Comprehensive Analysis of177Lu-lilotomab Satetraxetan in Lymphoma Cell Lines: Implications for Precision Radioimmunotherapy and Combination Schemes

177 Lu-lilotomab satetraxetan (Betalutin) is an anti-CD37 radioimmunoconjugate evaluated as single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). 177 Lu-lilotomab satetraxetan treatment is well-tolerated and shows consistent activity in most of the patients evaluated so far. Herein, we investigated the activity of 177 Lu-lilotomab satetraxetan in a panel of 55 lymphoma cell lines of B and T cell origin. CD37-targeted radioimmunotherapy was more effective in CD37-positive B-cell lymphomas (n=46) than negative CD37 negative T-cell lymphomas (n=9). Focusing on DLBCL cell lines, mutations such as BCL2 or MYC translocations were not correlated to sensitivity. However, BCL2 expression was higher in resistant than sensitive GCB-DLBCL cell lines, and the addition of the BCL2 inhibitor venetoclax showed synergism when added to the radioimmunoconjugate. Finally, the pattern of activity of 177 Lu-lilotomab satetraxetan differed from what was achieved with a CD37-targeting antibody-drug conjugate or with R-CHOP, indicating the potential benefit of the beta-emitter payload. In conclusion, this systematic analysis of the responsiveness of lymphoma cell lines to CD37-targeting radioimmunotherapy consolidated 177 Lu-lilotomab satetraxetan as a promising compound for the treatment of CD37 positive malignancies and identified candidate biomarkers and co-targets to detect and overcome cancer cell-intrinsic resistance mechanisms.