Behandlung und Ergebnisse von Patienten mit nicht-kleinzelligem Lungenkarzinom im fortgeschrittenen Stadium in der routine ambulanten Versorgung

Lungenkrebs im fortgeschrittenen Stadium ist eine der Haupttodesursachen im Zusammenhang mit Krebs. Ein erheblicher Teil dieser Patienten wird in Deutschland ambulant behandelt. Wir wollten die Ergebnisse von Patienten mit Lungenkrebs im fortgeschrittenen Stadium, die ambulant behandelt wurden, analysieren und untersuchen. Alle konsekutiven Patienten mit fortgeschrittenem unheilbarem nicht operierbarem nicht-kleinzelligem Lungenkrebs (NSCLC), die zwischen Juni 1995 und Dezember 2016 behandelt wurden, wurden retrospektiv analysiert. 736 Patienten mit einem medianen Alter von 66 Jahren (37–88 Jahre) konnten untersucht werden. Alle Patienten hatten zum Zeitpunkt der Präsentation eine lokal fortgeschrittene Erkrankung und 71% hatten eine metastatische Erkrankung. Das Adenokarzinom (61%) war der häufigste histologische Subtyp, gefolgt von Plattenepithelkarzinomen (28%). Die Mehrheit (93%) erhielt mindestens eine Chemotherapie. Im Mittel wurden 2,5 Behandlungslinien pro Patient (1–11) verabreicht, wobei die Platin-Dubletten-Chemotherapie die häufigste Behandlungsart war (524/650; 81%). 93% der Patienten starben während des Beobachtungszeitraums, hauptsächlich aufgrund des Tumors (76%). Das mediane Gesamtüberleben (OS) betrug 13.5 Monate (0,4–194.6). Patienten mit lokal fortgeschrittener Erkrankung hatten ein OS von 16.9 Monaten (1.2–188.5 +) im Vergleich zu 11,6 Monaten (0.4–194.6) bei Patienten mit Metastasen (p = 0.003). Die Fortschritte in der Krebstherapie haben das Ergebnis von Patienten mit fortgeschrittenem Lungenkrebs verbessert. Diese Patientengruppe profitiert von einer palliativen Chemotherapie, die ambulant erfolgreich durchgeführt werden kann. Die Ergebnisse sind vergleichbar mit randomisierten kontrollierten Studien und aktuellen Daten aus regionalen und internationalen Registern. Eine angemessene Nachsorge von Patienten mit Lungenkrebs, die eine kurative Therapie erhalten haben, führt zur Früherkennung eines Rückfalls und damit zu einem verbesserten Ergebnis. Ein gutes, umfassendes multidisziplinäres Team ist für die Versorgung dieser Patientenkohorte mit mehreren Komorbiditäten obligatorisch. Mit Hilfe eines kompetenten multidisziplinären Rahmens kann eine qualitativ hochwertige Versorgung ambulant näher an zu Hause erbracht werden

Adenovirus vector-specific T cells demonstrate a unique memory phenotype with high proliferative potential and coexpression of CCR5 and integrin α4_4β7_7

Background: The Step Study was a randomized trial to reduce HIV infection through vaccination with an adenovirus type 5-based gag/pol/nef construct; analysis following early cessation of the trial revealed an excess of HIV seroconversion in Ad5 seropositive men. This led to the suggestion that the Ad based vector may boost the number of CD4$^+$ CCR5$^+$ T-cells, target cells for HIV infection. Objectives: We sought to determine the immunophenotype and proliferative capacity of Ad5-specific T cells in the peripheral blood of adult donors to determine whether stimulation with replication defective Ad5 vectors could result in the significant expansion of a CD4$^+$ CCR5$^+$ T cell subset. Methods: Ad5 specific T cells were identified in the peripheral blood of healthy donors by IFN-$_y$ secretion assay and proliferative response was measured by CFSE labelling. Cells were analysed by flow cytometry to determine T cell differentiation marker, CCR5 and α$_4$β$_7$ expression on memory and proliferated cells. Results: Ad5-specific CD4$^+$ T cells within healthy adult donors exhibit a unique minimally differentiated memory phenotype with co-expression of CD45RA, CD45RO and CCR7. Stimulation with Ad vector leads to rapid expansion in vitro and a switch to an effector memory phenotype. Both short-term reactivated and proliferating Ad5-specific CD4+ T-cells express the HIV co-receptor CCR5 and the HIV gp120-binding integrin α$_4$β$_7$. Conclusion: Ad5-specific T cells demonstrate a phenotype and proliferative potential that would support HIV infection; these results are pertinent to the findings of the Step Study and future use of Ad5 as a vaccine vector

CD40-activated B cells induce anti-tumor immunity in vivo

The introduction of checkpoint inhibitors represents a major advance in cancer immunotherapy. Some studies on checkpoint inhibition demonstrate that combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40-activated B cells (CD40B cells) are potent antigen presenting cells by activating and expanding naïve and memory CD4 + and CD8 + and homing to the secondary lymphoid organs. In contrast to dendritic cells, the generation of highly pure CD40B cells is simple and time efficient and they can be expanded almost limitlessly from small blood samples of cancer patients. Here, we show that the vaccination with antigen-loaded CD40B cells induces a specific T-cell response in vivo comparable to that of dendritic cells. Moreover, we identify vaccination parameters, including injection route, cell dose and vaccination repetitions to optimize immunization and demonstrate that application of CD40B cells is safe in terms of toxicity in the recipient. We furthermore show that preventive immunization of tumor-bearing mice with tumor antigen-pulsed CD40B cells induces a protective anti-tumor immunity against B16.F10 melanomas and E.G7 lymphomas leading to reduced tumor growth. These results and our straightforward method of CD40B-cell generation underline the potential of CD40B cells for cancer immunotherapy

Preclinical studies of adenovirus-specific T-cells for adoptive transfer to haemopoietic stem cell transplant recipients

Allogeneic stem cell transplantation (SCT) is the only curative treatment option for many haematological malignancies. Adenovirus (Ad) infections are a significant cause of morbidity and mortality post SCT. Lack of effective anti-viral treatment for Ad disease has led to the development of adoptive immunotherapy of Ad-specific T-cells as a promising therapeutic option for patients in this setting. The aim of this project was to establish preclinical criteria for the development of a clinical trial comparing two T-cell enrichment methods- multimer selection and cytokine secretion selection to enrich Ad-specific T-cells for the purposes of adoptive transfer directly without the need for in vitro culture. Eight pHLA tetramers containing HLA class I restricted Ad epitopes were generated and their ability to identify and enrich Ad-specific T-cells investigated. HLA A*01 TDL tetramer consistently detected T-cells in all (13/13) healthy adult donors screened. Frequency and enrichement of Ad-specific T-cells by cytokine secretion and selection was also investigated. Despite the low frequency of Ad-specific T-cells, clinical grade enrichment was feasible by both methods. T-cells selected by both methods were then characterised for homing and proliferative potential. Ad-specific T-cells identified by either method had a high proliferative potential, possessed a novel minimally differentiated memory phenotype, were cytotoxic towards Ad species responsible for infections in SCT recipients and capable of limiting virus replication. In conclusion, Ad-specific T-cells enriched by multimer selection or cytokine secretion selection are suitable for adoptive transfer to patients with Ad infection following HSCT. Both methods also allow the monitoring of Ad-specific immune reconstitution after adoptive transfer

Multi-center observational study on the adherence, quality of life, and adverse events in lung cancer patients treated with tyrosine kinase inhibitors

Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen

Analysis of ZAP70 expression in adult acute lymphoblastic leukaemia by real time quantitative PCR

BACKGROUND: ZAP70 gene expression is associated with poor prognosis in B-cell lymphoproliferative disorders especially chronic lymphocytic leukaemia (CLL) but its role in adult B-ALL has not been established. On diagnostic samples from 76 patients with adult ALL (65 with B-ALL and 11 with T-ALL) ZAP70 mRNA expression levels were studied by real time-quantitative PCR (RT-qPCR) analysis. FINDINGS: A broad distribution of ZAP70 expression was observed in ALL, ranging from 0.002 to 5.3 fold that of the ZAP70 positive Jurkat reference cell line. No association was observed between expression levels and the presence of specific cytogenetic abnormalities. Five cases, including one case of T-ALL, had ZAP70 expression above the level of the Jurkat reference cell line. CONCLUSIONS: Our results confirm the frequent expression of ZAP70 in adult ALL. Limited comparisons made did highlight poor-risk patients with high ZAP70 expression, but due to lack of clinical information on patient samples we were unable to directly assess the impact on disease prognosis. ZAP-70 may be an important laboratory assay in adult ALL and further studies are warranted to study a potential correlation with cytogenetic and other genetic markers

HLA-Peptide Multimer Selection of Adenovirus-specific T Cells For Adoptive T-Cell Therapy

Adenovirus (Ad) infection is a cause of significant morbidity and mortality in hematopoietic stem cell transplant recipients and virus-specific immunotherapy is one option for improved control. Cellular immunity is an important component in suppression of Ad replication but the frequency and population distribution of Ad-specific CD8(+) T cells has not been systematically investigated. This is an important question in relation to the potential use of these cells for adoptive transfer. To address this question, HLA-peptide multimers were generated for 8 HLA class I-restricted Ad epitopes, which are highly conserved across Ad species. Epitope-specific CD8(+) T cells from healthy donors were identified by tetramer staining and HLA class I A*01-restricted TDL peptide staining T cells were characterized in relation to frequency, phenotype, and function. The cells demonstrated a minimally differentiated central memory phenotype (CD45RA(high), CD45RO(high), CCR7(high), CD62L(low), CD27(high), CD28(high), and CD57(low)) and were able to produce IFN- and proliferate extensively upon antigen stimulation in vitro. After proliferation, the phenotype switched to CD45RO(high), although it is interesting to note that CCR7 expression was retained. Despite their low frequency, tetramer-staining cells could be enriched with magnetic bead technology. Their characteristics should permit rapid establishment in vivo post adoptive transfer, increasing therapeutic options for patients with Ad infection. This is the first reported characterization of Ad-specific tetramer-staining T cells with a view to adoptive transfer to hematopoietic stem cell transplant patients with Ad infection. The efficacy of these cells needs to be further evaluated in the setting of a clinical trial

Patients with indolent lymphomas are at high risk of infections: experience from a German outpatient clinic

Abstract Background Patients with indolent B-cell non-Hodgkin lymphomas (B-NHLs) have an increased risk of infections which is caused by pathomechanisms of the diseases itself but also as a result of anti-tumor therapy. Especially the effects of anti-CD20 antibodies are well understood as these lead to decreased antibody production. Most studies regarding immunodeficiency in B-NHLs were conducted with multiple myeloma and chronic lymphocytic leukemia patients. As these studies not always represent the general population we collected and analyzed real world data from patients with indolent lymphomas and a control group (CG). Results Patients with B-NHLs undergoing therapy or who were regularly monitored in a watch and wait approach had, over the time of one year, an increased rate of infections compared to the CG of 145 healthy volunteers (mean: 11.66 vs. 7.13 infections per 1000 days). Consistent with this finding B-NHL patients received more antibiotic treatment (mean: 11.17 vs. 6.27 days) and were more often hospitalized than persons from the CG (mean: 5.19 vs. 0.99 days per 1000 days). Lymphoma patients without immunodeficiency had a lower infection rate than patients with non-symptomatic and symptomatic immunodeficiency (mean: 10.91 vs. 12.07 and 12.36 per 1000 days). The number of infections differed statistically significant for the subgroups and CG (7.13 per 1000 days). Patients with symptomatic immunodeficiency were mostly treated with regular immunoglobulin substitutions and infection rates were comparable to those of patients with asymptomatic immunodeficiency. Conclusions Our data suggest the use of an approach with regular immune monitoring including the measurement of immunoglobulin levels and regular appointments for clinical assessment of all indolent lymphoma patients in order to identify patients with increased risk of infections. It also raises the question if patients with immunodeficiency should be treated more often with regular immunoglobulin substitution, but so far more studies are necessary to answer this question