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Radioimmunotherapy of Disseminated Peritoneal Disease Targeting HER2
It is hypothesized that α-emitters will be most effective in the therapy of metastatic, small lesion disease, vascular-based disease, and vascular targets of tumors. The energy emissions of α-particle decays (4–9 MeV) are discrete and directly deposited over a short distance in tissue (40–100 μm), resulting in a high linear energy transfer. The lethality of α-particle radiation may be at a dose rate as low as 1 cGy/h, and direct cell killing may be executed with as few as 3–7 213Bi molecules localized to the surface of a tumor cell. The short path length of the emission could also be advantageous in limiting toxicity to normal tissues adjacent to tumor. The hypothesis for our study was that Herceptin radiolabeled with 213Bi would be therapeutic in two ways. First, Herceptin-targeted 213Bi treatment of disseminated peritoneal disease would be efficacious. Second, as a result of this demonstrated efficacy, Herceptin therapy targeting HER2 could be extended to the treatment of malignancies with low HER2 expression. A series of in vitro and in vivo studies were conducted to validate Herceptin as a viable targeting vehicle of α-radiation. The integrity and immunoreactivity of the MAb were maintained following radiolabeling. In vivo studies confirmed that radiolabeled Herceptin was effective in targeting the HER2 molecule. When mice bearing 3 d tumor burdens intraperitoneally (i.p.) were administered therapeutic doses of 213Bi-Herceptin (i.p.), a specific dose-dependent response of increased survival was observed (Figure 1). Consistent with the hypothesized merits of α- versus β–-emitting radionuclides, 213Bi-Herceptin lacked efficacy against a larger 5 d tumor burden. The α-emitters are postulated to be ideal for the treatment of smaller tumors/tumor burdens, disseminated disease, and micrometastatic disease, whereas a β–-emitting radionuclide such as 90Y is more appropriate for tumor lesions of about 1 cm or more. Determination of an obvious or real maximum tolerated dose of 213Bi-Herceptin was elusive. None of the animals succumbed to radiation death at the maximum doses administered. Using animal weights as a harbinger of toxicity, mice that received 1 mCi of 213Bi-Herceptin experienced the greatest weight loss. Based on these results, an effective dose of 500 to 750 μCi was established for use in future experiments. This decision was also based on the desire to combine RIT with other modalities such as chemotherapeutics that would alter tumor sensitivity to the radiation. In the two i.p. tumor models used, the Herceptin vehicle alone failed to elicit any effect on the survival of the animals, a persuasive argument for the treatment of patients with α-particle RIT, who are unresponsive to treatment with the unarmed MAb. Figure
1. Increasing μCi doses of 213Bi-CHX-A˝-Herceptin
(213Bi-Herceptin) were administered intraperitoneally (i.p.) to mice bearing 3
d LS-174T i.p. xenografts. (Panel A: These studies demonstrated the feasibility of locoregional administration of a MAb to target a short-lived radionuclide for the treatment of disseminated peritoneal disease. The effectiveness of Herceptin radiolabeled with an α-emitting radionuclide is attributed to both the nature of the disease and accessibility of the tumor. RIT targeting of the HER2 molecule is appealing in that it may prove beneficial even for those patients with a lower expression of the receptor who would not normally be eligible for immunotherapy. Patients with a scoring of 2+ or 3+ are typically selected for treatment with Herceptin; as a consequence, a low percentage of patients are actually eligible to receive it. RIT with Herceptin would greatly expand the population eligible for treatment. α-Particle RIT offers the opportunity of complementing the intrinsic cytostatic therapeutic efficacy of Herceptin with high linear energy transfer radiation. Studies are currently under way in our labs examining the potential of combining modalities such as targeted radiation therapy with chemotherapeutics and radiosensitizers. |
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adioimmunotherapy
(RIT)—the delivery of therapeutic radionuclides to cancer cells via
monoclonal antibodies (MAb)—has reemerged as a viable option for the treatment
and management of cancer patients. The cell surface antigen, HER2, provides
a molecular target to which site-specific, targeted radiation can be effectively
delivered via a well-defined, U.S. Food and Drug Administration (FDA)–approved
MAb (Herceptin). Monotherapy with Herceptin has resulted in a response rate
of 12% to 20% in metastatic breast cancer patients. A large percentage of eligible
patients, however, fail to respond to treatment and/or relapse. In addition
to breast cancer, HER2 is overexpressed in ovarian cancers and 35% to 45% of
all pancreatic adenocarcinomas. RIT offers an opportunity to complement and
enhance Herceptin’s intrinsic activity by direct incorporation of radiation
into the treatment regimen. 
mock-treated; 
