Nuclear imaging of PD-L1 expression promotes the synergistic antitumor efficacy of targeted radionuclide therapy and immune checkpoint blockade.

PURPOSE

In order to maximize synergistic effect of targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) as well as reduce the toxicity, we pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy.

METHODS

As a novel targeted radiotherapeutic agent, Lu-AB-3PRGD targeting integrin αβ was developed to achieve sustained antitumor effect by introducing an albumin binder (AB) into the structure of 3PRGD. The Lu-AB-3PRGD TRT as well as different types of combination therapies of Lu-AB-3PRGD TRT and anti-PD-L1 ICB were performed in animal models. The changes of PD-L1 expression in tumors after TRT were evaluated in vitro and in vivo by PD-L1-specific SPECT/CT imaging of Tc-MY1523.

RESULTS

Lu-AB-3PRGD showed improved tumor uptake and prolonged tumor retention, leading to significantly enhanced tumor growth suppression. Moreover, Lu-AB-3PRGD TRT remodeled the tumor immune microenvironment by upregulating PD-L1 expression and increasing tumor-infiltrating CD8 T cells, facilitating immunotherapy. We found that the anti-PD-L1 treatment was more effective during the upregulation of tumor PD-L1 expression, and the time window could be determined by Tc-MY1523 SPECT/CT.

CONCLUSION

We developed a novel and long-acting radiotherapeutic agent Lu-AB-3PRGD, and pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy, optimizing the therapeutic efficacy and reducing the cost and potential toxicity risks. This strategy could also be adapted for clinical practice, combining conventional radiotherapy or chemotherapy with ICB to enhance therapeutic efficacy.