IntroductionLow-grade non-Hodgkin lymphomas (B-NHLs) and B-cell chronic lymphocytic leukemia (B-CLL) are generally characterized by a smoldering clinical course. 1,2 Nonetheless, these diseases slowly progress and require intervention. Although remission can be obtained with chemotherapy and antibody directed to B-cell antigens such as CD20, most patients ultimately have relapses. [3][4][5] More aggressive treatments including allogeneic stem cell transplantation may eradicate disease, apparently in part by a T cell-mediated graft-versus-leukemia (GVL) effect. [6][7][8] Unfortunately, their high rate of morbidity and mortality limits their application to younger patients. 9,10 Because these malignancies are sensitive to both T cell-mediated and antibody-mediated cytotoxic effector functions, there has been increasing interest in combining these approaches and recruiting the host immune system to help eradicate the disease that remains after conventional treatments. Anti-idiotype vaccine or whole tumor cell-based vaccines have been used in several clinical trials, but although antitumor activity was observed, the effects were often limited and transient. [11][12][13][14] An alternative means of recruiting both the cellular and humoral arms of the immune response is to adoptively transfer T cells genetically modified to express a B cellspecific antibody incorporated in an artificial chimeric T-cell receptor (CAR). 15,16 These molecules combine the antigen-binding property of monoclonal antibodies with the lytic capacity and potential longevity of T lymphocytes to provide an enhanced antitumor effect. 16 Because B-NHL and B-CLL stably express CD19 or CD20 antigens, adoptive transfer of CD19-or CD20-specific CARs to T lymphocytes has been proposed. [17][18][19][20] However, adoptively transferred T cells, unlike monoclonal antibodies, may have almost indefinite persistence 21 so that success of this approach would likely be associated with long-term impairment of humoral immunity. We now propose an alternative target for chimeric T cells. B lymphocytes express surface monoclonal immunoglobulins with either or light chains. Because expression of / is clonally restricted, and because low-grade B-NHL and B-CLL are themselves clonal, the malignant cells in a given individual will express either or light chain. 22 Chimeric T lymphocytes targeting the light chain expressed by the tumor should spare normal B cells expressing the reciprocal light chain. Because no functional differences have been found between antibodies containing the or chains 23 and because light chain deficiency has been described in animals 24 and humans 24,25 without increased susceptibility to infection, sparing the normal population of B lymphocytes expressing the nontargeted light chain should have minimal adverse effects on patient immunity. We now demonstrate the feasibility of this approach using a light chain-specific chimeric T-cell receptor. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From culture with RPMI 1640 medi...

This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR) ¼ 0.7, P ¼ 0.02) translating into a trend for better overall survival (OS; HR ¼ 1.3; P ¼ 0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR ¼ 0.4, Po0.0.001) owing to high risk of nonrelapse mortality (NRM; HR ¼ 5.2, Po0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR ¼ 0.72; P ¼ 0.07) translating into a better OS (HR ¼ 1.8; Po0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR ¼ 0.65; P ¼ 0.02) but also with higher NRM (HR ¼ 3.5; Po0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (Po0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR ¼ 0.65; P ¼ 0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD.