CD20-Targeted α-Radionuclides Synergize with Immune Checkpoint Inhibition to Treat Murine Lymphoma

Treatment-refractory and relapsed disease remain leading causes of death for patients with lymphoma. Virtually all lymphomas are exquisitely sensitive to radiation, and α-particle radiation therapies are notably suited to targeting microcluster disease common in the setting of early relapse. Refractory or relapsed lymphoma may also involve the loss of therapeutic targets, but radiation may stimulate antitumor immune effects against disease with incomplete target expression. Such effects make immune checkpoint inhibition a compelling candidate for combination treatment. Methods: We evaluated the therapeutic efficacy of 211At-labeled antihuman CD20 monoclonal antibodies combined with immune checkpoint inhibition in human CD20 transgenic mice bearing murine lymphomas on opposing flanks that were either positive or negative for human CD20 expression (hCD20(+) and hCD20(-), respectively). Results: In the absence of 211At-hCD20, the antimurine checkpoint inhibitors PD1, CTLA4, CD47, and TIM3 had no efficacy given alone or in doublets. 211At-hCD20 given alone suppressed growth of both hCD20(+) and hCD20(-) tumors in a dose-dependent fashion, with predictably stronger suppression of hCD20(+) tumors. Strikingly, the addition of PD1 alone or the PD1 plus CTLA4 doublet to low-dose 211At-hCD20 significantly strengthened suppression of both tumors and increased mouse survival. Conclusion: Future translation of this synergistic combination of α-radiotherapy and immune checkpoint inhibition holds promise for the treatment of high-risk aggressive lymphomas, including cases with postinduction minimal residual disease or antigen loss after targeted therapies.