Prediction of 225Ac dose-response, based on 177Lu-pharmacokinetics

The last years, the potential of targeted alpha therapy (TAT) for cancer treatment becomes widely acknowledged, with ²²⁵Ac a highly promising candidate. Clinical studies for prostate cancer patients have demonstrated the improved efficacy of ²²⁵Ac -PSMA compared to their ¹⁷⁷Lu-labeled counterparts. As a result, ²²⁵Ac-therapy is emerging as adjuvant therapy for ¹⁷⁷Lu -therapy to improve efficacy and overcome the potential radio resistance to ¹⁷⁷Lu -therapy. However, ²²⁵Ac -therapy can induce significant side effects, which has led patients to request treatment discontinuation. These side effects should be addressed before ²²⁵Ac can be considered for earlier lines of treatment and not only for compassionate use. Therefore, the aim of this PhD is to contribute in increasing the clinical applicability of tumour and organ dosimetry for ²²⁵Ac -therapy to allow individualized treatment schemes  and move away from a 'one size fits all' approach.

Patient dosimetry requires activity quantification over time through imaging, which for ¹⁷⁷Lu is being established with quantitative SPECT imaging. For ²²⁵Ac this is challenging because of the low abundancy of the higher energy gammas and low administered activities, which currently precludes treatment concomitant dosimetry. Complementary approaches for determining ²²⁵Ac pharmacokinetics (PK) in patient tissues are therefore needed. For patients receiving ²²⁵Ac -therapy after conventional ¹⁷⁷Lu -therapy, one such approach is to consider ¹⁷⁷Lu PK data (from quantitative SPECT) as prior information to guide dose estimates for ²²⁵Ac cycles. This is further complicated on one hand by the differences in biological effectiveness between the emitted alpha radiation from ²²⁵Ac and the emitted bèta radiation from ¹⁷⁷Lu. Secondly, the impact of the recoiling daughter effect for ²²⁵Ac -therapy and the potential distribution of free ²¹³Bi daughter in the kidney, leading to renal toxicity needs to be evaluated, as this cannot be assessed with ¹⁷⁷Lu -ligands. 

In this PhD project the pharmacokinetic, dosimetric and radiobiological behavior of ²²⁵Ac - and ¹⁷⁷Lu -ligands will be investigated and compared in preclinical settings, both on cells and on mice. It will be part of a larger European project with a consortium composed out of preclinical and clinical centers. As a result this will increase the potential to translate the preclinical findings in the clinical applicability of image-guided dosimetry during ¹⁷⁷Lu - and ²²⁵Ac -therapy such that therapeutic doses can be tailored for each patient individually to achieve a better risk-benefit balance and improved efficacy.

Estimated duration