The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest

• Published in: Leukemia 2020-05, Vol.34 (5), p.1315-1328
• Main Authors: Pichard, Alexandre, Marcatili, Sara, Karam, Jihad, Constanzo, Julie, Ladjohounlou, Riad, Courteau, Alan, Jarlier, Marta, Bonnefoy, Nathalie, Patzke, Sebastian, Stenberg, Vilde, Coopman, Peter, Cartron, Guillaume, Navarro-Teulon, Isabelle, Repetto-Llamazares, Ada, Heyerdahl, Helen, Dahle, Jostein, Bardiès, Manuel, Pouget, Jean-Pierre
• Format: Article
• Language: English
• Subjects: 59; 59/78; 631/67/1059/2325; 631/67/1059/485; 631/67/1990/291/1621/1915; 64/60; 82/80; 96/1; 96/31; 96/95; 96/98; Antibodies; Apoptosis; B-cell lymphoma; Biocompatibility; Burkitt's lymphoma; Cancer; Cancer Research; CD20 antigen; Cell cycle; Cell proliferation; Chemotherapy; Critical Care Medicine; Cyclin-dependent kinases; Cytotoxicity; Hematology; Intensive; Internal Medicine; Kinases; Life Sciences; Lutetium; Lutetium isotopes; Lymphocytes B; Lymphoma; Mantle cell lymphoma; Medicine; Medicine & Public Health; Monoclonal antibodies; Non-Hodgkin's lymphoma; Oncology; Phosphorylation; Radioisotopes; Rituximab; Targeted cancer therapy; Toxicity; Tumors; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0677-4

Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 ( 177 Lu)-lilotomab (Betalutin ® ) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177 Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt’s lymphoma) cell xenografts, 177 Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177 Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177 Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177 Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177 Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.