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Radioimmunotherapy of Disseminated Peritoneal Disease Targeting HER2
Milenic
DE, Garmestani K, Brady ED, Albert PS, Ma D, Abdulla A, and Brechbiel MW. Targeting
of HER2 antigen for the treatment of disseminated peritoneal disease. Clin
Cancer Res 10: 7834–41, 2004.
 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.
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: 
mock-treated; 
250 μCi; 
500 μCi; and 
750 μCi 213Bi-Herceptin.
500 μCi 213Bi-HuIgG
was used as a non-specific control.) Toxicity of radioimmunotherapy with 213Bi-Herceptin
was determined by monitoring the animal weights for 2–3 weeks following radioimmunotherapy
(RIT). The maximum relative weight reduction was calculated for each of the treatment
groups and presented as box plots (Panel B). Specificity of the effect of the
radioimmunotherapy is illustrated with a comparison between the mice that received
either 500 μCi 213Bi-Herceptin
or 500 μCi 213Bi-HuIgG
(Panel C). The light line is the median. The upper region of the box represents
the third quartile. The lower portion is the first quartile. The brackets delineate
1.5 times the interquartile range, and the lines outside of the brackets represent
outlying observations.
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.
Martin Brechbiel, PhD
Senior Principal Investigator
Radiation Oncology Branch
NCI-Bethesda, Bldg. 10/Rm. 1B53
Tel: 301-496-0591
Fax: 301-402-1923
martinwb@mail.nih.gov
Diane E. Milenic, MS
Scientist
Radiation Oncology Branch
NCI-Bethesda, Bldg. 10/Rm. 1B53
Tel: 301-496-9086
Fax: 301-402-1923
dm71q@nih.gov
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