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Immunotherapy of hematological malignancies: what is new?

The belief that tumors can be identified and subsequently attacked by the immune system (IS) dates from the late nineteenth century, when Ehrlich postulated the existence of continuously arising ‘aberrant germs’ (tumors), the growth and development of which, unless stopped on time by the IS, would inevitably lead to death [1]. During the 1950s and 1960s, accumulating data supported this inspirational suggestion. The observation of spontaneous regression in certain tumors, and the finding of the later-called ‘tumor infiltrating lymphocytes’ or TILs [2], the presence of which appeared to preclude a favorable prognosis in some forms of cancer, lead Burnett and Thomas to formulate the Theory of Immune Surveillance [1]. Briefly, this theory accepted the generation of cancer cells as a normal phenomenon in humans; the IS, however, would identify and eliminate these cells before they developed into clinically evident cancer [1]. A number of experimental approaches aimed to stimulate the IS followed. These early attempts of immunotherapy (IT) adopted tumor-specific strategies (antibodies targeted against tumor antigens, vaccination with tumor cell extracts) and non-specific methods (BCG vaccine, vaccination with Corynebacterium parvum extracts, levamisole) [1]. Naive as these approaches may seem, occasional reports of partial (most times) and even complete responses (CR) were published [1]. The Theory of Immune Surveillance, however, would not provide a comprehensive explanation for the actual development of clinical cancer. In other words, should the IS efficiently cover this postulated surveillance function, how was it possible that some cancer cells bypassed this system, leading to the development of cancer? This question (the so-called ‘immune paradox of cancer’), for which only theoretical models would give an answer, justified, in many ways, the disrepute these strategies fell into, in the late 1970s. In parallel, and with no initial relation with these developments, bone marrow transplantation (BMT) was introduced by Thomas as treatment for malignant and non-malignant conditions [3]. Initially designed as a method for eliminating a malfunctioning bone marrow with chemotherapy and radiotherapy, followed by its replacement with a ‘healthy’ hemopoietic system from a donor, the antitumor success of BMT was soon found to depend on additional factors: in 1963, Mathe reported the first description of graft-versus-host disease (GvHD) [4] in a patient receiving an allogeneic BMT as treatment for leukemia. Most interestingly, Mathe proposed the occurrence of this secondary disease might favor the elimination of leukemia cells surviving the pretransplant chemoand radiotherapy [5]. This early suggestion of an antitumor effect linked to GvHD was later confirmed in statistical analysis of international BMT registries [6], defining the so-called graft-versus-leukemia (GvL) effect. Similar investigations proved relapse rates were lower with increasing antigenic disparity [7], which explained the high relapse rate seen in patients receiving grafts from identical twins [8]. Finally, a common immune (and T-cell-linked) pathogenesis for GvHD and GvL was identified [9], as the use of T-cell depletion, as well as other procedures aimed to block T-cell responses [10] in order to prevent GvHD, led to an increased relapse rate. Coincidentally, evidence was provided suggesting chemotherapy as standard treatment for leukemia could only eliminate the actively reproducing tumor cells, whilst the IS was required to eliminate minimal residual disease [11]. This historical overview allows an understanding of the reasons why IT for hematological conditions has been much centered on BMT: lessons learnt from this procedure have led to the birth of new strategies for the treatment of malignancies via cell-driven therapies. However, promising developments in the area of tumortargeted antibodies have taken place in recent years. The treatment of lymphoid malignancies has experienced radical changes, as monoclonal antibodies (mAb) have been accepted as components of standard therapeutic schemes. The aim of the present review is to present an updated overview of the IT methods and strategies with potential use in hematological malignancies. For merely academic purposes, all these approaches will be classified as ‘antibody-based therapies’ and ‘cell-driven strategies’, although the frontiers between these two categories are somehow arbitrary, as the IS should be considered a single system where alterations in one arm inevitably lead to changes in the other, and contributions from both immunocompetent cells and receptor-antibodies pairs are required for the optimal functioning of any of these strategies.