De Novo Screening of Metallodrugs for Combination Immunotherapy using Immunocompetent Patient-derived Tumor Organoids

Pt-based combination therapy is an effective strategy to improve the response rate of cancer patients to immune checkpoint inhibitors (ICIs) in the clinic, but a highly efficient and clinically relevant screening method to evaluate the combination efficacy is lacking. Here, we develop a patient-derived bladder tumor organoids model that maintains endogenous T cells. This system could discriminate the efficacy of clinical Pt dugs in combination with anti-PD-1. Furthermore, a homemade library containing twenty-nine PtIV complexes was collected and systematically screened to characterize their individual potency as well as the synergy of these complexes with anti-PD-1. Through this model, we discovered: 1) some PtIV complexes such as Pt-5, Pt-8 and Pt-24 can not only effectively kill tumors, but also promote antitumor immunity through secreting cytotoxic cytokines and expanding TCR clones at low concentrations as chemoimmunotherapeutics, and 2) some PtIV complexes such as Pt-9 and Pt-10 show only a synergistic effect with anti-PD-1 without tumor killing effect. We also established an organoid model by adding patients own peripheral blood mononuclear cells (PBMCs) to evaluate theses complexes in T-cell deficient tumors, showing similar effects as in endogenous T-cell preserving organoids. Overall, this is the first effort to use immune-competent, patient-derived tumor organoids for the discovery and study of metalloimmunotherapeutics, accelerating their clinical translation.