Comprehensive analysis of <scp> ¹⁷⁷ Lu </scp> ‐lilotomab satetraxetan in lymphoma cell lines: Implications for precision radioimmunotherapy and combination schemes

¹⁷⁷Lu-lilotomab satetraxetan (Betalutin) is an anti-CD37 radioimmunoconjugate evaluated as a single administration therapy for the treatment of patients with relapsed/refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). ¹⁷⁷Lu-lilotomab satetraxetan treatment is well tolerated and shows consistent activity in most of the patients evaluated so far. Herein, we investigated the activity of ¹⁷⁷Lu-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 in 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 in 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 ¹⁷⁷Lu-lilotomab satetraxetan differed from what was achieved with a CD37-targeting antibody-drug conjugate or with Rituximab cyclophosphamide hydroxydaunorubicin (doxorubicin) oncovin prednisone (R-CHOP), indicating the potential benefit of the beta-emitter payload. This systematic analysis of the responsiveness of lymphoma cell lines to CD37-targeting radioimmunotherapy consolidated ¹⁷⁷Lu-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.