Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy

• DOI: 10.1136/jitc-2021-002387
• Publication Date: 2022-10-25T18:50:16Z
• Authors: Pascale Lejeune; Véronique Cruciani; Axel Berg-Larsen; Andreas Schlicker; Anne Mobergslien; Lisa Bartnitzky; Sandra Berndt; Sabine Zitzmann-K...; Claudia Kamfenkel; Stefan Stargard; Stefanie Hammer; Jennifer S Jørgensen; Malene Jackerott; Carsten H Nielsen; Christoph A Schatz; Hartwig Hennekes; Jenny Karlsson; Alan S Cuthbertson; Dominik Mumberg; Urs B Hagemann
• Keywords: Mesothelin; Immune checkpoint; Pseudomonas exotoxin

Background Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode action (MoA) is the induction difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on immune system largely unknown. Here, we investigated immunostimulatory mesothelin-targeted conjugate (MSLN-TTC) in vitro and vivo monotherapy combination with inhibitor checkpoint programmed death receptor ligand 1 (PD-L1) immunocompetent mice. Methods The murine cell line MC38 was transfected human gene encoding for MSLN (hMSLN) to enable binding non-cross-reactive MSLN-TTC. MSLN-TTC were studied cancer lines MC38-hMSLN cells. efficacy MoA as or anti-PD-L1 tumor-bearing C57BL/6 Experiments supported by RNA sequencing, flow cytometry, immunohistochemistry, mesoscale, TaqMan PCR analyses study underlying effects. In depletion CD8+ T cells studies Rag2/Il2Rg double knockout mice conducted investigate importance Results treatment induced upregulation sensing pathway transcripts ( IL-6 , CCL20 CXCL10 stimulator interferon genes STING )-related genes) determined RNASeq analysis. results, including phospho-STING activation, confirmed protein level. Danger-associated molecular pattern molecules upregulated parallel, leading dendritic (DC) activation . showed strong antitumor activity (T:C 0.38, p<0.05) a single agent MSLN-expressing Combining further enhanced 0.08, p<0.001) evidenced increased number tumor-free surviving animals. caused migration CD103+ cDC1 DCs infiltration into tumors, which anti-PD-L1. Intriguingly, T-cell decreased efficacy. Conclusions These data demonstrate that TTCs involves system. findings relevance other radiotherapies may guide clinical strategies.