Molecular imaging in cancer immunotherapy and drug development

This thesis showcases various applications of molecular imaging in the field of cancer medicine. Ultimately, these studies aim to support cancer drug development, explore possibilities for patient selection and generally broaden our understanding of the effects that drugs have on the body. With a high societal need for improved cancer treatment and the pharmaceutical industry thriving, the future applications for molecular imaging in this field are endless. Nevertheless, we focus our attention on the impact that the studies described in this thesis have made in their different research fields and what their implications are for future research. Suggestions for further research are summarized in Table 1. Table 1: Suggestions for Future Research Molecular Imaging in Cancer Nanomedicine • Use molecular imaging to evaluate tumor accumulation of nanoparticles in humans in vivo • Use molecular imaging to study the effects of vascular and microenvironment modulatory drugs on tumor accumulation Molecular Imaging with Immune Checkpoint Inhibitors with 89Zr-immuno-PET • Consider spatio-temporal dynamics of the drug target when performing molecular imaging with immune checkpoint inhibitors • Use outcome measures that take plasma availability into account. The tumor-to-plasma ratio can be easily implemented • Establish a baseline of target-negative uptake in tumor lesions • Support development and validation of pharmacokinetic models for tumor uptake Molecular Imaging of PD-L1 with 18F-BMS-986192 • Explore the potential of spleen uptake of 18F-BMS-986192 as a prognostic or predictive biomarker in a larger cohort of patients with NSCLC • Translational studies (e.g. with mIHC or imaging mass cytometry) are needed to clarify what cells underlie 18F-BMS-986192 uptake in tumor, TDLNs and organs Emerging Molecular Imaging Biomarkers for Immunotherapy • CD8 and effector CD8 PET imaging should be further explored as pharmacodynamic or early response biomarkers • Experience with myeloid imaging is thus far limited, but deserves more attention and further (pre)clinical exploration • Molecular imaging of ex-vivo labeled cells enables tracking of immune cell subset in vivo, and can be applied for adoptive T cell (including CAR T cell) therapies Blood- and Tissue-based Biomarkers for Neoadjuvant Immunotherapy in HNSCC Immunophenotyping of PBMCs • Explore CD8+PD-1+ TIGIT+ T cells as a predictive biomarker for ICIs • CD39 warrants further exploration as a negative predictive biomarker for ICIs as well as a therapeutic target • A novel CD8dim T-cells with an exhausted immunophenotype and a negative correlation regarding response to ICI, warrants further characterization Multiplex immunohistochemistry • CD8 T cell infiltration score has potential to predict response to ICIs • Intra-tumoral CD8+FoxP3+ T cells are positively, and Eomes+ Tregs and mature dendritic cells negatively related to response to ICI Clinical Trials with Neoadjuvant Immunotherapy in HNSCC • Consider a clinical trial design where major responders are assigned to a waitand-see approach (delaying or ultimately even avoiding surgery and/or adjuvant chemoradiotherapy). 18F-FDG PET can be employed to monitor response • Explore the feasibility and efficacy of intra-oral injection of ipilimumab with the aim to reduce immune related adverse events, while maintaining efficacy • Targeting the adenosine pathway could be of interest as a novel strategy in HNSCC