Mark-Alexander Schwarzbich

The immune inhibitory receptor osteoactivin is upregulated in monocyte-derived dendritic cells by BCR–ABL tyrosine kinase inhibitors

Multiple approaches presently aim to combine targeted therapies using tyrosine kinase inhibitors with immunotherapy. Ex vivo-generated dendritic cells are frequently used in such strategies due to their unique ability to initiate primary T-cell immune responses. Besides governing tumor cell growth, many kinases targeted by tyrosine kinase inhibitors are involved in the development and function of dendritic cells and thus tyrosine kinase inhibitor therapy may cause immunoinhibitory side effects. We here report that exposure of developing human monocyte-derived dendritic cells to the BCR–ABL inhibitors imatinib, dasatinib, and nilotinib results in profound upregulation of the transmembrane glycoprotein osteoactivin that has recently been characterized as a negative regulator of T-cell activation. Thus, in line with osteoactivin upregulation, exposure to tyrosine kinase inhibitors resulted in significantly reduced stimulatory capacity of dendritic cells in mixed lymphocyte reactions that could be restored by the addition of blocking anti-osteoactivin antibody. Our data demonstrate that tyrosine kinase inhibitor-mediated inhibition of dendritic cell function is, at least in great part, mediated by upregulation of the immune inhibitory molecule osteoactivin.

Analysis of clinical characteristics and outcome of patients with previously untreated diffuse large B-cell lymphoma and renal involvement in the rituximab era

Abstract Renal involvement in patients with lymphoma is rare but associated with poor prognosis. We analyzed characteristics and outcome of 22 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and renal involvement treated with a rituximab-containing regimen in curative intent. The majority of patients presented in advanced disease, 86% were Ann Arbor stage ≥ III and had an IPI score ≥ 3. Renal impairment was present in 32%. Outcome was poor with three-year progression-free survival (PFS) 44% and three-year overall survival (OS) 52% and significantly worse compared to DLBCL without renal involvement (p < 0.01). Patients with high-risk IPI had a significantly inferior prognosis compared to intermediate-risk IPI (three-year OS 0% vs. 75%, p = 0.01) as did those with renal impairment. A high rate of central nervous system (CNS) relapse (8/22) was observed. Intravenous high-dose methotrexate and intrathecal therapy showed a trend toward prolonged time to CNS relapse. Implementation of CNS prophylaxis might therefore be considered in these high-risk patients.

Outcome after high-dose chemotherapy and autologous stem cell transplantation in patients with aggressive B-cell non-Hodgkin's lymphoma

For more than two decades, high‐dose chemotherapy (HDT) and autologous blood stem cell transplantation (ABSCT) were treatment options for patients with aggressive B‐cell non‐Hodgkins lymphoma (B‐NHL). However, the ideal timing and the collective patient benefits are still being debated.

Cellular Immunotherapy in B-Cell Malignancy.

In recent years, cellular immunotherapy in B-cell malignancies has been driven by adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs). CARs consist of a single chain variable fragment (scFv) of a monoclonal antibody, a spacer domain, a transmembrane domain, an intracellular signaling domain, and additional costimulatory domains. The bulk of clinical data available is on CD19-targeting CAR T cells for the treatment of B-cell acute lymphocytic leukemia (B-ALL), chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma. Results so far have been promising with impressive rates and depth of remission especially among B-ALL patients. However, CAR T-cell therapy is a complex multi-step process, and clinical trials so far differ profoundly in CAR construct used, gene transfer method, composition of the cellular product, lymphodepletion, and CAR T-cell dose used. Randomized trials will be needed to conclusively evaluate the implications of these differences. The treatment concept is associated with significant neurotoxicity and potentially lethal cytokine release syndrome, both of which require specific management. Improvements in CAR design may help to overcome toxicity, the effects of an immunosuppressive microenvironment, and tumor escape by development of antigen-negative clones. This review will explain the mechanism of action, summarize the clinical experience with this treatment modality so far, and explore future developments in the field.

In Burkitt lymphoma patients who relapse after induction with a short-intensive chemoimmunotherapy protocol, aggressive salvage chemotherapy therapy is ineffective: a single-center retrospective study

Dear Editor, Burkitt lymphoma (BL) is a highly aggressive non-hodgkin lymphoma (NHL) representing about 1% of mature NHLs [1]. The German Multicenter Study Group for Adult ALL conducted the multicenter GMALL-B-ALL/NHL2002 trial, which used a short-intensive protocol based on rituximab, high-dose methotrexate, and triple intrathecal therapy, with a reduced regimen for patients >55 years old. This trial reported an 88% complete response (CR) rate, and 5-year overall survival (OS) and progression-free survival (PFS) rates of 80% and 75%, respectively [2]. Thus, treatment according to this protocol, which has become the standard of care for adult BL patients at our institution, is curative in the majority of patients. However, almost identical rates for OS and PFS reported from recent trials [2–5] indicate that there is a lack of effective salvage therapies, and there is an extreme paucity of data regarding treatment options for patients who relapse with BL after induction with modern, short-intensive induction regimens. As a result, it seems questionable whether it is advisable to employ aggressive salvage chemotherapy for relapsed/ refractory BL. Therefore, we retrospectively analyzed the electronic records of all patients (n = 38) who were newly diagnosed with Burkitt lymphoma, Burkitt-like lymphoma, B-cell lymphoma unclassifiable with features intermediate between DLBCL, and Burkitt lymphoma (BCLU) or Burkitt leukemia between 2003 and 2013 in our institution and were treated with curative intent. Patients were enrolled in the GMALL-B-ALL/NHL2002 trial if eligible until 2011; afterwards, we continued to treat patients according to the trial protocol. We then looked in detail at patients with relapsed/ refractory disease (n = 9, 24%). There was (and is to date) no standard treatment for relapsed/refractory BL at our institution, so that a variety of curative or palliative approaches were used, based on individual treatment decisions (Fig. 1). Five patients received intensive salvage chemotherapy (with a curative intent), only two of which achieved a second remission: one CR and one PR, the latter of which lasted only a few weeks. The (only) patient who achieved a second CR proceeded to receive an allogeneic bone marrow transplantation from an HLA-compatible unrelated donor after conditioning therapy with busulfan/fludarabine/cyclophosphamide/ATG in 2007. Post-transplant, she suffered from gastrointestinal graft-versus-host disease and unfortunately died from infectious complications (pneumonia) 7 months after receiving the allogeneic bone marrow graft (recorded as death in CR). In general, the role of hematopoietic stem cell or bone marrow transplant, whether autologous or allogeneic, is difficult to assess in BL since most studies published to date present retrospective data * Martin Cremer martin.cremer@med.uni-heidelberg.de