RORing T cells target CLL and MCL

The genetic engineering of T cells, mediated by several vector systems (among which γ-retroviral vectors are currently preponderant), aims not only to redirect the antigen specificity of T cells but also to generate T cells that are endowed with enhanced signaling and other antitumoral properties to sustain their survival and function within the tumor microenvironment.^1,2  What T-cell type (naive T cells, memory T cells, virus-specific T cells, T-cell precursors) to engineer “for best results” remains a hotly debated topic.

Antigen specificity is imparted by the genetic transfer of a single antigen receptor, consisting of either physiologic, HLA-restricted T-cell receptors (TCRs)³  or artificial, non-HLA-restricted receptors, which vary in the molecular composition and are broadly referred to as chimeric antigen receptor (CARs).⁴  Most CARs use an antibody-derived antigen-binding motif to recognize antigen, and comprise activating and costimulatory signaling domains in their cytoplasmic portion. CARs are thus targeted to cell-surface antigens and do not have to be matched to the patient's HLA.

In the hematologic malignancies, CD19, which is relevant to chronic and acute leukemias as well as non-Hodgkin lymphomas, has emerged as a pivotal target antigen.^5,6  It is the focus of more than a dozen active protocols in the United States, all of which are based on the infusion of CD19-targeted T cells. Over 15 centers are planning trials based on this approach in the United States, Europe, and Japan. At a recent meeting of the BMT CTN Network held in May 2010, it was determined that 19 patients had already been treated with CD19-targeted T cells in the United States. CD19 is normally expressed in the B-cell lineage from the pro-B-cell stage on albeit not in plasma cells. Importantly, it is not found in hematopoietic stem cells and in other hematopoietic lineages. The targeting of CD19 is thus expected to induce B-cell aplasia, which has been verified in animal models. The duration and consequences of this induced B-cell deficit are yet to be fully investigated, but there is ample precedent for the successful clinical management of similar conditions after bone marrow transplantation or monoclonal antibody therapy. The broad relevance of CD19 to the majority of leukemias and lymphomas notwithstanding, the availability of a highly tumor-specific target antigen would avert the risk of a sustained B-cell deficit.

In this issue of Blood, Hudecek et al establish ROR1 as a novel target for CAR-mediated T-cell therapy.⁷  ROR1 is a cell-surface antigen receptor with an extra cellular domain that contains Ig-like, Frizzled and Kringle domains, which may act in Wnt signaling and promote tumor cell survival.^8,9  It is expressed during fetal development and not known to be expressed postnatally elsewhere than in early maturing B cells, the pancreas, and adipose tissue.⁹  Significantly, it is expressed at a high level in chronic lymphocytic leukemia (B-CLL), a subset of acute lymphoblastic leukemia (B-ALL), and, as shown by Hudecek et al, in mantle cell lymphoma (MCL). In their study, Hudecek and colleagues describe a novel ROR1-specific CAR and demonstrate its ability to redirect patient T cells against CLL and MCL tumor cells, resulting in efficient in vitro cytotoxicity and other key functional T-cell responses including cytokine secretion and proliferation. While these studies stop short of demonstrating T-cell efficacy in mice bearing systemic leukemia or lymphoma—and a much-anticipated comparison to CD19 targeting—this report conclusively brings ROR1 to the fore as an attractive target for immunotherapeutic strategies in selected leukemias and lymphomas.

As the potency of genetically enhanced T lymphocytes gains strength, so does the concern over toxicity, including on-target effects (whereby T cells attack tissues that normally express the targeted antigen). Several reports underscore the ability of genetically targeted T cells to react against normal tissues, for example, carbonic anhydrase IX in biliary epithelium¹⁰  and MART-1 in the inner ear,¹¹  eye, and in patients with renal cancer or melanoma who were given T cells targeted against these antigens. These undesirable effects may, however, be manageable and do not constitute grounds for not investigating differentiation antigens such as CD19 (which is highly restricted to the B-cell lineage) or an oncofetal antigen-like receptor such as ROR1. The consequences of low-level ROR1 expression in adipocytes and possibly some pancreatic cells will have to be closely investigated.