Georg Pall

LST1: A Gene with Extensive Alternative Splicing and Immunomodulatory Function

The gene of the leukocyte-specific transcript (LST1) is encoded within the TNF region of the human MHC. The LST1 gene is constitutively expressed in leukocytes and dendritic cells, and it is characterized by extensive alternative splicing. We identified 7 different LST1 splice variants in PBMC; thus, 14 LST1 splice variants (LST1/A-LST1/N) have been detected in various cell types. These isoforms code for transmembrane as well as soluble LST1 proteins characterized by two alternative open reading frames at their 3′ end. We demonstrate the presence of the transmembrane variant LST1/C on the cell surface of the monocytic cell lines U937 and THP1. Recombinant expression of LST1/C permitted its profound inhibitory effect on lymphocyte proliferation to be observed. In contrast, the alternative transmembrane variant LST1/A, the extracellular domain of which shows no amino acid sequence homology to LST1/C exerted a weaker but similar inhibitory effect on PBMC. These data demonstrate the protein expression of LST1 on the cell surface of mononuclear cells, and they show an inhibitory effect on lymphocyte proliferation of two LST1 proteins although they have only a very short amino acid homology.

Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL)

In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.

Das kleinzellige Bronchialkarzinom

SummaryWith about 20% of all lung cancers small cell lung cancer (SCLC) represents a major subset of this entity. Although therapeutic improvements did not receive as much attention as in non small cell lung cancer (NSCLC), many small steps of clinical progress have been achieved within the last 20 years. An optimal treatment should be based on an interdisciplinary treatment plan. The standard treatment in localized stages represents combined radiation and chemotherapy. Cisplatin and etoposide are in this concern considered as a gold standard. 3D-planned conformal radiotherapy should start as early as possible and should be applied concomitantly to chemotherapy and in certain cases even in a hyperfractionated treatment protocol. In very early stages surgical resection could be an option in selected cases. In advanced stages a platinum-based doublet offers high response rates. As already established in limited disease prophylactic cranial irradiation is now also indicated in extensive disease in case of any tumor remission. In the second line treatment and in patients with reduced performance status topotecan is recommended. Similar as in NSCLC pemetrexed might become an alternative treatment option in the second line setting. In the field of new targeted therapies bevacizumab achieved the most promising results. The present review highlights historical milestones and up-to-date trends in radiotherapy, chemotherapy and surgery. Furthermore, the role of experimental strategies and the management of certain special clinical situations are discussed.ZusammenfassungDas kleinzellige Bronchialkarzinom (Small Cell Lung Cancer, SCLC) stellt mit ungefähr 20% einen wesentlichen Teil der Bronchialkarzinome dar. Beim SCLC konnten in den letzten zwanzig Jahren viele klinisch relevante Verbesserungen erzielt werden. Im Vergleich zum nichtkleinzelligen Bronchialkarzinom (Non Small Cell Lung Cancer, NSCLC) gelingt der Fortschritt hier jedoch nur in kleinen Schritten. Die Grundlage einer optimalen Behandlung beinhaltet heute eine interdisziplinäre Therapieplanung. Im lokalisierten Stadium stellt die Radiochemotherapie die Standardbehandlung dar. Dabei gilt eine platinhältige Kombinationstherapie nach wie vor als Goldstandard. Eine moderne dreidimensional geplante Strahlentherapie sollte so früh wie möglich konkordant zur Chemotherapie und im Einzelfall sogar hyperfraktioniert erfolgen. Im Frühstadium ist im Einzelfall auch eine operative Sanierung zu erwägen. Im fortgeschrittenen Stadium zeigt eine platinhältige Kombinationschemotherapie die besten Resultate. Bei Tumorremission ist sowohl im Frühstadium als auch im fortgeschrittenen Stadium eine prophylaktische Schädelbestrahlung indiziert. In der Zweitliniensituation und bei reduziertem Allgemeinzustand wird der Einsatz von Topotecan empfohlen. Pemetrexed könnte sich ähnlich wie beim NSCLC ebenfalls in der Zweitlinientherapieals Alternative etablieren. Bei den gezielten Tumortherapien sind die Daten zu Bevacizumab erfolgversprechend. In dieser Übersichtsarbeit werden die historischen Meilensteine und die aktuellen Trends der Chemotherapie, Strahlentherapie und Chirurgie beleuchtet. Weiters wird die Bedeutung experimenteller Therapieansätze und das Management spezieller klinischer Situationen diskutiert.

Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study)

Background Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles. Methods Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2) and docetaxel (75 mg/m2 d1) q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly). The primary endpoint was radiological response according to RECIST. Results 40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95%) underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months. Conclusions Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected. Trial Registration EU Clinical Trials Register; Eudract-Nr: 2006-004639-31

Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: results from the exploratory, controlled, randomized, international phase II IMPULSE study

Abstract Background The immune surveillance reactivator lefitolimod (MGN1703), a DNA-based TLR9 agonist, might foster innate and adaptive immune response and thus improve immune-mediated control of residual cancer disease. The IMPULSE phase II study evaluated the efficacy and safety of lefitolimod as maintenance treatment in extensive-stage small-cell lung cancer (ES-SCLC) after objective response to first-line chemotherapy, an indication with a high unmet medical need and stagnant treatment improvement in the last decades. Patients and methods 103 patients with ES-SCLC and objective tumor response (as per RECIST 1.1) following four cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod maintenance therapy or local standard of care at a ratio of 3 : 2 until progression or unacceptable toxicity. Results From 103 patients enrolled, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first-line therapy were balanced. Lefitolimod exhibited a favorable safety profile and pharmacodynamic assessment confirmed the mode-of-action showing a clear activation of monocytes and production of interferon-gamma-induced protein 10 (IP-10). While in the intent-to-treat (ITT) population no relevant effect of lefitolimod on progression-free and overall survival (OS) could be observed, two predefined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: in patients with a low frequency of activated CD86+ B cells (hazard ratio, HR 0.53, 95% CI: 0.26–1.08; n = 38 of 88 analyzed) and in patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95% CI: 0.20–1.17, n = 25 of 103). Conclusions The IMPULSE study showed no relevant effect of lefitolimod on the main efficacy end point OS in the ITT, but (1) the expected pharmacodynamic response to lefitolimod, (2) positive OS efficacy signals in two predefined subgroups and (3) a favorable safety profile. These data support further exploration of lefitolimod in SCLC.

Das kleinzellige Bronchialkarzinom@@@Small cell lung cancer

SummaryWith about 20% of all lung cancers small cell lung cancer (SCLC) represents a major subset of this entity. Although therapeutic improvements did not receive as much attention as in non small cell lung cancer (NSCLC), many small steps of clinical progress have been achieved within the last 20 years. An optimal treatment should be based on an interdisciplinary treatment plan. The standard treatment in localized stages represents combined radiation and chemotherapy. Cisplatin and etoposide are in this concern considered as a gold standard. 3D-planned conformal radiotherapy should start as early as possible and should be applied concomitantly to chemotherapy and in certain cases even in a hyperfractionated treatment protocol. In very early stages surgical resection could be an option in selected cases. In advanced stages a platinum-based doublet offers high response rates. As already established in limited disease prophylactic cranial irradiation is now also indicated in extensive disease in case of any tumor remission. In the second line treatment and in patients with reduced performance status topotecan is recommended. Similar as in NSCLC pemetrexed might become an alternative treatment option in the second line setting. In the field of new targeted therapies bevacizumab achieved the most promising results. The present review highlights historical milestones and up-to-date trends in radiotherapy, chemotherapy and surgery. Furthermore, the role of experimental strategies and the management of certain special clinical situations are discussed.ZusammenfassungDas kleinzellige Bronchialkarzinom (Small Cell Lung Cancer, SCLC) stellt mit ungefähr 20% einen wesentlichen Teil der Bronchialkarzinome dar. Beim SCLC konnten in den letzten zwanzig Jahren viele klinisch relevante Verbesserungen erzielt werden. Im Vergleich zum nichtkleinzelligen Bronchialkarzinom (Non Small Cell Lung Cancer, NSCLC) gelingt der Fortschritt hier jedoch nur in kleinen Schritten. Die Grundlage einer optimalen Behandlung beinhaltet heute eine interdisziplinäre Therapieplanung. Im lokalisierten Stadium stellt die Radiochemotherapie die Standardbehandlung dar. Dabei gilt eine platinhältige Kombinationstherapie nach wie vor als Goldstandard. Eine moderne dreidimensional geplante Strahlentherapie sollte so früh wie möglich konkordant zur Chemotherapie und im Einzelfall sogar hyperfraktioniert erfolgen. Im Frühstadium ist im Einzelfall auch eine operative Sanierung zu erwägen. Im fortgeschrittenen Stadium zeigt eine platinhältige Kombinationschemotherapie die besten Resultate. Bei Tumorremission ist sowohl im Frühstadium als auch im fortgeschrittenen Stadium eine prophylaktische Schädelbestrahlung indiziert. In der Zweitliniensituation und bei reduziertem Allgemeinzustand wird der Einsatz von Topotecan empfohlen. Pemetrexed könnte sich ähnlich wie beim NSCLC ebenfalls in der Zweitlinientherapieals Alternative etablieren. Bei den gezielten Tumortherapien sind die Daten zu Bevacizumab erfolgversprechend. In dieser Übersichtsarbeit werden die historischen Meilensteine und die aktuellen Trends der Chemotherapie, Strahlentherapie und Chirurgie beleuchtet. Weiters wird die Bedeutung experimenteller Therapieansätze und das Management spezieller klinischer Situationen diskutiert.

Transplantation of IL-2-transduced murine bone marrow is associated with dose-dependent toxicity.

OBJECTIVE The purpose of this study was to investigate the effects of interleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxic function and systemic toxicity following syngeneic bone marrow transplantation. MATERIAL AND METHODS Marrow of 5-fluorouracil pretreated donor mice were transfected with a retroviral vector containing the murine IL-2 gene and transplanted into lethally irradiated syngeneic hosts. RESULTS Productive insertion of the IL-2 gene could be demonstrated at various intervals post-transplant without impairment of hematopoietic engraftment. Endogenously augmented IL-2 release resulted in a selective increase in CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as well as significant cytolytic activity against syngeneic leukemia cells in vitro. Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity. Infusion of marrow transduced with high-titer, high-expressing IL-2 retrovirus resulted in significant morbidity and mortality in the recipients. Our studies demonstrate that mortality was secondary to severe lymphocytic infiltration of liver and lung, which was associated with increased expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. Reducing the number of IL-2-transduced cells in the bone marrow inoculum, however, resulted in significantly improved survival with no adverse events being evident during the post-transplant period. CONCLUSION Delivery of IL-2 to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells, however, the overall feasibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo.