22 november 2016: Bron: Journal of transational medicine

Het succes van immuuntherapie lijkt vooral afhankelijk van vooraf te meten DNA mutaties en receptorenexpressie stellen onderzoekers op een congres over immuuntherapie bij melanomen.  Echter ook stellen zij dat immuuntherapie zonder vooraf vastgestelde biomarkers zeker ook succes kan hebben, zoals bv via verschillende vormen van  T-cel stimulerende behandelingen of algemene dendritische celtherapie. al of niet in combinatie met andere middelen / medicijnen.

In The Journal of translational Medicine is afgelopen week (16 november 2016)  een artikel verschenen met als titel:  Future perspectives in melanoma research Meeting report from the “Melanoma Bridge”. Napoli, December 1st–4th 2015

Hier een korte vrije vertaling van een gedeelte uit het originele abstract, zie verder onderaan de foto en dit artikel

Journal of Translational Medicine

Bron: Translational Medicine

Afgelopen jaar vond in Napels dit 6e "Melanoma Bridge Meeting" plaats. Er vonden vier sessies plaats met de focus op 4 verschillende aspecten:

De vier sessies op deze bijeenkomst richtte zich op 

  1. Moleculaire en immuuntherapeutische ontwikkelingen
  2. Combinatietherapieën
  3. Nieuwe ontwikkelingen specifiek in immuuntherapie
  4. Micro omgeving van tumor en biomarkers.

Recente ontwikkelingen in de tumor biologie en immunologie heeft geleid tot de ontwikkeling van nieuwe gerichte immuuntherapeutische middelen die progressievrije overleving (PFS) en algehele overleving (OS) van kankerpatiënten verlengen. Immuuntherapie met name is een zeer succesvolle benadering gebleken voor patiënten met kanker zoals melanoom, niet-kleincellige longkanker (NSCLC), niercelcarcinoom (RCC), blaaskanker en ziekte van Hodgkin.
In het bijzonder zijn veel klinische successen geboekt met behulp van checkpoint receptorblokkering, waaronder T-cel remmende receptoren zoals cytotoxische-T-lymfocyt-geassocieerd antigeen 4 (CTLA-4) en de geprogrammeerde celdood-1 (PD-1) en zijn ligand PD-L1.

Maar ondanks bewezen successen op immunotherapeutische interventies doen deze zich alleen voor in een relatief klein aantal patiënten. Getracht wordt om reacties op immuuntherapie te verbeteren door de ontwikkeling van biomarkers. Het optimaliseren van biomarkers voor immunotherapie zou kunnen helpen de juiste patiënten te selecteren voor de behandeling en helpen bij het controleren van de ziekte. Het monitoren zou de kennis op respons, progressie van de ziekte en de resistentie kunnen verbeteren, welke natuurlijk de uitdagingen zijn voor het immuuntherapeutische veld in de oncologie. 

Belangrijk is ook dat biomarkers kunnen helpen om rationele combinatietherapieën te ontwerpen. Bovendien kunnen biomarkers helpen de werkingsmechanisme van verschillende middelen te ontrafelen, de dosis te bepalen en volgorde van combinaties van geneesmiddelen vast te stellen.

Echter, biomarkers en ontwikkeling van begeleidende assays van kanker immunotherapie is een uitdaging om verschillende redenen: (i) multipliciteit van immunotherapeutische middelen met verschillende werkingsmechanismen waaronder immuuntherapie met gerichte, activerende en remmende T-celreceptoren (bijvoorbeeld, CTLA-4, PD-1, enz.); adoptieve T-cel therapieën met in weefsel infiltrerende lymfocyten (TIL), chimeer antigen receptoren (CAR-T-cells), en T-cel receptor (TCR) bevatten gemodificeerde T-cellen.............................

Daarna wordt het abstract m.i. te medisch technisch en heb ik maar niet verder vertaald, maar artsen en wetenschappers zullen dit ongetwijfeld begrijpen. Maar zie daarvoor het volledige studierapport: Future perspectives in melanoma research  dat vrij is te lezen en een interessante referentielijst heeft.

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Hier het abstract plus die referentielijst:


In conclusion, immunotherapies have emerged as the most promising class of drugs to treat patients with cancer with diverse tumor types, however many patients do not respond to these therapies. Therefore, determining which patients derive clinical benefit from immune checkpoint agents remains an important clinical question and efforts to identify predictive markers of response are ongoing. The analytical and clinical validation of predictive biomarkers require appropriate clinical studies in which the evaluation of the clinical utility of the biomarker is a pre-specified endpoint of the study. A variety of study designs have been proposed for this purpose. Although, the randomized biomarker stratified design provides the most rigorous assessment of biomarker clinical utility, other study designs might be acceptable depending on the clinical context.

Future perspectives in melanoma research

Meeting report from the “Melanoma Bridge”. Napoli, December 1st–4th 2015
  • Paolo A. AsciertoEmail author,
  • Sanjiv Agarwala,
  • Gerardo Botti,
  • Alessandra Cesano,
  • Gennaro Ciliberto,
  • Michael A. Davies,
  • Sandra Demaria,
  • Reinhard Dummer,
  • Alexander M. Eggermont,
  • Soldano Ferrone,
  • Yang Xin Fu,
  • Thomas F. Gajewski,
  • Claus Garbe,
  • Veronica Huber,
  • Samir Khleif,
  • Michael Krauthammer,
  • Roger S. Lo,
  • Giuseppe Masucci,
  • Giuseppe Palmieri,
  • Michael Postow,
  • Igor Puzanov,
  • Ann Silk,
  • Stefani Spranger,
  • David F. Stroncek,
  • Ahmad Tarhini,
  • Janis M. Taube,
  • Alessandro Testori,
  • Ena Wang,
  • Jennifer A. Wargo,
  • Cassian Yee,
  • Hassane Zarour,
  • Laurence Zitvogel,
  • Bernard A. Fox,
  • Nicola Mozzillo,
  • Francesco M. Marincola and
  • Magdalena ThurinEmail author
Journal of Translational Medicine201614:313

DOI: 10.1186/s12967-016-1070-y

©  The Author(s) 2016

Received: 19 September 2016

Accepted: 27 October 2016

Published: 15 November 2016

Abstract

The sixth “Melanoma Bridge Meeting” took place in Naples, Italy, December 1st–4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin’s disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients’ population. This meeting’s specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays.

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pembrolizumab, anti-PD medicijnen, immuuntherapie, PD-1 ligand mutatie, overall overleving, progressievrije tijd, immuuntherapie, melanomen, nivolumab


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