Intraperitoneal alpha therapy with 224Ra-labeled microparticles combined with chemotherapy in an ovarian cancer mouse model

Roxanne Wouters; Sara Westrøm; Yani Berckmans; Matteo Riva; Jolien Ceusters; Tina B Bønsdorff; Ignace Vergote; An Coosemans

doi:10.3389/fmed.2022.995325

Intraperitoneal alpha therapy with ²²⁴Ra-labeled microparticles combined with chemotherapy in an ovarian cancer mouse model

Front Med (Lausanne). 2022 Oct 10:9:995325. doi: 10.3389/fmed.2022.995325. eCollection 2022.

Authors

Roxanne Wouters^{1

2}, Sara Westrøm², Yani Berckmans¹, Matteo Riva^{1

3}, Jolien Ceusters², Tina B Bønsdorff², Ignace Vergote^{4

5}, An Coosemans¹

Affiliations

¹ Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
² Oncoinvent AS, Oslo, Norway.
³ Department of Neurosurgery, Mont-Godinne Hospital, UCL Namur, Yvoir, Belgium.
⁴ Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
⁵ Department of Oncology, Gynecological Oncology, KU Leuven, Leuven, Belgium.

Abstract

A novel alpha-therapy consisting of ²²⁴Ra-labeled calcium carbonate microparticles (²²⁴Ra-CaCO₃-MP) has been designed to treat micrometastatic peritoneal disease via intraperitoneal (IP) administration. This preclinical study aimed to evaluate its efficacy and tolerability when given as a single treatment or in combination with standard of care chemotherapy regimens, in a syngeneic model of ovarian cancer in immune competent mice. Female C57BL/6 mice bearing ID8-fLuc ovarian cancer were treated with ²²⁴Ra-CaCO₃-MP 1 day after IP tumor cell inoculation. The activity dosages of ²²⁴Ra ranged from 14 to 39 kBq/mouse. Additionally, ²²⁴Ra-CaCO₃-MP treatment was followed by either carboplatin (80 mg/kg)-pegylated liposomal doxorubicin (PLD, 1.6 mg/kg) or carboplatin (60 mg/kg)-paclitaxel (10 mg/kg) on day 14 post tumor cell inoculation. All treatments were administered via IP injections. Readouts included survival, clinical signs, and body weight development over time. There was a slight therapeutic benefit after single treatment with ²²⁴Ra-CaCO₃-MP compared to the vehicle control, with median survival ratios (MSRs) ranging between 1.1 and 1.3. The sequential administration of ²²⁴Ra-CaCO₃-MP with either carboplatin-paclitaxel or carboplatin-PLD indicated a synergistic effect on overall survival at certain ²²⁴Ra activities. Moreover, the combinations tested appeared well tolerated in terms of weight assessment in the first 4 weeks after treatment. Overall, this research supports the further evaluation of ²²⁴Ra-CaCO₃-MP in patients with ovarian cancer. However, the most optimal chemotherapy regimen to combine with ²²⁴Ra-CaCO₃-MP should be identified to fully exploit its therapeutic potential.

Keywords: alpha therapy; carboplatin; chemotherapy; ovarian cancer; paclitaxel; pegylated liposomal doxorubicin; radium-224.