Martina A. McAteer

Background: The clinical translation of positron emission tomography (PET) radiotracers for cancer management presents complex challenges. We have developed consensus-based recommendations for preclinical and clinical assessment of novel and established radiotracers, applied to image different cancer types, to improve the standardisation of translational methodologies and accelerate clinical implementation. Methods: A consensus process was developed using the RAND/UCLA Appropriateness Method (RAM) to gather insights from a multidisciplinary panel of 38 key stakeholders on the appropriateness of preclinical and clinical methodologies and stakeholder engagement for PET radiotracer translation. Panellists independently completed a consensus survey of 57 questions, rating each on a 9-point Likert scale. Subsequently, panellists attended a consensus meeting to discuss survey outcomes and readjust scores independently if desired. Survey items with median scores ≥ 7 were considered ‘required/appropriate’, ≤ 3 ‘not required/inappropriate’, and 4–6 indicated ‘uncertainty remained’. Consensus was determined as ~ 70% participant agreement on whether the item was ‘required/appropriate’ or ‘not required/not appropriate’. Results: Consensus was achieved for 38 of 57 (67%) survey questions related to preclinical and clinical methodologies, and stakeholder engagement. For evaluating established radiotracers in new cancer types, in vitro and preclinical studies were considered unnecessary, clinical pharmacokinetic studies were considered appropriate, and clinical dosimetry and biodistribution studies were considered unnecessary, if sufficient previous data existed. There was ‘agreement without consensus’ that clinical repeatability and reproducibility studies are required while ‘uncertainty remained’ regarding the need for comparison studies. For novel radiotracers, in vitro and preclinical studies, such as dosimetry and/or biodistribution studies and tumour histological assessment were considered appropriate, as well as comprehensive clinical validation. Conversely, preclinical reproducibility studies were considered unnecessary and ‘uncertainties remained’ regarding preclinical pharmacokinetic and repeatability evaluation. Other consensus areas included standardisation of clinical study protocols, streamlined regulatory frameworks and patient and public involvement. While a centralised UK clinical imaging research infrastructure and open access federated data repository were considered necessary, there was ‘agreement without consensus’ regarding the requirement for a centralised UK preclinical imaging infrastructure. Conclusions: We provide consensus-based recommendations, emphasising streamlined methodologies and regulatory frameworks, together with active stakeholder engagement, for improving PET radiotracer standardisation, reproducibility and clinical implementation in oncology.

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8⁺, whilst proinsulin-specific clones were both CD8⁺ and CD4⁺. Proinsulin-specific CD8⁺ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8 ⁺ , whilst proinsulin-specific clones were both CD8 ⁺ and CD4 ⁺ . Proinsulin-specific CD8 ⁺ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response intradermally is divided between targeting the gold core and the antigenic cargo, this offers a route to improving Trm formation in response to vaccines. In addition, our scRNAseq data indicate that focussing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies

Summary: The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.