Molecular imaging in cancer immunotherapy and drug development
Authors:   , Miedema Iris Harriëtte Cornelia 
Published: October 2024

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