Aim:
Our goal within this PoC project was to translate and apply a senescence-specific imaging compound in patients to evaluate its potential for cancer therapy management, providing novel information about the temporal variations and quantitative nature of tumor senescence.
Planned activities:
Within this PoC proposal we aimed to (i) translate our preclinical studies into first patients, (ii) establish a full-GMP compliant tracer production pipeline, (iii) compile all required paperwork and approvals to perform clinical studies, (iv) obtain the manufacturing license enabling a multicenter study, and (v) perform a phase 0/I clinical study with all required in vitro cross-validations of 10 patients.
Results:
After commissioning the pharmaceutical grade precursor from ABX (Radeberg, Germany), the GMP-compliant synthesis of FPyGal was established by the Tuebingen Radiopharmacy, along with all relevant and associated quality control measures. A full toxicology evaluation had been performed, which is a precondition for a clinical translation. The end product is a safe and reproducible tracer with high chemical and radio-chemical purity that is suitable for clinical imaging. The paperwork and documentation for the proposed clinical trial was meticulously gathered, completed and submitted to the regulating authorities. The proposed trial has been carefully planned but is still awaiting approval from the regulatory authorities. Concurrently, the tracer has been successfully used by collaborating physicians under compassionate use guidelines on patients receiving senogenic (senescence promoting) and senolytic (senescent cell-killing) therapy. In one exemplary case, a human glioma patient who received senogenic therapy was scanned with fluoroethyl tyrosine (PET tracer for tumor proliferation) and FPyGal. The uptake of the two tracers revealed striking differences in metabolism between different brain regions and may reflect areas of active proliferation or senescence. After receiving senolytic therapy, treatment aimed at the eradication of senescent cells, the uptake of FPyGal in previously senescent brain regions is remarkably lower, indicating therapeutic success.
Conclusions:
We have established the production of a robust and reproducible GMP-compliant senescence PET tracer. Our intended clinical trial has been thoroughly planned, with all required documentation already in the hands of the regulatory authorities. Upon approval, the study will be immediately initiated. Through the avenue of compassionate use guideline, we have already used the tracer in selected human patients and presumably identified senescence in tumor regions and metastases that would have been otherwise missed. [18F]FPyGal was administered in an activity dose of 370 MBq (±50 MBq). This activity dose was shown to be a safe dosage in named-patient use administrations (“Heilversuche”), conducted in subjects potentially qualifying for senolytic antineoplastic therapies. For several of the patients the treatment protocol has been adjusted accordingly. We have demonstrated the first successful use of image-guided senescence-inducing and senolytic therapy, which marks the genesis of a completely new approach to personalized medicine.
Socioeconomic impact:
The high cost of medical care and lost economic productivity highlight the monumental impact of cancer on society. More so, the extreme heterogeneity of both the disease and afflicted patients makes it difficult to apply a single standard of care. As senescence has been identified as a fundamental stress response in tumors, the image-guided application of senogenic and senolytic chemotherapeutics offers a powerful tool to help personalize the treatment provided.
