Wiener klinische Wochenschrift Education / Immuntherapie in der Onkologie

(VLID)357214

Wiener klinische Wochenschrift / Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls

Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.(VLID)357482

Therapie des kastrationsrefraktären Prostatakarzinoms

Zusammenfassung Innerhalb der letzten zwei Jahre hat die Therapie des kastrationsrefraktären Prostatakarzinoms (CRPC) große Fortschritte gemacht. Sowohl die COU-AA-301 Phase-III-Studie als auch die TROPIC Studie zeigten einen Überlebensvorteil für Patienten nach Docetaxel-Versagen, die mit Abirateron beziehungsweise Cabazitaxel behandelt wurden. In einem Umfeld von wachsendem Interesse an chemotherapeutischen Optionen und neuen Medikamenten war es unser Ziel, als multidisziplinäres Team die verfügbare Datenlage zu analysieren und einen Standard für die medizinische Behandlung des Prostatakarzinoms außerhalb klinischer Studien zu definieren. Vor diesem Hintergrund evaluieren wir die momentanen Behandlungsempfehlungen sorgfältig und auf Basis der verfügbaren Anhaltspunkte, beleuchten mögliche zukünftige Behandlungsoptionen und diskutieren wichtige klinische Themen wie die Behandlung bis zur Progression versus den Vorteilen von Chemoholidays und die Definition bestimmter Patientensubgruppen. Zusätzlich legen wir besonderes Augenmerk auf neue molekulare Wirkstoffklassen, deren Verfügbarkeit in naher Zukunft erwartet wird, wie z. B. MDV3100 und Sipuleucel T. Die Rolle und Bedeutung der Palliation mittels Strahlentherapie und der proaktiven medikamentösen analgetischen Therapie wird ebenso diskutiert wie neue Therapieoptionen der mit Knochenmetastasen assoziierten Beschwerden. Die Vielzahl an Behandlungsoptionen für Patienten mit fortgeschrittenem Prostatakarzinom verlangt eindeutig eine enge Zusammenarbeit zwischen Urologen, Onkologen und Strahlentherapeuten. Summary Within the last two years the therapy of castration resistant prostate cancer (CRPC) has made major advances. Both the COU-AA-301 phase III trial and the TROPIC trial showed a survival benefit for patients after docetaxel failure treated with abiraterone or cabazitaxel, respectively. With rising interest for chemotherapeutic options and novel drugs, our goal was to review within the context of a multidisciplinary team the available evidence and explore the standards for medical treatment of prostate cancer outside of clinical trials. From this background, we are carefully evaluating the current treatment recommendations, based on the available evidence, and highlight potential future treatment options but also discuss important clinical topics like treatment until progression versus the advantage of chemo holidays and definition of particular patient subgroups. Additionally, we focus on novel molecular entities, which will most likely be available in the near future, such as MDV3100 and Sipuleucel T. The role and importance of palliation with radiotherapy and proactive medical management of pain is also discussed, as well as new options for bone directed therapy. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists

The PI3-Kinase/mTOR-Targeting Drug NVP-BEZ235 Inhibits Growth and IgE-Dependent Activation of Human Mast Cells and Basophils

<div><p>The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring ³H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC₅₀ values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1^nu mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC₅₀ 0.5–1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.</p> </div

Effects of NVP-BEZ235 on proliferation in HMC-1 cells and KU812 cells.

<p>A,B: HMC-1.1 cells (left panels), HMC-1.2 cells (middle panels), and KU812 cells (right panels) were cultured in control medium (Co), control medium with DMSO 1∶1,000 (DMSO Co), or with increasing concentrations (0.001 µM–1 µM) of NVP-BEZ235 (A) or RAD001 (B) at 37°C for 48 hours. Thereafter, ³H-thymidine uptake was measured. Results show the percentage of ³H-thymidine uptake compared to control (Co) and represent the mean±S.D. of three independent experiments in each cell line. Asterisk (*): p<0.05. C: Bone marrow MNC from six patients with SM were incubated in control medium (Co) or in various concentrations of NVP-BEZ235 (as indicated) at 37°C for 48 hours. Then, ³H-thymidine uptake was measured. Results show the percentage of ³H-thymidine uptake compared to Co and represent the mean±S.D. of six donors. Asterisk (*): p<0.05.</p