Targeting CD52 as a novel therapeutic strategy in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma (PTCL) that is characterized by unique clinical and biological features [1]. It most commonly affects older patients, has an equal male to female ratio, and frequently presents with unusual manifestations such as skin rash, hepatosplenomegaly, and constitutional manifestations, distinguishing it from other peripheral T-cell lymphomas [2]. It is associated with disordered immune regulation and, interestingly, manifests features of both immune system hyperactivity such as hypergammaglobulinemia as well as autoimmune phenomena and immunodeficiency. Indeed, patients frequently succumb to infectious complications rather than disease progression. While Epstein–Barr virus (EBV) and B-cell dysregulation are thought to play important roles in the pathogenesis of the disease, their exact mechanistic contributions are poorly understood, and the putative cell of origin of AITL remains a controversial issue. Recently, it has been demonstrated that the neoplastic cells of angioimmunoblastic T-cell lymphoma overexpress the chemokine CXCL13, and this, in addition to the fact that the neoplastic T-cells express CD4, CD10, and occasionally BCL-6, suggests that the disease is derived from follicular helper T-cells (TFH) [3,4]. Recent gene expression profiling work supports this derivation, as it has demonstrated overexpression of several genes characteristic of follicular T helper cells in AITL [5]. EBV-positive B-cells are almost always present to some degree within AITL, and while it was originally believed that EBV reactivation in AITL was due to decreased immune surveillance, the finding of EBV-positive B-cells early in the course of the disease suggests a possible role for EBV in early pathogenesis that may involve the activation of TFH cells [6,7]. Though there has been much recent progress in understanding the biology of AITL, the outcome for patients with this disease who receive conventional chemotherapy has been disappointing, with median survivals of 36 months and 5-year survival rates of 30–35% [7]. Indeed the international peripheral Tcell and natural killer/T-cell lymphoma study demonstrated that there does not appear to be a significant benefit to anthracycline administration in the upfront treatment of this disease [8]. These poor clinical outcomes have led to much interest in developing novel approaches for AITL. Over the past few years, interesting therapeutic strategies that have shown promise, albeit in small numbers of patients, have included immunomodulation with agents such as cyclosporine, which may mediate its effects by deregulating T-cell activation through the calcineurin-nuclear factor of the activated T-cell signaling pathway, and in this way may reduce the production of various cytokines and alter the immune dysregulation associated with AITL [9]. Inhibition of angiogenesis with drugs such as bevacizumab is also an interesting therapeutic strategy that is under investigation [10]. The article by Amengual and Raphael is interesting in that they report sustained durable responses— lasting at least 21 months—in three patients with refractory AITL who received single-agent alemtuzumab [11]. Alemtuzumab (Campath 1H) is a ‘humanized’ rat immunoglobulin G1 (IgG1)