Interfering with CD40 ligation: a sensitive matter in chronic lymphocytic leukemia

In normal B-cell biology the CD40/CD40 ligand interaction is a key point in B-cell antigen recognition, differentiation and proliferation. CD40 is a member of the tumor necrosis factor receptor (TNFR) family which transfers signals capable of regulating a range of diverse cellular responses, including proliferation and cell differentiation as well as growth suppression and apoptosis [1]. Although it was first described and characterized in B cells, CD40 is present on many different cell types, including dendritic cells, endothelial cells, fibroblasts and macrophages, and various non-lymphoid cells display both the receptor and its ligand [2]. In vivo activated T lymphocytes express CD40 ligand, which interacts with other CD40 expressing cells providing the appropriate signal that leads to cell proliferation and enhanced survival and greater expression of co-stimulatory molecules such as CD80 and CD86, as well as the production of chemokines and cytokines. Binding to CD40 also activates nuclear factor κB (NF-κB) signaling, and upon activation the latter up-regulates the transcription of several genes, including the inhibitors of apoptosis proteins (IAPs), other inhibitory proteins, Bcl-xl and other pathways including Janus kinase 3–signal transducer and activator of transcription 3 (JAK3–STAT3) and phosphatidyl inositol 3-kinase (P13K)–Akt, thereby contributing to the anti-apoptotic events induced by CD40 ligation in B cells [3,4].

Malignant B-cells in patients with chronic lymphocytic leukemia (CLL) undergo activation when stimulated with CD40 ligand, athough with significant inter-patient heterogeneity in the extent of response [5]. Because of this, targeting CD40 ligand signaling has been considered a potential therapeutic strategy in this disease. In this issue of Leukemia and Lymphoma, Byrd and collaborators report a phase I trial of lucatumumab (HCD122), a fully humanized anti-CD40 antibody of the immunoglobulin G1 (IgG1) isotype that targets human CD40. In preclinical studies, lucatumumab was shown to block CD40 ligand-mediated proliferation of normal B cells as well as CLL cells. Besides binding to CD40 with high affinity, lucatumumab has also been found, in vitro, to mediate clearance of CLL cells via antibody-dependent cell-mediated cytotoxicity as well as by opsonization.

Byrd and colleagues [6] show in this report that the safety profile of lucatumumab is favorable, with elevation of the pancreatic enzymes being the limiting factor to dose escalation, and identify 3 mg/kg as the dose recommended for subsequent studies. In this study of 26 patients, complete saturation of CD40 was demonstrated, and the pharmacokinetic profile was typical for this class of monoclonal antibody. Clinical activity was minimal in this early-phase trial, with one patient achieving a partial remission and an additional 17 patients having stable disease. However, the most interesting aspect of this initial experience with lucatumumab is the favorable toxicity profile that offers the potential of combining this novel antibody with chemotherapy and other therapeutic agents with established activity in CLL.

Gene therapy strategies targeting CD40/CD40 ligand have also been investigated and published. Adenoviral vectors were shown in preclinical studies to be able to transduce CLL cells to express CD40 ligand [7]. Based on this approach, Wierda and colleagues demonstrated that adenovirus vector-induced autologous CLL cells transduced ex vivo with murine CD40 ligand could be safely infused in patients with CLL. This early study also showed some clinical activity [8]. Due to the development of antibodies against the murine CD40 ligand, a subsequent trial from the same group utilized the recombinant humanized CD40 binding protein ISF35 to transduce autologous tumor cells ex vivo. In this study with humanized CD40, again evidence of clinical activity was shown, with minimal toxicity, and there was no formation of antibody against humanized CD40 binding protein [9].

Thus, the initial experience with therapies targeting CD40/CD40 ligand interaction is encouraging. However, we should be mindful that CLL cells from different patients have a variable response to CD40 ligand stimulation, with inter-clone variability, implying that the clinical courses of patients with various degrees of sensitivity to CD40 ligation may be quite different [5]. Based on this observation, we can at this time hypothesize that CD40-directed therapy would probably be of greater benefit to patients whose CLL cells are responsive to CD40 ligation.

Potential conflict of interest

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