Some like it hot: lymphoma radioimmunotherapy.

Radioimmunotherapy (RIT or RAIT) dates back more than 2 decades and has evolved to encompass a variety of tumorseeking antibodies in various forms, with different radionuclides, different delivery methods, for different clinical indications (usually advanced disease).1 Although selective antibody targeting has been demonstrated, the radiation doses delivered have been insufficient to markedly improve outcomes in most solid tumors. However, these agents do show efficacy in the more radiation-sensitive lymphomas, thus resulting in approval of the first RIT products, 131I-tositumomab and 90Yibritumomab tiuxetan, for treatment of lowgrade and transformed non-Hodgkin lymphoma (NHL).2 Despite results with anti-CD20 RIT being superior to rituximab therapy,2 hematologists usually prefer other therapies. But if pretargeted RIT shows superior efficacy with mitigated toxicities, these newer agents could constitute the next generation of RIT for use in combination with other therapeutic modalities, perhaps gaining greater adoption. Pretargeted RIT separates tumor targeting with a nonradioactive antibody from a secondary radioactive effector (eg, radiolabeled biotin or a hapten-peptide) that binds to the antibody after it has been cleared from the blood and has localized on tumor cells.3 In this issue, Pagel et al use a streptavidin-antibody construct followed by a clearing agent that removes the complex from the blood, followed by administration of radiolabeled biotin that binds to streptavidin-antibody localized on tumor cells.4 While studying the therapeutic effects with 3 antibody systems in 3 human lymphoma xenografts models, they found that pretargeted RIT is more effective than direct RIT, but also showed that anti-CD20 RIT is not improved by combination therapy with anti–HLA-DR and/or anti-CD22 RIT, since RIT of the more highly expressed CD20 in these tumors was already very potent. Antibody cocktails, where different antibody specificities are used, would expect to have a higher accretion in tumor, possibly binding to more tumor cells, but are not an improvement if a dose reduction is required for each individual antibody. In the study by Pagel et al, anti-CD22 RIT alone, either pretargeted or directly targeted, was less effective in these models than the other 2 antibodies, yet another radiolabeled anti-CD22 antibody, as cited by the authors, has shown efficacy in patients with NHL.5 So the first question is, how predictive are these models for translation to humans? The most obvious issue is that mice lack the antigen “sink” encountered in patients for each of these antigens, since human CD20 or human CD22 are not expressed on non-tumor cells in these models, and this factor may be critical in determining a therapeutic index of an experimental agent that only targets human antigens. A second observation is that antigen expression could predict which antibody performed best in vivo, suggesting that a similar evaluation could be predictive in clinical specimens. Unfortunately, prior imaging to determine targeting of a radiolabeled antibody to be used in RIT has not been predictive of clinical efficacy in anti-CD22 and anti-CD20 RIT,5,6 suggesting there are other factors controlling Principal methods for radioimmunotherapy. (A) Conventional directly-radiolabeled antibody. (B) Three-step pretargeted radioimmunotherapy (RIT) used by Pagel et al,4 comprising injection of streptavidin-antibody conjugate, followed by a clearing agent, and then administration of radiolabeled biotin. (C) Two-step bispecific, trivalent antibody (bsAb) pretargeted RIT (“affinity enhancement system”), whereby a bsAb is injected and binds to tumor with 2 of the 3 antibody arms. It is followed by injection of a radiolabeled hapten-peptide that binds to the third arm of the bsAb once the latter has cleared from the blood naturally.