Researchers at the Med Uni Innsbruck describe mechanisms of resistance to cancer immunotherapy

Cancer immunotherapy is changing the way we treat cancer. Approved drugs target the immune system’s own ability to eliminate tumor cells and combat the cancer. However, only 10-20% of the patients are responding to these drugs. Moreover, recent data show that some of these patients develop resistance to cancer immunotherapeutics after one or two years. Austrian researchers now provide a first explanation for this unfavorable course.
Cancer progression is a complex process. Tumor cells develop very differently depending on their place of origin, genetic makeup or tumor microenvironment and they have numerous mutations. This heterogeneity of the tumor is currently a hot topic in cancer research. A joint research work by APERIM coordinator Zlatko Trajanoski and cell genetics experts of the Medical University of Innsbruck is now providing possible answers on the mechanisms of resistance to cancer immunotherapy. The findings were published recently in Nature Communications.

Heterogeneous versus homogeneous tumor development The researchers were using genetic and immunological methods and were able to demonstrate that tumors become genetically more homogeneous during the course of immunotherapy. Subsequently, the tumor cells are not recognized by the immune system and the tumor grows larger. “During the course of cancer Immunotherapy a so-called immune editing occurs, meaning that tumor cells with certain mutations are eliminated and thereby reducing the genetic heterogeneity of the tumor ,” Trajanoski explains the new finding. Extensive methodology Using an immunodeficient mouse model, researchers were able to distinguish the effects of the immune system from genetic influences. Suprisingly, the tumor development in the mouse model was neutral, ie without positive or negative selection. The findings of the Innsbruck research work are based on a remarkably comprehensive methodology with Next Generation Sequencing technology, immunological characterization and bioinformatics analyzes.

The researchers propose that in order to predict the development of resistance, a comprehensive analysis of the tumor sample for its genetic heterogeneity should be carried out. This could eventually result in an adaptation of the therapy in terms of dosage and time Management.

Original paper full text
http://dx.doi.org/10.1038/s41467-017-02424-0

 

Online Database of T Cell Receptor Sequences was recently published

The database called VDJdb, developed by research group around Dmitriy Chudakov from Masarykova University, helps to reach the next step towards a new level of understanding the adaptive immune system.

Modern sequencing technologies are generating huge numbers of TCR sequences. However, up to now the sequencing data could hardly be linked to functionality of the phenotype TCRs i.e. the ability to recognize certain epitopes presented on a cell surface. Within APERIM finally the comprehensive repository VDJdb was developed, which collects information on TCR sequences with known antigen specificities. The primary goal of this work was to create an open source database and to facilitate access to existing information on T-cell receptor antigen specificities.

Within the cooperation in the APERIM network the establishment of this database is also essential for the development of a further software, called TCR2Epitope. Can Keşmir and her colleagues from the University of Utrecht are working on that visionary tool, which would in the future allow to predict the interaction between TCRs and certain epitopes. The therapeutic application of that tool presents an innovative method to support T cell-mediated cancer immunotherapy.

The infrastructure behind VDJdb allows community-driven data acquisition, proofreading and aggregation in order to establish a comprehensive repository of T-cell receptor sequences with known antigen specifities. The VDJdb database accumulates data from both – previously published papers and obtained via personal communications. Several research groups around the world could be attracted to fulfil the database. Currently the VDJdb includes more than 12000 TCR variants with known specificities and it is rapidly growing.

The database was recently published in Nucleic Acids Research (full paper).

The online database VDJdb is available under https://vdjdb.cdr3.net/

APERIM Partners present preliminary results at the annual meeting in Utrecht

The venerable University of Utrecht, in short distance to Amsterdam, was venue of the 2nd partner meeting of APERIM. From 3rd to 4th of April APERIM partners met to present and discuss first project results. In particular, developed software and databases to address specific challenges in the field of cancer immunology were presented. Regarding the planned objectives, good progress could be achieved. Various software prototypes have been developed and a number of web databases developed during the course of the project are now publicly accessible:

Data Integration and development of an advanced bioinformatic platform
The Cancer Immunome Atlas Database – TCIA was launched by the Medical University of Innsbruck. TCIA provides a comprehensive view of the cellular composition of the intratumoral immune infiltrates as well as cancer antigens of >8000 samples from The Cancer Genome Atlas (TCGA), which were analysed using state-of-the-art immunogenomic analytical pipelines.
Link: http://tcia.at

Automated quantification tool for tumor infiltrating lymphocytes (TILs) to stratify colorectal cancer patients
Partner Definiens developed the TIL analyser software as an image analysis solution to detect, quantify and evaluate tumour infiltrating lymphocytes in slide H&E images. This software is now tested and evaluated by APERIM partner data. INSERM in parallel is working the annotation of whole slide images in order to stratify CRC patients using immunoscore. Partner CNIC worked on the digital TIL sorter to quantify TILs from RNA-Seq data. A prototype software is established and will now be tested and evaluated, before it is integrated in TCIA bioinformatic platform.

Development of an analytical pipeline for NGS-guided personalised cancer vaccines
Three software parts will form this pipeline package. Partner TRON already successfully developed the iCaM2.0 NGSanalyser software, which is actually evaluated with clinical data. To predict which targets of the tumor surface will be immunogenic, University of Utrecht is working intensively on the second software, the immunopredictor with the planned delivery date in fall. As further important parts of the pipeline, University of Tübingen developed the EpitopeSelector as an open source software, further a novel approach to solve the subsequent problem of assembling the selected neo-epitopes into the final vaccine and a necessary framework to rapidly develop such advanced computational immunology approaches.

Links:
https://github.com/APERIM-EU/WP3-EpitopeSelector
ttps://github.com/FRED-2/OptiVac
https://github.com/FRED-2/fred2

The integration of all applications in one pipeline to identify optimal cancer vaccine targets will be reached by the end of the Project.

Predicting T-cell receptor (TCR) specifity for adoptive T-cell cancer therapy
Based on available NGS data Partner AptaIT generated a TCR Kit to analyse deriving TCR sequences. This software will now be tested and evaluated with further data. In order to develop a novel method to predict TCR specificity, Masaryk University built a database containing more than 5000 TCRs with known specificities, which can be now extended with additional datasets.
Link: https://vdjdb.cdr3.net/
Additionally, together with research results from University of Utrecht concerning epitope structures (pMHC), a TCR ontology database was generated.
Link: https://github.com/antigenomics/vdjdb-db
All tools together will finally help to describe TCR reactivity in human cancers.

In the remaining project year, Partners with access to clinical data will provide these data to test and evaluate the developed software modules and to fill open access databases. Preliminary results already show the high value and successful progress of the innovative APERIM bioinformatics platform.

Group picture Aperim

Partners of the H2020 project APERIM, coordinated by Univ.-Prof. Zlatko Trajanoski (front left) met in Utrecht to present and discuss preliminary project results.

 

 

Partner CNIC presents APERIM research in The New York Academy of Sciences

March 7th,
Last week The New York Academy of Sciences hosted the symposium “Quantitative Approaches in Immuno-Oncology”. Dr Carlos Torroja from Centro National de Investigationes Cardiovasculares Carlos III (CNIC) thereby presented first APERIM results in a much-noticed poster.
The symposium aimed to explore the promising field of immunotherapy in cancer treatment, covering the breadth of approaches needed to quantify interactions between tumors and the immune system. Quantitative Immuno-Oncology—sitting at the interface between immuno-oncology and quantitative approaches from mathematics, physics, and computer science—has emerged as a field that can significantly advance the ability to interpret existing large datasets, and perform predictive analyses.
In his poster Carlos Torroja presented first results of the APERIM project. The reserachers around Fátima Sánchez-Cabo (CNIC) and Zlatko Trajanoski from the Medical University of Innsbruck applied deep learning on a set of markers selected as very predictive of the amount of lymphocytes and tested it on the 1207 breast cancer samples from TCGA. The results agreed relatively well with the annotated amount of lymphocytes from TCGA and furthermore also the predicted survival time of the groups.

Download Poster


Image: © Fátima Sánchez-Cabo

Further Information:
Prof Dr Fátima Sánchez Cabo
Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain
Fátima Sánchez Cabo: fscabo@cnic.es

Science-paper with Input of APERIM´s work group

Researchers from the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital show that even if one’s own immune cells cannot recognize and fight their tumors, someone else’s immune cells might. Their proof of principle study was published in the journal Science on May 19th.

The published data show that adding mutated DNA from cancer cells into immune stimulating cells from healthy donors create an immune response by the healthy immune cells. By inserting the tumor cell recognition elements from the donor immune cells back into the immune cells of the cancer patients, the researchers were able to make cancer patients’ own immune cells recognize cancer cells.

The APERIM work group of the Netherlands Cancer Institute contributed with first project results to this remarkable study. Within APERIM, Ton Schumacher aims to further investigate the role of tumor-specific mutations and the resulting neo-antigens as targets for immunotherapy, both to be able to predict T-cell reactivity and to find ways to enhance neo-antigen specific T cell immunity in cancer patients.

Source:

Original paper:

Press release Euerkalert:

Contact:

Ton Schumacher
Senior Member NKI-AVL & Professor of Immunotechnology Leiden University
The Netherlands Cancer Institute
http://www.nki.nl/divisions/immunology/schumacher-t-group/
t.schumacher (at) nki.nl

Tumor instability and impact on patient survival: it all depends on the immune response.

Genetic and molecular characteristics are often used to classify tumors because stratification is the first step towards individualized cancer medicine with the aim to find the optimal treatment for each patient. In colorectal cancer for an example the diagnosis to have a genetic instable tumor indicates a favorable prognosis for the patient. Researchers from the Laboratory of Integrative Cancer Immunology led by Jérôme Galon (Inserm, Universités Pierre-

et-Marie-Curie et Paris Descartes, Cordeliers Research Center in Paris, France), in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca, now could prove that the immunologic environment in and around colorectal cancer even plays a greater role to

stratify tumors than classification based on tumor (in)stability. These results could have important clinical implications for immunotherapy. The article detailing these results is published in the journal Immunity on March 15th 2016.

Press Release

 

Contact: Jérôme GALON

Laboratory of Integrative Cancer Immunology

INSERM UMRS1138, Cordeliers Research Center

15 rue de l’Ecole de Medecine, 75006, Paris, France

Email: jerome.galon@crc.jussieu.fr

 

Source: Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability, Immunity, 44, 1–14, March 15, 2016  Full text

1st Annual Meeting in Seefeld

Between Innsbruck and Munich Seefeld offers a beautiful landscape and renowned conference hotels, so the first annual partner meeting took place from March 9-10, 2016 in that inspiring surrounding area chaired by the coordinator Univ.-Prof. Dr Zlatko Trajanoski from the Medical University of Innsbruck. Representatives of all eleven partner institutes and companies met to exchange scientific results, control achievements and define next steps. Two members of the International scientific advisory board (ISAB), the ethical advisor as well as the EU project officer participated and further strengthened the progress of the project with their helpful recommendations.

APERIM_Team