A re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma: prospects for dual-targeted antibody/radioantibody therapy

Abstract

Antibody-based therapies, both unconjugated antibodies and radioimmunotherapy, have had a significant impact on the treatment of non-Hodgkin lymphoma. Single-agent rituximab is an effective therapy, but it is being increasingly used with combination chemotherapy to improve the objective response and its duration. The approved anti-CD20 radioimmunoconjugates ( 90 Y-ibritumomab tiuxetan or 131 I-tositumomab) have had encouraging results, with trials now seeking to incorporate a radioimmunoconjugate in various settings. However, new preclinical data raise important questions concerning current radioimmunoconjugate treatment regimens and ways to improve them. In radioconjugate therapy, nearly 900 mg of the unlabeled anti-CD20 IgG antibody is predosed to the patient before the anti-CD20 antibody conjugated to either 90 Y or 131 I is given. Combining an unconjugated anti-CD20 antibody therapy with a radioimmunoconjugate binding to a noncompeting antigen might improve responses by allowing optimal uptake of each agent. Preclinical models have indicated that careful consideration should be given to predosing when using competing antibodies, but that consolidation anti-CD20 therapy enhances the efficacy of radioimmunoconjugate therapy. New technologies, such as pretargeted radioimmunotherapy, also hold promise by reducing toxicity without sacrificing efficacy, and consideration should be given to fractionating or giving multiple radioimmunoconjugate treatments. This perspective discusses how these issues could affect current and future clinical trials. IntroductionTargeting cancer with radiolabeled antibodies, first demonstrated by diagnostic imaging 1 and subsequently developed into radioimmunotherapy (RAIT), has remained an active field of study for more than 30 years. 2 Today, 2 radiolabeled anti-CD20 IgG antibodies, 90 Y-ibritumomab tiuxetan (Zevalin; Cell Therapeutics, Seattle, WA; Bayer Schering Healthcare, Berlin, Germany) and 131 Itositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA), are approved for treatment of patients with follicular and transformed non-Hodgkin lymphoma (NHL) who failed or relapsed from prior therapies, including rituximab and standard chemotherapy. 3,4 Although results from ongoing clinical studies support the use of such radioimmunoconjugates in various front-line and salvage treatment settings, 5-19 important issues remain regarding how these agents are administered, yet also suggest some potential new treatment paradigms. 20 Current radioimmunoconjugate therapy of NHL: development and practiceWe believe a major issue is the role and dose of unconjugated anti-CD20 antibody given prior to the radioimmunoconjugate in both products. In the United States, patients first receive 250 mg/m 2 of rituximab a few hours before receiving 111 In-ibritumomab; 2 to 3 days later, an imaging study then establishes a "normal" biodistribution pattern, and then another 250 mg/m 2 predose of rituximab is given before 90 Y-ibritumomab within 1 week of the first dose. In Europe, the 111 In imaging study is n...

Update on the rational use of (90)Y-ibritumomab tiuxetan in the treatment of follicular lymphoma

“…Nevertheless, it has been argued recently that the routine rituximab application before RIT might also compromise the effectiveness of treatment by competition for binding sites on tumor cells. 18 This view is supported by a preclinical lymphoma xenograft model, where indeed larger doses seem to block subsequent binding of the radiolabeled anti-CD20 monoclonal antibody. 19 However, in a recently performed phase I/II study, higher pretreatment rituximab doses (4 × 375 mg/m 2 weekly) achieved a beneficial effect in terms of increasing the half-life of the radioimmunoconjugate.…”

Differential Effects of Predosing on Tumor and Tissue Uptake of an111In-Labeled Anti-TENB2 Antibody–Drug Conjugate

“…For example, predosing is used in approved radioimmunotherapy approaches using both 90 Y-ibritumomab tiuxetan (Zevalin; Bayer Schering Pharma AG) and 131 I-tositumomab (Bexxar; GlaxoSmithKline) and has become standard practice in radioimmunotherapy targeting the CD20 antigen (30,31). However, few examples exist for translation of such dosing strategies for ADCs (32).…”

“…2C). The high level of tumor uptake (.200 %ID/g) may be rationalized by the use of a residualizing probe, tumors that are significantly smaller than 1 g, and the high TENB2 expression level (31) in the LuCap 77 model. Although the level of uptake (%ID/g) in the intestines is much lower than in the tumor, the gut's contribution to blood pharmacokinetics is important because the weight of murine intestine is roughly 10-fold that of the tumors.…”

Advances in the treatment of hematologic malignancies using immunoconjugates

“…29 Dual-targeted RIC and unlabeled antibody has been explored. 30 Combining 90 Y-epratuzumab with the anti-CD20 antibody veltuzumab was well-tolerated and yielded an ORR of 53% in relapsed/refractory aggressive NHL.…”