD20 antibody and donor lymphocyte infusion

Abstract

Donor lymphocyte infusions (DLIs) after allo-SCT displayed limited use in CLL and highly malignant nonHodgkin's lymphoma (NHL). Here we studied whether Bi20 (FBTA05), a novel trifunctional bispecific antibody targeting CD20 on lymphoma cells and CD3 on T cells, could induce GVL responses in combination with DLI or mobilized PBSCT after allogeneic transplantation in these diseases. Six patients (three cases with p53-mutated CLL and three with high-grade NHL (HG-NHL)) refractory to standard therapy were treated with escalating doses of Bi20 (range 10-2000 lg) followed by DLI or SCT. Thereby, all CLL patients showed a prompt but transient clinical and hematological response. In one patient with HG-NHL, we observed a halt in progression for almost 4 months. Side effects (fever, chills and bone pain) were tolerable and appeared at antibody dose levels between 40 and 200 lg. The cytokine profile was characterized by transient increases of IL-6, IL-8 and IL-10. Neither human anti-mouse antibodies nor GVHD developed, allowing repeated treatment courses. In summary, the trifunctional antibody Bi20 induced prompt antitumor responses in extensively pretreated, p53-mutated alemtuzumab and rituximab refractory patients indicating its therapeutic potential.

Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery

“…After several therapy cycles, anti-drug antibodies may hamper the clinical use not only by neutralizing the trAb-dependent therapeutic effect, but also by forming aggregates that could lead to severe adverse events in vivo. However, as trAbs are typically used in extremely low amounts, such effects have not been observed in clinical trials so far (8,18,19). Our preclinical studies demonstrate that application of much higher doses in humans would be feasible, provided that the appropriate application route is chosen.…”

“…However, such regimens are often associated with undesired adverse effects such as flulike symptoms, chills, and fever that are due to off-site T-cell activation and systemic cytokine release (18,19,26). TrAbs, which recruit different types of immune effector cells to the tumor cells and thereby also induce a T-cell memory (6,7), are one of the most potent immunologic antitumor reagents hitherto used in cancer patients.…”

“…TrAbs, which recruit different types of immune effector cells to the tumor cells and thereby also induce a T-cell memory (6,7), are one of the most potent immunologic antitumor reagents hitherto used in cancer patients. These Ig constructs, which are effective at nanogram/mL concentrations (18,27), may raise particular safety concerns (18,19). Although trAb-induced cytokine-related adverse events are manageable in the clinics by using low starting doses and subsequent dose escalation (18,28), there must be constant efforts to further improve patients' safety thus increasing the treatment options for trAbs in the near future.…”

“…Several clinical trials indicated that both intraperitoneal (8,9,16,17) and intravenous (18)(19)(20) administration is feasible. However, we argued that for broader clinical applicability of trAbs, the subcutaneous delivery may offer several benefits, for example, a shortened application time (minutes vs. hours) and a further improved safety profile.…”

Allogeneic Immunotherapy to Optimize the Graft-versus-Tumor Effect: Concepts and Controversies

“…50 Another promising approach is the combination of DLI with novel antibodies that can direct and activate effector cells directly at the site of tumor; this is another strategy that theoretically could overcome possible resistance mechanisms to GVT induction without excessive toxicity. 51 An alternative strategy to maintaining activation of donor T cells is inhibition of negative regulators of activity such as CTLA-4. Ipilimumab, an anti-CTLA4 monoclonal antibody, has been tested as therapy for relapse in 29 patients; 3 responses were noted, including 2 of 14 patients with relapsed HD and 1 patient with relapsed mantle cell lymphoma.…”