Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab

Abstract

Severe side effects and few long-term remissions frequently limit the treatment of advanced malignant diseases. Bispecific antibodies are currently emerging as a new option for the treatment of malignant diseases, which can potentially engage all cytotoxic T cells of a patient for tumor cell lysis. Blinatumomab, a bispecific single-chain BiTE antibody construct with dual specificity for CD19 and CD3, is a front runner of this antibody class. We here summarize the current state of development of blinatumomab for the treatment of patients with B-cell non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphocytic leukemia (ALL). High response rates and durable remissions are observed in first clinical trials, indicating that T cells can be potently redirected for efficient and lasting elimination of malignant cells.

Introduction

Based on the observation that T cells are involved in cancer immune surveillance and their incidence within solid tumors can impact patients' survival, various approaches have been undertaken over the last decades to use this cell type of the immune system for controlling tumor growth or even induce tumor regression [1], [2], [3], [4]. T cell-based therapeutic approaches include vaccines, adoptive transfer of autologous, ex-vivo expanded T cells, and T cell-activating antibodies [5], [6], [7], [8]. Further attempts use a combination of vaccines in combination with IL-2, IFN2α GM-CSF, or CpG for stimulation of the activity of T cells or antigen presenting cells. While all such approaches have shown some limited activity, only bispecific T cell-engaging antibodies have demonstrated high response rates and durable remissions in patients with hematological malignancies [8], [9].

The low response rates of most approaches trying to elicit or support tumor antigen-specific T cell responses in patients with malignant diseases are most likely due to escape variants of tumor cells that are selected under therapy and which later cause recurrence and disease progression. Tumor cells can be selected over time to express mechanisms allowing their escape from recognition by T cells, or their inactivation. These mechanisms include loss of molecules involved in T cell recognition, such as MHC class I, TAP transporter, ß2 microglobulin, or the expression by cancer cells of immunosuppressive molecules, such as IDO, IL-10, TGF-β, PD-L1/B7-H1, or FasL [10], [11]. While all these escape mechanisms will inhibit in one or the other way the development of antigen-specific T cell responses, the direct engagement of pre-existing, polyclonal T cell clones with the help of bispecific antibodies may not be impacted to the same extent.

Bispecific antibodies are designed to bind with one arm to a surface antigen on cancer cells of the same kind as is recognized by monoclonal antibodies. These target antigens can, for instance, be overexpressed growth factor receptors, such as EGFR or HER-2, or cell differentiation antigen such as CD20, CD22 or CD19, where the ablation of an entire cell compartment along with cancer cells is tolerated by the patient. With the second arm, bispecific antibodies bind to an activating, invariant component of the T cell receptor. Through the temporarily forced interaction between T cell and cancer cell, any cytotoxic T cell will become activated and can now cause redirected lysis as otherwise performed by antigen-specific cytotoxic T cell clones. BiTE antibodies are one class of bispecific antibodies that have been very well characterized in this regard [8], [12]. In the following, we will review the clinical experience with a CD19/CD3-bispecific BiTE antibody called blinatumomab (MT103) for the treatment of NHL and ALL patients.