The advancements in immunotherapy are one of the most promising and life-saving therapeutic areas of the last decade. Within the field of oncology, it has boosted the development of precision medicine. Molecular imaging with labeled drugs can be used for response monitoring and in drug development for these new immunotherapies. Imaging modalities, such as PET, boost early decision-making on drug efficacy and ensure a faster drug development process.
Bench et al. proves that PET/CT with Zr-89-labeled atezolizumab is able to monitor therapy response in immunotherapy with immune checkpoint inhibitors in oncology [1].
In line with this, Niemeijer et al. summarized imaging efforts of immune responses with PET in oncology [2]. They show that several approaches to image immune check points (PD-1, PD-L1 and CTLA-4) and CD8+ T-cell infiltration by using the labeled drug as a biomarker are promising tools to predict treatment in oncology.
The advantage of the strategy in the above-mentioned studies is that you use the same compound for response monitoring as for therapy and you will get a direct measure of efficacy. Monitoring treatment response with standard imaging methods, such as CT and MRI, are based on a decrease in tumor size. However, in immunotherapy a massive influx of immune cells might increase the size of the tumor. Thus, standard imaging methods might underestimate treatment response. Another commonly used method to monitor treatment response is [18F]FDG-PET. This method also has difficulties to show treatment response when an influx of immune cells occurs. Namely, [18F]FDG accumulates in both tumor cells and immune cells, which makes treatment response monitoring difficult.
PET in immunotherapy development.
Even more interesting is the fact that labeling of the drug with a PET radionuclide (e.g., zirconium-89 or fluorine-18) can be used for drug development. With this strategy it is possible to check whether a drug will reach the intended target and if it will not be taken up by healthy tissue in an early clinical development phase. Thus, by labeling the drug in an early clinical phase you can determine if this drug is promising for targeting in humans disease. It also allows you to make an early decision whether to proceed to further clinical testing on efficacy with the tested compound. In a later drug development stage, labeled drugs can be used as a selection tool to include individuals where the drug accumulates in the tumor. This makes it possible to measure the true efficacy of a drug in an “enriched population”.
By using the FDA approved microdosing principle, where very low, non-pharmacologically, amounts of the labeled drug are injected in human subjects; you will be able to accelerate your drug discovery process. This is among others due to the limited requirements for preclinical toxicity testing. Furthermore, it also leads to a reduced risk in investment in expensive clinical drug development programs, as microdosing gives insight into the drug targeting properties. This should be done before the start of traditional clinical phase 1-4, where only clinical outcome is evaluated rather than direct targeting of the drug.
Molecular Imaging in immunotherapy.
Besides oncology, molecular imaging can also be used in immunotherapy of other diseases. Among others rheumatoid arthritis, inflammatory bowel disease, diabetes, etcetera. For example, in vivo targeting of monoclonal antibodies that target cytokines, excreted by immune cells, can be used to image drug targeting in rheumatoid arthritis and inflammatory bowel disease. In analogy to tumor imaging, monoclonal antibodies that target immune check point inhibitors and CD8+ T-cells can be used to study immune processes in type 1 diabetes. It can help to understand the mechanism of the disease and the development of novel therapeutics approaches.
Taken together, molecular imaging with labeled drugs can be used for response monitoring and in drug development. It is not restricted to oncology and can be applied in many diseases. Nor is it restricted to the use of radiolabeling, as also drugs labeled with a fluorescent dye can be used to image drug interactions in vivo.
At TRACER we are specialized in both nuclear and optical molecular imaging. We support among others the development of new drugs in the oncology space. Find out more about our drug development services here.
References.
- Bensch et al. Nat Med. 2018 Dec;24(12):1852-185
- Niemeijer et al. J Nucl Med. 2020 Feb 21. pii: jnumed.119.236158