Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

Abstract

Background: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD.

Methods/design: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial.

Discussion: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse.

Trial registration: NCT01138579.

Figure 1

FBTA05 (anti-CD3 x anti-CD20 trAb) – mode of action. In a MHC-independent manner polyclonal T cells are redirected to and activated at tumor cells by trAb-mediated recognition of CD3 and tumor-associated antigens (TAAs) such as CD20. At the same time or subsequently FcγR-positive accessory cells such as monocytes/macrophages, dendritic cells (DCs) or natural killer cells interact with the Fc part of trAbs. Through this cellular crosstalk all participating immune cells are strongly activated. Hence, T cells receive a second co-stimulatory signal, while accessory immune cells are stimulated via FcγR crosslinking which leads to the release of proinflammatory cytokines. Thus, tumor cells are effectively eliminated by a concerted attack of cytotoxic T cells and accessory immune cells using different killer mechanisms such as ADCC, phagocytosis, or perforin/granzyme-mediated lysis and apoptosis induction. Finally, T cell proliferation occurs as does phagocytosis of necrotic/apoptotic tumor particles which are then processed, and presented by stimulated professional antigen presenting cells (i.e. DCs), an important prerequisite for the induction of long-lasting vaccination-like effects against tumors. ADCC (antibody dependent cellular cytotoxicity); CMC (complement-mediated cytotoxicity); DC-CK1 (Dendritic cell cytokine 1); IL (interleukin); LFA (leukocyte function-associated antigen); TNF-α (Tumor necrosis factor α).

Figure 2

Treatment schedule. The FBTA05 treatment schedule consists of three parts: the drug induction part (safety part) and the dose maintenance / escalation parts (course I / II). Thereby the safety part is the same for each study patient, with FBTA05 applications of 10 μg on day 0, 20 μg on day 3 and 50 μg on day 7. FBTA05 dose adjustment for the subsequent treatment courses I and II, will be performed according to the respective cohort A-D (Table 1). Infusion of donor lymphocytes (DLI) will be dose-escalated (Table 3) and applied subsequent to the respective antibody infusions on day 7, day 35 and day 63 of the treatment schedule. The red arrows indicate the application of FBTA05, the green arrows the infusion of donor lymphocytes.