Pulsed high intensity focused ultrasound increases penetration and therapeutic efficacy of monoclonal antibodies in murine xenograft tumors.

The success of radioimmunotherapy for solid tumors remains elusive due to poor biodistribution and insufficient tumor accumulation, in part, due to the unique tumor microenvironment resulting in heterogeneous tumor antibody distribution. Pulsed high intensity focused ultrasound (pulsed-HIFU) has previously been shown to increase the accumulation of (111)In labeled B3 antibody (recognizes Lewis(y) antigen). The objective of this study was to investigate the tumor penetration and therapeutic efficacy of pulsed-HIFU exposures combined with (90)Y labeled B3 mAb in an A431 solid tumor model. The ability of pulsed-HIFU (1 M Hz, spatial averaged temporal peak intensity=2685 W cm(-2); pulse repetition frequency=1 Hz; duty cycle=5%) to improve the tumor penetration and therapeutic efficacy of (90)Y labeled B3 mAb ((90)Y-B3) was evaluated in Le(y)-positive A431 tumors. Antibody penetration from the tumor surface and blood vessel surface was evaluated with fluorescently labeled B3, epi-fluorescent microscopy, and custom image analysis. Tumor size was monitored to determine treatment efficacy, indicated by survival, following various treatments with pulsed-HIFU and/or (90)Y-B3. The pulsed-HIFU exposures did not affect the vascular parameters including microvascular density, vascular size, and vascular architecture; although 1.6-fold more antibody was delivered to the solid tumors when combined with pulsed-HIFU. The distribution and penetration of the antibodies were significantly improved (p-value<0.05) when combined with pulsed-HIFU, only in the tumor periphery. Pretreatment with pulsed-HIFU significantly improved (p-value<0.05) survival over control treatments.

Radioimmunotherapy in follicular lymphoma.

The exquisite sensitivity of haematological malignancies to targeted radiation make Radioimmunotherapy (RIT) a theoretically attractive therapeutic approach. Furthermore, impressive results initially achieved by the pioneers in this field and more recently in larger studies have demonstrated the high clinical activity of RIT in follicular NHL (FL). For more than a decade clinical RIT of FL has been dominated by targeting the CD20 antigen and a number of pivotal clinical studies have resulted in the approval by the US FDA (Food and Drug Administration) of two radioimmunconjugates, (131)I-tositumomab (Bexxar) and (90)Y-ibritumomab (Zevalin). (90)Y-ibritumomab tiuxetan was subsequently approved within the EU in 2004 and more recently in the EU and in the US as a front line "consolidation" treatment in follicular NHL. Recent data have demonstrated that fractionated radioimmunotherapy targeting CD22 with (90)Y-epratuzumab tetraxetan achieved a high degree of durable complete responses in relapsed/refractory NHL. Despite the fact that these RIT agents clearly have unique non-cross reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab, they have not been widely adopted by haemato-oncology community to date. This chapter reviews the progress that has been made in the development of clinical radioimmunotherapy in follicular lymphoma and suggest some guidelines to use it appropriately in first-line but also in the increasing number of patients emerging who are rituximab-refractory.