Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

IntroductionImmune-mediated disorders often present as a combination of destructive tissue damage and variable systemic organ manifestations based on an overwhelming T-and/or B-cell reaction. There has been great interest recently in targeting the interleukin-2 (IL-2) pathway by specific immunosuppressive drugs and the use of CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells (Tregs) for the treatment of such inflammatory conditions. 1,2 To specifically modulate aberrant immune responses such as acute graft-versus-host disease (aGVHD), allograft rejection, or autoimmune disorders by immunosuppressive therapy, while sparing Treg activity, a more detailed insight into the biologic differences between Tconv and Tregs is crucial. One critical requirement for Treg function and expansion in preventing aGVHD is calcineurin-dependent IL-2 production, 3 which is affected by the immunosuppressant cyclosporin A (CSA). In light of the finding that the interaction between NFATc and Foxp3 is required for the suppressive effects of Treg cell 4,5 interference with nuclear factor of activated T cells (NFAT) by CSA may also contribute to the observed effects of CSA on Treg biology. We and others have shown that rapamycin (RAPA) but not CSA allows for Treg expansion and function in mice 3,6,7 and in humans. 8,9 In contrast to CSA, RAPA inhibits mammalian target of rapamycin (mTOR) pathway activity, which is downstream of IL-2/phosphatidylinositol 3-kinase (PI3K) signaling. 10 This pathway is negatively regulated by PTEN (phosphatase and tensin homolog deleted on chromosome 10), a phosphoinositol 3,4,5-triphosphatase that catalyzes the reverse reaction of PI3K. 11 Other pathways that are activated in response to IL-2 signaling that may be preferentially used when mTOR is inhibited include the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) and the mitogen-activated protein kinase (MAPK) pathway. Recent data have demonstrated an essential role for IL-2 receptor (R)␤-dependent STAT5 signaling for the development of Tregs. 12 Here we describe the in vivo impact of mTOR inhibition on expansion, migration, Foxp3 expression, and activity of Tregs after allogeneic hematopoietic cell transplantation (aHCT). From a mechanistic standpoint, we studied the differential impact of RAPA on Tconv and Tregs with respect to PI3K/mTOR and STAT5 pathway activity. Methods MiceC57BL/6 (H-2k b , Thy-1.2), FVB (H-2k q ), BALB/c (H-2k d , Thy-1.2), and C57BL/6 PTEN tm1Hwu mice were purchased from the Jackson Laboratory (Bar Harbor, ME) or Charles River Laboratories (Wilmington, MA). C57BL/6 Lck-Cre mice were a kind gift from Dr J. Crabtree (Stanford University, Stanford, CA). Mice were used between 6 and 12 weeks of age. For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Only sex-matched combinations were used for transplant experiments. The luciferase-expressing (luc ϩ ) transgenic FVB/N L2G85 were described previously 13 and backcrossed for more than 10 generations to the C57BL/6 background. All animal prot...

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There has been accumulating evidence that CD4 1 CD25 1 FoxP3 expressing regulatory T cells (Treg) are highly concentrated in tumors, thereby fostering an immune-privileged microenvironment. Some studies have shown that T-cell receptor (TCR) stimulation can convert conventional T cells into Treg. Follicular lymphoma (FL) B cells can enhance this Treg conversion. We investigated whether FL tumor B cells, as opposed to normal B cells, are unique in their ability to convert effector T cells into Treg. We found that tumor B cells alone, without artificial TCR stimulation, could induce conventional T cells to express FoxP3 and to acquire regulatory function. In contrast to their malignant counterpart, normal B cells did not induce Treg conversion. Treg conversion was independent of the T cell background, as T cells isolated from FL or normal peripheral blood were equally susceptible to being converted by tumor B cells. Our study provides evidence for a tumor-specific mechanism by which FL tumor cells promote immune escape through the induction of Treg. ' 2008 Wiley-Liss, Inc.Key words: tumor microenvironment; immune escape Tumors induce immunologic tolerance by several mechanisms, involving tolerogenic antigen presenting cells, Foxp3 1 CD4 1 CD25 1 regulatory T cells (Treg) and soluble immunoregulatory factors. 1-4 An increased frequency of Treg was first observed in the peripheral blood of patients with bronchial carcinoma when compared with healthy individuals. 5 Then similar findings were reported in patients with a variety of cancer types. This was followed by several reports indicating that Treg can be actively recruited and expanded in the tumor microenvironment. 4,[6][7][8][9] Treg that are found within the tumor microenvironment are highly suppressive and abrogate effector function of cytotoxic T cells as well as NK cell-mediated cytotoxicity. 1,7,[10][11][12][13] These data have important clinical implications, as targeting Treg cells can enhance therapeutic antitumor effect in both humans and animal models. [14][15][16][17][18] Interestingly, depletion of Treg cells led to crossreactive tumor immunity against tumors of diverse origins. 19 Factors that have been described to be important for Treg induction within the tumor include TGF-b, IL-10, H-Ferritin, IDO and Prostaglandin E 2 (PGE 2 ). 9,20-22 These findings highlight the importance of understanding the mechanisms of immune-escape in the tumor microenvironment.Stimulation of the T-cell receptor (TCR) or priming with dendritic cells can induce FoxP3 expression and the acquisition of Treg activity in CD4 1 CD25 2 T cells from normal PBMC. [23][24][25] Yang et al. extended these findings and demonstrated that tumor infiltrating T cells in follicular lymphoma (FL) -involved lymph nodes could also be induced to express FoxP3 through TCR stimulation. Furthermore, they showed that CD701 malignant B cells could facilitate this conversion of conventional T cells to Treg in FL. 26 In this study, we investigated whether Treg induction in FL is a tumor-specific phe...

IntroductionAcute graft-versus-host disease (aGvHD) is one of the major complications after allogeneic bone marrow transplantation (BMT), which limits the success of this otherwise life-saving strategy. 1 Our group and others have demonstrated that naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (Treg cells) can reduce the incidence and severity of murine aGvHD. [2][3][4][5] In spite of findings that cell-cell contact is critical for Treg-mediated suppression in vitro and that IL-10 production 6 and TGF-␤ surface expression 7 are relevant in vivo, the mechanisms by which Treg cells exert suppressor activity in the setting of aGvHD are poorly understood. Recent reports have described the role of apoptosis induction by activated Treg cells of conventional T cells (Tconv cells) and B cells as a mechanism of suppression. [8][9][10][11][12] The TNF-R superfamily member CD30 has been shown to be expressed on Tr1 regulatory cells that down-modulate nickelspecific immune responses 13 and to be relevant for Treg-mediated protection from allograft rejection. 9 In human immune-mediated diseases, CD30 is expressed on T cells that serve a regulatory role in rheumatoid arthritis 14 and on cells that accumulate at the inflammatory sites of patients with systemic sclerosis 15,16 and chronic GvHD. 15 Expression of CD30 is detected late after T-cell activation in vitro with immobilized CD3 mAb 17 and activationinduced CD30 is found on T helper 1 (Th1), Th0, and Th2 cell clones. 18,19 CD30 signaling up-regulates the lymph node homing molecule CCR7, 20 provides costimulatory signals to T cells, and enhances their proliferative responses to suboptimal stimulation via T-cell receptor (TCR) engagement. 17,21 The ligand for CD30 (CD30L, or CD153) is a membraneassociated glycoprotein related to TNF, 21 which is known to be expressed on thymic epithelial cells (TECs), antigen presenting cells (APCs), activated T cells, neutrophils, eosinophils, and resting B cells. 22,23 CD30-deficient C57B/6 mice display elevated numbers of thymocytes and a gross defect in negative selection, 24 although this was not found in all mouse strains. 25 Overexpression of CD30 on T cells results in augmented thymocyte depletion upon treatment with a superantigen, 26 suggesting an important role for CD30/CD153 interactions in thymic deletion of autoreactive T cells. Recently, the thymic medulla has been demonstrated to be an anatomic site where Treg cells interact with activated dendritic cells (DCs) and Hassall corpuscles 27 that express CD153. 23 In this report, we investigated the role of CD30 signaling in Treg-cell function, demonstrating a critical role for CD30/CD153 interactions early after adoptive transfer. Materials and methods MiceFVB/N (H-2k q , Thy-1.1), C57B/6 (H-2k b , Thy-1.1 or Thy-1.2), C57B/ 6 eGFPϩ , and Balb/c (H-2k d , Thy-1.2) mice were purchased from Jackson Laboratory (Bar Harbor, ME) or Charles River Laboratory (Wilmington, MA). CD30-deficient C57B/6 mice were kindly provided by Dr T. Mak (University of Toronto, ON, Canada); Balb/c...