The combined use of an immunotoxin and a radioimmunoconjugate to treat disseminated human B-cell lymphoma in immunodeficient mice

Immunoconjugates (ICs) consist of a targeting moiety and a toxic moiety and have the specificity that traditional cancer therapy lacks. At appropriate doses, ICs are safe and effective in treating various cancers in experimental animals and in humans. However, because cures are rarely achieved using single agents, regimens involving combinations of agents with different mechanisms of action must be evaluated. In this study, we explored the efficacy and toxicity of a combination of two IC therapies, radioimmunotherapy (RIT) and immunotoxin (IT) therapy, to treat advanced, disseminated human lymphoma in immunodeficient mice. We proposed to use the bystander effect of RIT to reduce large tumor burdens, followed by an IT to eliminate residual tumor cells. Our results indicate that, when used alone, both RIT and IT therapy were safe and effective, but not curative. When the two therapies were combined, efficacy and toxicity became dependent on the temporal order of administration. Thus, with the doses used in this study, when RIT was administered after IT therapy, the regimen was curative. In contrast, when RIT was administered before IT therapy, the combination was highly toxic or even lethal. Both RIT and IT therapy induced pulmonary vascular leak, but with different kinetics. When RIT was given prior to IT therapy, the pulmonary vascular leak became life-threatening but not when the two agents were administered in the reverse order.