Improving the efficacy of radioimmunotherapy for non-Hodgkin lymphomas

Abstract

Approximately 66,000 Americans develop non-Hodgkin lymphoma (NHL) each year. Although the use of unlabeled antibodies such as rituximab has significantly improved survival when combined with standard chemotherapy regimens, approximately two-thirds of lymphoma patients eventually develop disease recurrence and die of their disease. Novel treatments are urgently needed to cure these patients. One strategy involves the use of radiolabeled immunoconjugates that specifically localize radiation delivery to sites of lymphoma while minimizing toxicity to normal tissues. A growing number of studies support the contention that radiolabeled antibody therapy can improve overall survival of lymphoma patients and lead to durable remissions, with probable cures, in many patients. Various approaches for enhancing the effectiveness of radioimmunoconjugates have been studied, including: use in newly diagnosed lymphoma patients, combination with chemotherapy or other monoclonal antibodies, use with hematopoietic stem cell transplantation, multistep pretargeting strategies to further minimize toxicity, and simultaneous targeting of multiple B-cell antigens. This article summarizes the current knowledge supporting the use of radioimmunotherapy, an underused but effective treatment modality in NHL patients.

Figure 1

Studies using radioimmunotherapy with or without chemotherapy for previously untreated lymphoma patients (references –18). Abbreviations used: N, number of patients; CR, complete response; PR, partial response; B, Bexxar/iodine-131 tositimomab; Z, Zevalin/yttrium-90 ibritumomab tiuxetan.

Figure 2

Median progression-free survival of patients with advanced grade 1 or 2 follicular lymphoma treated with Zevalin/yttrium-90 ibritumomab tiuxetan consolidation after first remission (thin line) compared to controls (thick line) [reproduced with permission from Morschhauser et al., J Clin Oncol 2008; 26:5160.]

Figure 3

Schematic illustration demonstrating targeted exposure of tumor tissue versus normal tissue using radioimmunotherapy compared to conventional total body irradiation as conditioning prior to hematopoietic stem cell transplant.

Figure 4

Comparison of overall survival in patients treated with myeloablative iodine-131 tositimomab, cyclophosphamide, and etoposide (I-131-B1/Cy/VP-16) followed by autologous transplant versus non-randomized controls conditioned with total body irradiation, cyclophosphamide and etoposide (TBI/Cy/VP-16) [reproduced with permission from Press et al., Blood 2000;16:2938.]

Figure 5

Improved tumor to normal organ ratio of absorbed radioactivity with the pretargeting approach compared to conventional radioimmunotherapy. Gamma images taken of mice bearing bilateral lymphoma xenografts 24 hours after treatment with either directly labeled 111-indium 1F5 (anti-CD20) antibody (conventional) or unlabeled 1F5 antibody-streptavidin conjugate followed by 111-Indium DOTA-biotin (pretargeted). Abbreviations: T, tumor; B, blood pool. [reproduced with permission from Subbiah et al., J Nuc Med 2003;44:440.]