Radioimmunotherapy of Non-Hodgkin Lymphoma is Improved without Increasing Toxicity by Combination with Antibody immunotherapy.
Authors: Sharkey Robert M , Mattes M. Jules , Karacay Habibe , Chang Chien-Hsing , Rossi Edmund A , McBride William J , Goldenberg David M. 
Published: April 2020

Abstract
Radioimmunotherapy (RAIT) is an effective treatment for follicular and transformed non-Hodgkin lymphoma (NHL) that combines a small amount of a radiolabeled anti-CD20 IgG with a large pre-dose of unlabeled anti-CD20 IgG (~900 mg). While a portion of this pre-dose is used to reduce radioconjugate uptake in the spleen and increase its circulation half-life, an excessive amount of unlabeled anti-CD20 IgG could interfere with the radioconjugate’s uptake in the tumor, perhaps compromising RAIT’s full therapeutic potential. In an animal model bearing the Burkitt human B-cell lymphoma xenografts (Ramos), we explored alternative approaches to enhance radionuclide targeting to the tumor without compromising the therapeutic benefit derived from the unconjugated anti-CD20 IgG and without increasing host toxicity. One approach utilized a 90Y-labeled, humanized anti-CD22 IgG (epratuzumab) combined with a therapeutic pre-dose of 1.0 mg of the humanized anti-CD20 IgG (veltuzumab) 1 day before the 90Y-epratuzumab (0.05 mg/0.175 mCi), with 3 additional veltuzumab doses of 0.5 mg given weekly thereafter. Biodistribution studies showed the anti-CD20 IgG did not affect tumor uptake of the 90Y-epratuzumab, but when 1.0 mg of anti-CD20 veltuzumab (human equivalent of 280 mg) was given 1 day, or even 1 h, in advance of radiolabeled veltuzumab, that tumor uptake was reduced 50%. The combination of 90Y-epratuzumab with unlabeled veltuzumab resulted in 80% (12/15) of the animals being tumor-free 18 weeks later, whereas either treatment alone was only able to induce a transient response within 1 week that lasted no more than 2 weeks. The addition of a similar treatment regimen of unlabeled epratuzumab or unlabeled veltuzumab to 90Y-veltuzumab produced similar short-term responses as 90Y-veltuzumab alone, with all tumors regrowing within 1–2 weeks of achieving their peak response. However, when the veltuzumab treatment regimen was initiated 1 week after the 90Y-veltuzumab dose, 6/10 of the animals were tumor-free 18 weeks later. This combination therapy was also evaluated for the method of pretargeted RAIT. We also have found that anti-CD20 bispecific antibody pretargeting that localizes a 90Y-labeled hapten-peptide provides improved therapeutic responses compared to the directly radiolabeled 90Y-veltuzumab without the associated severe hematologic toxicity at only 30% of its maximum tolerated dose. Tumor uptake of the 90Y-hapten-peptide was reduced by as much as 70% when 1 mg of veltuzumab was given as a pre-dose that resulted in a significant impairment of anti-tumor responses. However, therapeutic responses were enhanced when the pre-dose was lowered to 0.25 mg, despite a 50% reduction in tumor uptake of the pretargeted 90Y-hapten-peptide. Additional enhancements occurred when unlabeled veltuzumab was given after the 90Y-hapten-peptide pretargeting. These studies suggest a number of strategies that can enhance the therapeutic response of targeted radionuclides, including the use of anti-CD22 radioconjugate combined with non-competing veltuzumab, reducing the anti-CD20 pre-dose that is given with an anti-CD20 based targeting procedure (with emphasis on using the anti-CD20 IgG as a consolidation therapy), and applying RAIT with bispecific antibody pretargeting that is able to enhance anti-tumor responses with less severe hematologic toxicity that also benefits from consolidated veltuzumab therapy. Thus, combination direct RAIT or pre-targeted RAIT with non-competing antibody immunotherapy should be tested clinically. (Supported in part by a PHS grant P01 CA103985 from the NCI.)