CAIX-targeted α therapy directed against hypoxic tumor cells in combination with immune checkpoint inhibitors in a syngeneic mouse tumor model

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Tumor hypoxia is a major factor in therapy resistance.A potential strategy to treat hypoxic tumors is targeted α therapy (TAT), since α particles can cause complex DNA damage independent of oxygen levels.Here, we investigate the potential of TAT as monotherapy and in combination with immune checkpoint inhibitors (ICI) to treat hypoxic tumors.Methods: Monoclonal anti-CAIX antibody DOTA-MSC3 was labeled with indium-111 ( 111 In) or actinium-225 ( 225 Ac), and binding to CAIX-expressing hypoxic tumor cells was determined in vitro.Subsequently, the in vivo biodistribution and dosimetry of radiolabeled DOTA-MSC3 was assessed in B16F10-OVA tumor-bearing mice, and its spatial distribution in the tumor (autoradiography) was correlated to CAIX expression measured by immunofluorescence.Finally, tumor growth and survival were determined upon treatment with [ 225 Ac]Ac-DOTA-MSC3 with and without ICI.Results: 111 In-and 225 Ac-labeled DOTA-MSC3 bound specifically to CAIX-expressing hypoxic tumor cells.In vivo, uptake of both radiopharmaceuticals in B16F10-OVA tumors was spatially correlated with CAIX-positive hypoxic tumor regions.[ 225 Ac]Ac-DOTA-MSC3 significantly prolonged survival of mice compared with PBS control (p=0.0032).Furthermore, the combination of [ 225 Ac]Ac-DOTA-MSC3 and ICI significantly delayed tumor growth and prolonged survival compared with PBS control (p=0.0022 and p=0.0019, respectively).Conclusion: Overall, these results demonstrate first proof-of-concept of the potential of CAIX-TAT to treat hypoxic tumors by targeting CAIX-positive hypoxic tumor regions.CAIX-TAT combined with ICI was most effective in inhibiting tumor growth and prolonging survival of tumor-bearing mice.Future studies are required to investigate the radiobiological and immunological effects of CAIX-TAT, to guide optimization of this treatment in combination with ICI.

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