Periodic Reporting for period 2 - ISPIC (Image-Guided Surgery (IGS) and Personalised Postoperative Immunotherapy To Improving Cancer Outcome) Reporting period: 2018-01-01 to 2019-12-31 Summary of the context and overall objectives of the project Scientists worldwide have been studying the role of the immune system in fighting cancer for many years. However, it was only recently that the field of cancer immunotherapy has gained momentum as evidence emerged of lasting anti-cancer benefits to patients who previously had very few treatment options. It is important for our society if we can contain (if not cure completely) this disease and to eliminate its potential to spread. Cancer immunotherapy is now seen as a breakthrough as it has the potential to revolutionise the way we treat many forms of cancer. The current state-of-art for the management of cancer starts with surgery, after identification of an accessible tumour mass. Surgery remains an effective treatment option for many types of cancer today and it is considered curative treatment for most solid tumours. It forms part of a multidisciplinary approach used in conjunction with radiotherapy or chemotherapy. These approaches, however, have several limitations, including inability of surgical resection to affect distal metastatic disease, toxicity to healthy tissues with chemotherapy and lack of effectiveness of radiation therapy in more aggressive tumours. The observation that cancer can relapse months or years after initial surgery implies that micrometastases still resides within the body in a latent state. The basic concept of our proposal is to develop a biomaterials-based encapsulated, defined library of different immunotherapeutic biomolecules after surgery as part of a novel cancer management strategy. The work revolves around the recruitment and mobility of young clinical, scientific and technological researchers between thirteen consortium beneficiaries and across six different countries. The goal of this study is to address the issues of postoperative immunomodulation that are needed to improve cancer outcome across a specialised, interdisciplinary and cross-sector group of European laboratories. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far RESULTS OVERVIEW AND THEIR EXPLOITATION AND DISSEMINATIONThe achievements so far for the ISPIC project can be categorised into a) identification of immune gene signatures / molecular profiles before, during and after cancer, b) development and testing of preclinical models and c) synthesis of biodegradable materials for nanoparticle-based cancer immunotherapy.Identification of immune gene signatures / molecular profiles We took a global approach to identify preclinical immune regulatory gene signatures before and after surgery and during adjuvant immunotherapy using mass spectrometry imaging (MSI) and mass cytometry (CyTOF2). As immunotherapies targeting co-stimulatory blockade is becoming a major focus for cancer therapeutics, it is important to understand the spatial and temporal nature of immune gene expression when a patient is under cancer management. This includes longitudinal monitoring of molecular profiles before surgery, immediately after surgery and during adjuvant immunotherapy. The t-SNE tool is a novel machine learning algorithm for dimensionality reduction that is particularly well suited for the visualization of high-dimensional datasets. Development and testing of preclinical models: Canine: The in vivo models for testing our nanoparticles involved a combination of transgenic mouse models, patient-derived xenograph (PDX) models and canines. The most promising combination immunotherapy was further tested in dogs that had undergone tumour resection. The canine models were also utilised to develop new image-guided surgery (IGS) techniques, where targeted fluorescent probes, allowed resection of tumours with highlighted margins able to demarcate healthy and diseased tissue. A new prototype camera system from Perkin-Elmer was installed in the operating theatre for the IGS work in dogs. Synthesis of biodegradable materials for nanoparticle-based cancer immunotherapy: We have synthesised hydrogels, UCNPs and PLGA for our work and a defined biomaterials-based library of immunotherapeutic combinations has been generated. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Progress Beyond State-of-ArtVaccine adjuvants: Vaccines have generated one of the largest impacts on human health in history, but there is a rising need for vaccines that are not only potent, but that also allow control over the specific nature of immune response. Synthetic biomaterials offer opportunities to address immunological questions from new perspectives, and a few biomaterials such as UCNPs and PLGA are now known to exhibit intrinsic adjuvant properties. These polymers trigger ‘danger’ pathways with links between structural properties (e.g. hydrophobicity, charge, molecular weight) of the biomaterials and adjuvant activity. Recent advances in vaccine development and, in particular, the increasing use of recombinant subunit and synthetic vaccines means the need for improved adjuvants is becoming a priority. Moreover, there are many specialised areas with their own unique needs for suitable adjuvant technology. For cancer vaccines, adjuvant emulsions have been utilised, where the formation of a depot at the injection site enables the slow release of antigen and the stimulation of antibody producing plasma cells and specific T-cells. Expected ResultsA new method for synthesis and functionalization of gold nanoparticles for their detection in the NIR-II window: When compared with the shorter-wavelength regions of the electromagnetic spectrum, NIR imaging at wavelengths in the 700–900 nm range has increased the ability of researchers and clinicians to peer deeper into the mammalian body to visualize functional activity and anatomical structures. We present new insights into the formation of gold, silver and gold–silver bimetallic nanoparticles where ethanol, glycerol, formaldehyde, acetaldehyde and acetone are able to demonstrate their capability of reducing gold and silver ions at ambient temperature within an alkaline medium. Alkalinity was found to be an influencing factor for nanoparticle formation, where the reducing species of gold and silver ions is an alkoxide. The universal nature of the reaction mechanism will impact upon our ability to prepare colloidal plasmonic nanoparticles (PNPs) which have unique optical, chemical, electronic and catalytic properties. They may be applied in various elds including plasmonics, sensing, catalysis, and biomedical imaging in the NIR-II window.Socio-Economic ImpactThere are several important socio-economic impacting factors as a result of our discoveries:a) The use of biomaterials in cancer immunotherapy design will bring down the price of immuno-oncology drugs by way of lower concentrations being used yet still maintaining the same therapeutic efficacy.b) Molecular in vivo imaging of T cell localization and activation in a rodent model is the first step towards being able to translate this to the clinic. This means we could eventually have this type of therapeutic monitoring in patients in the future and having the means to provide more personalised medicine.c) The introduction of new vaccine adjuvants made of biomaterials will bring less toxicity and more efficacious vaccines onto the marketd) The harnessing of the body’s own immune system to fighting cancer will bring about improved quality of life and better survival for those patients affected by cancer. Immunocompetent PDX used for the development and testing of immunotherapeutics
