Download The New Golden Era for Radioimmunotherapy

Radioimmunotherapy may have applications
in many solid tumors as well as in lymphomas.
Nick Patten. Interior With Still Life. Oil on panel, 24ʺ × 36ʺ.
The New Golden Era for Radioimmunotherapy:
Not Just for Lymphomas Anymore
Michael B. Tomblyn, MD, MS, Michael J. Katin, MD, and Paul E. Wallner, DO
Background: Radioimmunotherapy (RIT) has been approved for the treatment of B-cell non-Hodgkin
lymphomas in the United States for more than a decade. However, the history of the development of RIT agents
for advanced-stage solid malignancies dates back much further, and recent advances have renewed interest
in this approach for solid tumors.
Methods: This paper reviews available evidence for the preclinical and clinical development of RIT agents
for solid tumors.
Results: Several RIT agents have been studied for the treatment of a variety of solid malignancies, particularly
colorectal, breast, prostate, ovarian, pancreatic, hepatocellular, and primary brain tumors. Multiple novel
RIT agents are in active clinical investigation, either as single agents or combined with radiosensitizing
chemotherapy or with external beam radiotherapy. Improvements in antibody (and antibody fragment) design
and the availability of novel radionuclides have improved the therapeutic window for these agents.
Conclusions: RIT for solid malignancies shows promise, typically with fewer adverse events than traditional
cytotoxic systemic therapy. The greatest efficacy will likely be in the adjuvant setting of minimal residual
disease. Newer radionuclides, particularly alpha-emitters, offer increased antitumor potency with less toxicity.
Physicians and patients should be encouraged to participate in clinical trials of these promising agents.
Introduction
The concept of radiolabeled antibodies targeted
against tumor cells is hardly novel, having been first
described in the early 1950s.1 Initially, investigators
From the Department of Radiation Oncology at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida (MBT), and
21st Century Oncology, Fort Myers, Florida (MJK), and Voorhees,
New Jersey (PEW).
Submitted August 15, 2012; accepted October 15, 2012.
Address correspondence to Michael B. Tomblyn, MD, MS, Department of Radiation Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, MCC-RAD ONC, Tampa, FL 33612. E-mail: Michael.
[email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
Dr Tomblyn has received research support from Immunomedics,
Inc. Dr Wallner was the chair of the American Society for Radiation Oncology’s Systemic Targeted Radionuclide Therapy program.
60 Cancer Control
utilized radiolabeled polyclonal antibodies from various mammalian species for radioimmunodetection
and the first attempts at radioimmunotherapy (RIT).2,3
In 1975, Köhler and Milstein4 developed hybridoma
techniques that paved the way to the production of
monoclonal antibodies. Within a few years, early
radiolabeled monoclonal antibodies were reported
to eliminate melanomas in a murine model.5,6 Soon
afterward, the first clinical human experiences with
RIT were conducted.7
Results from many of these early clinical studies
of RIT were somewhat mixed, owing to the relatively
modest radiosensitivity of epithelial cancers to lowdose radiation, the heterogeneous expression of target
antigens in normal tissues, and the immunogenicity
of these typically murine or lupine antibodies, preventing efforts at repeat dosing. These and other
fundamental challenges for RIT have been compreJanuary 2013, Vol. 20, No. 1
hensively reviewed elsewhere8 and are beyond the
scope of this review.
More recently, attention has turned to the development of RIT agents for the treatment of B-cell
non-Hodgkin lymphomas, which are inherently radiosensitive and express antigens not typically found in
normal tissue. Ibritumomab is a murine monoclonal
antibody that binds to CD20, which is found on the
surface of mature B cells and most B-cell malignancies. This antibody utilizes the linker-chelator tiuxetan
to hold yttrium-90 (90Y), a beta-emitting radioisotope,
for the purpose of RIT. However, repeat dosing with
90Y ibritumomab tiuxetan led to the development of
human antimurine antibodies (HAMAs). A chimeric
version of the antibody was produced — rituximab
— that exhibited a significant antilymphoma effect
in the absence of the radioisotope and without the
development of HAMAs. In 1997, rituximab was the
first monoclonal antibody to receive approval by the
US Food and Drug Administration (FDA).9
During the next several years, the development of
RIT agents for B-cell non-Hodgkin lymphoma continued, which led to the FDA approval of 90Y ibritumomab
tiuxetan in 200210 and iodine-131 (131I) tositumomab
in 2003.11 Both agents are indicated for relapsed or
refractory low-grade B-cell non-Hodgkin lymphomas,
while 90Y ibritumomab tiuxetan is also used in the
frontline setting following at least a partial response
(PR) to induction chemoimmunotherapy. Several other RIT agents for lymphomas have been investigated.
Perhaps the most promising is 90Y epratuzumab tetraxetan, which is currently in clinical trials for aggressive B-cell lymphomas,12 newly diagnosed follicular
lymphoma, and B-cell acute lymphoblastic leukemia
(NCT01101581, NCT01147393, and NCT01354457).
The role of RIT for B-cell non-Hodgkin lymphomas
has recently been reviewed.13 In general, solid tumors
are much less radiosensitive than B-cell lymphomas,
requiring higher delivered doses for significant clinical
efficacy.14 Here, we review major attempts at solid
tumor RIT and emerging techniques for improving the
therapeutic window of this modality in the treatment
of advanced solid malignancies.
Colorectal Cancer
Cancer of the colon and rectum is the third most
common form of malignancy in the United States,
accounting for 9% of all cancer cases.15 In 2012, an
estimated 143,460 new cases were diagnosed and
51,690 patients died of types of colorectal cancer
(CRC).15,16 Some of the earliest RIT experiences have
been in CRC, principally due to the early discovery of
carcinoembryonic antigen (CEA) and tumor-associated
glycoprotein 72 (TAG-72), both of which are often
highly expressed in CRC tumors. Beginning in the
late 1980s, investigators began to examine 131I-labeled
anti-CEA antibodies and antibody fragments in xenograft models of metastatic CRC.17-20 In dosimetric studies, investigators quickly realized that the absorbed
January 2013, Vol. 20, No. 1
tumor dose is inversely proportional to the radius
of the tumor mass, making the treatment of bulky
tumor burden impractical for RIT but promising for
micrometastatic disease.21-23
Due to its early characterization and ubiquity of
expression in CRC,24 CEA has been the most common
target for RIT in this disease. Lane et al25 reported
one of the earliest human trials of an anti-CEA radiolabeled antibody. Seventeen patients with CRC received
the murine 131I-A5B7 anti-CEA antibody, either as the
intact immunoglobulin (Ig)-G form or as the F(abʹ)2
fragment. This study reported 1 complete response
(CR) and 1 PR. One important observation was that
the smaller antibody fragments localized to tumor
faster than did IgG.
Another important anti-CEA antibody, neutrophil
proteinase-4 (NP-4), has been extensively evaluated.
A phase I/II trial of 131I-NP-4, a murine IgG1 antibody,
treated 57 patients, 29 of whom had CRC.26 A single
objective response was seen in the study, with 4 patients exhibiting minor responses. The same group
then examined the F(abʹ)2 fragment of this antibody
in a small phase I trial with 13 patients, 8 of whom
had CRC.27 All patients had a relatively small burden
of disease with no mass larger than 3 cm in diameter.
Four patients exhibited stable disease (SD) lasting up
to 7 months.
MN-14 is a murine IgG monoclonal antibody
against CEA with an order-of-magnitude greater affinity for the antigen than NP-4. Juweid et al28 reported the results of a phase I trial of rhenium-188
(188Re)-MN-14 in 10 patients with CRC. A fractionated
approach was used due to the relatively short halflife of 188Re, with 2 or 3 divided doses given to study
participants to deliver higher doses with less toxicity
than that seen with a 131I-labeled antibody. The group
reported a maximum tolerated dose (MTD) of 60 mCi/
m2, with the ability to deliver this on an outpatient
basis. Two patients in the study developed HAMAs.
The concern over the potential immunogenicity
posed by treatment with murine monoclonal antibodies led to the development of a humanized version
of their anti-CEA antibody, humanized MN-14 (hMN14). Two studies have been reported in patients with
small-volume disease.29,30 In both studies, 16% of
patients exhibited an objective response, with 42% to
45% showing a mixed or minor response to RIT. The
group also performed several studies of adjuvant 131IhMN-14 following R0 resection of hepatic metastases
in patients with CRC.30-33 The median disease-free
survival (DFS) in these studies was approximately 18
months, with 5-year overall survival (OS) in nearly
half of the treated patients.
The antibody cT84.66, a chimeric IgG anti-CEA
antibody against the A3 epitope of CEA, is highly
selective for tumor CEA expression and binds with
great affinity.34 Wong et al35-38 have published several reports on cT84.66, and several phase I studies
have been performed with this 90Y-labeled antibody
Cancer Control 61
in patients with CRC, with minor responses ranging
from 31% to 57%.
Several other murine anti-CEA RIT agents have
been evaluated in early phase clinical trials, including 131I-NP-4, 131I-F6 F(abʹ)2, 131I-A5B7, 131I-COL-1, and
186Re-NR-CO-2 F(abʹ) , all with modest objective re2
sponses.39-45
CEA is not the only antigen targeted for RIT in
patients with CRC. TAG-72 is another popular target
with significant clinical experience. The antibody
most utilized to target TAG-72 has been the murine
IgG, CC49. Several groups have published their experiences with CC49, most often labeled with 131I.
Divgi et al46 reported the results of a phase I trial of
24 patients treated with 131I-CC49 in which 25% of
patients exhibited SD or a minor response to RIT. The
MTD was reported to be 75 mCi/m2, and all patients
developed HAMAs. Murray et al47 reported a similar
phase II study in which followed 15 patients with CRC
receiving 131I-CC49 at 75 mCi/m2. Minor responses
were seen in approximately 20% of patients, and all
but 1 patient developed HAMAs. Wheeler et al48 reported the results of a phase II trial of 131I-CC49 in
15 patients with CRC, using interleukin (IL)-1 in an
attempt to reduce hematologic toxicity. Five 5 patients
exhibited a minor response to therapy. Mulligan et al49
reported on the use of 177Lu-CC49 and found 15 mCi/
m2 to be the MTD. In that study, 2 patients showed
a minor response.
Divgi et al46 also reported a study of fractionated 131I-CC49 in 6 patients with CRC, all of whom
received up to 4 infusions of RIT at 15 mCi/m2 per
infusion. A total of 4 patients were able to receive all
scheduled infusions. There was little immunogenicity
because patients were also treated with deoxyspergualin, which limited the development of HAMAs in
this study.
Two phase I studies examined high-dose RIT followed by an autologous stem cell rescue using the
anti-TAG-72 CC49 antibody. Tempero et al50 studied
14 patients who received high-dose 131I-CC49 (50-300
mCi/m2). Absorbed doses to tumor were calculated to
be as high as 33 Gy. A total of 12 patients received autologous rescue. The same group performed a similar
study with 90Y-CC49 in 12 patients at increasing doses
from 0.3 to 0.5 mCi/kg.51 No objective responses were
noted, but 2 patients had minor responses.
Another antibody directed against TAG-72 is the
chimeric IgG, cB72.3. Meredith et al52 reported the
results of a phase I study of 131I-cB72.3 in patients
with CRC. Doses ranged from 18 to 36 mCi/m2, with
no significant dose-limiting toxicities (DLTs) identified. One-third of the patients showed evidence of
minor responses.
Epithelial cellular adhesion molecule (Ep-CAM)
is highly expressed on gastrointestinal epithelium as
well as CRC. Unlike CEA, it is not generally shed
into the circulation, making Ep-CAM a promising RIT
target. Antibodies binding to Ep-CAM tend to be
62 Cancer Control
rapidly internalized into the cell, leading to excellent
intratumoral retention of the antibody. Some of the
earliest experience used the murine IgG 125I-CO 17-1A.
A phase I study of 53 patients (25 with CRC) used
125I-CO 17-1A in a fractionated approach, with up to
17 cycles of therapy and with doses ranging from 3 to
25 mCi each cycle.53 Most of the patients also received
whole-liver external beam radiotherapy in conjunction
with the RIT. One PR and 11 mixed responses or SD
were reported. No significant liver toxicity was seen
with this combination therapy. The chimeric version
of this antibody, 125I-17-1A, was evaluated in a phase
I study, with 28 patients with CRC receiving 20 to 250
mCi.54 Ten patients who were reported to have SD
from the RIT. No significant DLTs were reported in
either study of RIT with the 17-1A antibody.
NR-LU-10 is a murine IgG against Ep-CAM and has
been evaluated in the phase I setting of 15 patients
(10 with CRC).45 Labeled with 186Re, the antibody
was not associated with objective responses, and all
patients developed HAMAs. The MTD was found
to be 90 mCi/m2. The chimeric version of this antibody, 186Re-NR-LU-13, was evaluated in a small phase
I study.55 Patients were treated with 25 to 60 mCi/
m2. Two of the 9 patients had SD. The majority of
patients demonstrated evidence of immunogenicity
despite the chimeric nature of the antibody.
A33 is another antigen highly expressed by colonic epithelium and CRC and is also not shed into
the circulation. Like Ep-CAM, an antibody binding to
A33 is internalized. Two phase I/II studies have been
reported using the murine IgG, A33.56,57 Welt et al56
reported their experience with 131I-A33 in 23 patients
with CRC in which 3 patients exhibited a mixed response to therapy, with a reported MTD of 75 mCi/
m2. The same group also performed a similar trial
in 21 patients with CRC using 125I-A33.57 All patients
were chemorefractory and received from 50 to 350
mCi/m2. They reported a single mixed response and
no DLTs. A humanized version of the antibody was
reported as part of a phase I study of 15 patients with
CRC in which the MTD was reported to be 40 mCi/
m2.58 Four patients exhibited immunogenicity to the
humanized antibody, and 4 patients demonstrated SD
in response to RIT.
In summary, there is a rich clinical experience of
early phase clinical trials reported for RIT in patients
with CRC. Several promising targets have been identified, including CEA, TAG-72, Ep-CAM, and A33. Overall, the results have been somewhat disappointing,
with few objective responses. However, in the setting
of minimal residual disease, some studies have demonstrated favorable progression-free survival (PFS)
and OS compared with historic outcomes.
Breast Cancer
Breast cancer (BC) is the leading malignancy in women in the United States, with an estimated 226,870 new
cases diagnosed in 2012, along with 39,510 deaths
January 2013, Vol. 20, No. 1
from the disease.15,16 BC is also one of the more
radiosensitive solid tumors, with external beam radiation capable of eliminating microscopic residual
disease following lumpectomy.59,60 Several promising
antigenic targets have been identified for RIT in BC,
including CEA. T84.66, described above for its use
in CRC, has also been studied in patients with BC.
A phase I trial of 90Y-diethylenetriaminepentaacetate
(DTPA)-cT84.66 in 7 patients with BC was reported
by Wong et al.61 RIT was administered at 15 or 22.5
mCi/m2. No DLTs were reported, and all patients successfully engrafted following an autologous stem cell
infusion. One PR and 2 cases of SD were described.
MUC-1, a mucin epitope, is commonly expressed
on the surface of BC cells. Several reports reveal efficient radioimmunodetection of BC using anti-MUC-1
monoclonal antibodies.62-65 Schrier et al66 reported on
a phase I trial of high-dose murine 90Y-DTPA-BrE-3
and autologous stem cell rescue in 9 women with BC.
Single RIT doses of 15 or 20 mCi/m2 were given, with
no DLTs. One-half of the patients with measurable
disease exhibited objective PRs to therapy.66 However,
most patients developed HAMAs, limiting the ability to
consider repeat dosing. A humanized version of the
antibody has also been evaluated for use with stem
cell support.67 Two patients exhibited objective PRs;
each patient had a mixed response and SD.
L6 is another antigen highly expressed on the
surface of the majority of BC cells as well as some
lung, prostate, and ovarian cancers and in the vascular
endothelium.68 Investigators have studied a chimeric
anti-L6 monoclonal antibody (131I-chL6) in patients
with BC. Richman et al69 reported the results of a
phase I study of fractionated 131I-chL6 RIT in the setting of high-dose therapy followed by autologous stem
cell rescue. Three patients were treated with up to 3
cycles of RIT. One patient treated with cyclosporine
did not develop HAMAs but the others did.69 The
authors concluded that fractionation may allow for
total dose escalation with less normal tissue toxicity
and that cyclosporine may have a role in reducing
the immunogenicity of RIT.69 The same group later
reported the results of repeat dosing of 131I-chL6, up
to 4 monthly cycles, without stem cell support in 10
patients with BC.70 Objective clinical responses were
seen in one-half of those treated.70
The anti-TAG-72 monoclonal antibody CC49 has
also been evaluated in BC, labeled with either lutetium-177 (177Lu) or 131I.49,71,72 Pretreatment with interferon alfa led to a nearly 50% increase in expression of
TAG-72 on immunohistochemistry, which corresponded to a significantly increased uptake of 131I-CC49
in tumors.71,72 Patients exhibited 1 PR and 2 minor
responses to therapy in a total of 15 participants.71,72
In summary, several active targets have been identified in BC for RIT, including CEA, TAG-72, MUC1, and L6. Modest responses have been seen, with
greater responses in the setting of high-dose RIT followed by autologous stem cell rescue. Interferon alfa
January 2013, Vol. 20, No. 1
may have the ability to upregulate expression of key
RIT targets in patients with BC. Murine antibodies
result in a high expression of HAMAs, limiting repeat
dosing strategies.
Prostate Cancer
Prostate cancer (PC) is the most common noncutaneous malignancy in men in the United States, with an estimated 241,740 new cases and 28,170 deaths from the
disease in 2012.15,16 It has been nearly 30 years since
the first successful antibody targeting of PC.73 Perhaps
the earliest clinical use of therapeutic RIT was reported
by Meredith et al,74 who targeted TAG-72 with 131I-CC49
in 15 patients with androgen-independent PC. The
antibody localized well to known areas of metastatic
disease with no significant toxicity. However, there
were no patients with a biochemical response, and
all patients developed HAMAs. Of the patients with
painful skeletal lesions, 60% described an improvement in their reported pain.74 A follow-up study by
the same group used interferon alfa to increase tumor
localization of 131I-CC49.75 They found an absorbed
dose in excess of 25 Gy in the majority of visualized
tumors. Two patients exhibited minor responses, and
pain relief from skeletal metastases was common in
this study. No major toxicities were reported.
The L6 antigen, described above as a BC target,
has also been evaluated for PC.76 O’Donnell et al77 examined 90Y-DOTA-chL6 in mice bearing PC xenografts
and described a 100% response rate at an MTD of 150
mCi. Myelosuppression was seen but was fully reversible, and improved OS was seen in mice receiving the
highest doses. The same group reported the results
of a murine xenograft model, combining 90Y-DOTAchL6 and taxane chemotherapy. This resulted in a 67%
cure rate for mice receiving both RIT and docetaxel,
a 20% cure rate with RIT plus paclitaxel, and there
was no cure rate in RIT alone, chemotherapy alone,
or in the control groups.78
MUC-1 has also been shown to be upregulated
in androgen-independent PC cells, making it a good
target for RIT.79 A murine monoclonal antibody, m170,
was initially examined in 17 patients with metastatic,
androgen-independent PC in a phase I, dose-escalation trial labeled with 90Y.80 No DLTs were reached,
and toxicity was limited to reversible myelosuppression. A majority of patients with pain at study entry reported a significant reduction in pain following therapy. The same group performed a phase I
study of 90Y-2IT-BAD-m170 combined with low-dose
paclitaxel in patients with PC.81 Two patients receiving combined modality therapy developed grade 4
neutropenia as opposed to none in the group receiving only RIT. Only 1 patient exhibited evidence of
immunogenicity due to concurrent cyclosporine use.
Prostate-specific membrane antigen (PSMA) is
another rational PC target for RIT. PSMA is a hormone-independent, transmembrane glycoprotein that
is minimally shed into the circulation and rarely exCancer Control 63
pressed outside the prostate.82 Once bound, PSMA
becomes internalized into the PC cell, destined for
endosomal recycling. CYT-356 (ProstaScint; Cytogen
Corp, Princeton, NJ) is an 111In-labeled monoclonal
antibody against the 7E11-C5.3 epitope of PSMA and
is commercially used for imaging of metastatic PC foci.
Deb et al83 reported the results of a phase I trial of
escalating doses of 90Y-CYT-356 in 12 patients with
metastatic PC. The MTD was 9 mCi/m2. No objective
responses were reported, but higher doses seemed to
be associated with longer PFS. No immunogenicity
was seen in any patient at 4 weeks.
J591, an IgG monoclonal antibody against the
extracellular domain of PSMA, has also been evaluated
in patients with PC.84 Labeled with the alpha-emitter
bismuth-213 (213Bi), the antibody 213Bi-J591 was first
described in a PC cell line and in athymic mice bearing
PC xenografts, which is where it showed an ability to
stop growth of PC spheroids in vitro and significantly
reduce prostate-specific antigen (PSA) in vivo.85
Bander et al86 reported on a phase I trial of 177LuJ591 in 35 patients with androgen-independent metastatic PC. The single-dose MTD was determined to
be 70 mCi/m2 and the repeat MTD was 30 mCi/m2 for
up to 3 doses. There was no evidence of immunogenicity. A majority of patients exhibited a reduction
or stabilization of PSA levels in response to therapy.
Milowsky et al87 performed a similar phase I study
using 90Y-J591 in 29 patients with metastatic PC. The
MTD was reported to be 17.5 mCi/m2. Six patients
exhibited stabilization of PSA, and 2 had significant
drops in the tumor marker. The same group dosimetrically compared 177Lu-J591 with 90Y-J591 and
reported that the absorbed dose to the bone marrow
was approximately 3 times higher with 90Y, which was
largely a function of the higher mean path length of
the emitted beta particle.88 Ongoing phase II trials
of 177Lu-J591 are currently open for accrual for patients with androgen-independent PC (NCT00859781,
NCT00195039).
In summary, a number of rational RIT targets have
been described for PC, including TAG-72, L6, MUC-1,
and PSMA. By contrast to most solid tumor types,
patients with PC have exhibited some reasonable responses to RIT, particularly in the combined modality
setting when delivered with taxane chemotherapy.
Patients with PC who also have skeletal metastases experienced significant pain relief, even with RIT alone.
The most promising agent currently in active clinical
trials is 177Lu-J591, which targets PSMA.
Ovarian Cancer
Approximately 22,280 cases of ovarian cancer (OC)
were diagnosed in the United States in 2012, with an
estimated 15,500 deaths caused by the disease.15,16
Approximately 24 RIT constructs have been evaluated
in preclinical and/or clinical studies. Intraperitoneal
administration of RIT for advanced OC was first described more than 25 years ago.89 Human milk fat
64 Cancer Control
globule (HMFG) 1 is a murine monoclonal antibody
directed against MUC-1. A phase I/II clinical trial of
intraperitoneal 90Y-HMFG1 suggested an extended
PFS following CR to surgery and chemotherapy with
RIT.90 The follow-up randomized controlled trial of
intraperitoneal 90Y-HMFG1 showed no clinical benefit
in adding an RIT agent compared with standard care
following a complete clinical remission after chemotherapy and surgery.91 However, the study did show
a decrease in intraperitoneal relapse rates.92
Placental-like alkaline phosphatase (PLAP) is a
surface membrane enzyme expressed in the majority of ovarian tumors.93,94 Hu2PLAP is a human IgG
monoclonal antibody directed against PLAP and has
been used clinically for the radioimmunodetection of
ovarian tumors, labeled with 111In and 123I. Both labeled agents were shown to localize to PLAP-positive
ovarian tumors with no significant toxicity, and 2 of
the 30 patients in the study exhibited immunogenicity.95 No therapeutic studies using Hu2PLAP have
been reported to date.
Trastuzumab is a humanized IgG monoclonal antibody directed against the extracellular domain of the
oncoprotein human epidermal growth factor receptor
2 (HER-2)/neu, commonly overexpressed in breast,
ovarian, and gastrointestinal tumors.96 This antibody
has been labeled with several radionuclides for preclinical and clinical studies, including 90Y,97 177Lu,98
188Re,99 astatine-211 (211At),100,101 lead-212 (212Pb),102
actinium-225 (225Ac),103 and thorium-227 (227Th).104
There is an ongoing phase I study of intraperitoneal
212Pb-trastuzumab for patients with advanced OC with
positive pelvic washings or peritoneal studding.105
Pertuzumab is a human monoclonal antibody
directed against the HER-2 dimerization domain. Labeled with 177Lu, this agent has been evaluated in a
murine xenograft model. Mice treated with 177Lupertuzumab exhibited a delayed tumor progression
without evidence of significant toxicity.106
As with previously described solid tumors, TAG72 is frequently expressed on the surface of ovarian
tumors. CC49, labeled with 90Y or 177Lu, has been
evaluated in a number of OC clinical studies. Meredith et al107 reported the results of a phase I study
in 12 patients with advanced OC, intraperitoneally
delivering 177Lu-CC49. No MTD was reached up to
30 mCi/m2, and RIT was well tolerated, with only
mild myelosuppression. Only 1 of 8 patients with
gross disease showed an objective response, but 3 of
the 4 patients with occult disease remained without
evidence of progression after 18 months. The same
group reported on a phase I/II study of intraperitoneal 177Lu-CC49 in 27 chemotherapy-refractory patients.108 As with the prior study, only 1 patient with
gross disease responded, but 80% of those with occult
disease remained disease-free for up to 3 years; the
MTD was determined to be 45 mCi/m2. A phase I
study of 90Y-CC49 was published by Alvarez et al109
in which 20 patients with OC and intra-abdominal
January 2013, Vol. 20, No. 1
disease were treated with immunotherapy, paclitaxel,
and escalated doses of 90Y-CC49. The MTD in this
combined modality setting was 24.2 mCi/m2. Patients
with nonmeasurable disease had durable responses,
while 2 patients with measurable disease exhibited
PRs to therapy.
OC125 is a murine F(abʹ)2 monoclonal antibody
fragment directed against CA-125, an OC tumor marker. Three clinical studies have been published using
this antibody for intraperitoneal administration.110-112
In the first study, 90Y-OC125 was infused into 5 participants going for a second-look surgery.110 Intraoperative scintigraphy was performed to localize tumor foci
for additional resection. In addition, the investigators
performed normal organ dosimetric measurements
that showed most of the infused dose remaining within
the intraperitoneal space and approximately a 6:1 concentration of tumor to normal tissue. Mahé et al111
reported the results of a phase II trial of 131I-OC125 in
patients with OC and minimal residual disease following surgery and chemotherapy. Participants received
120 mCi of RIT given intraperitoneally approximately
1 week following surgery. Three patients exhibited
SD, while 3 progressed; all 6 patients demonstrated
HAMAs following RIT, and the primary adverse events
were hematologic. A phase I study by Muto et al112 examined escalating intraperitoneal doses of 131I-OC125
in women with refractory OC, with doses ranging from
18 to 144 mCi in a single dose. The MTD was reported
to be 100 mCi, with unacceptable hematologic and
gastrointestinal toxicity above this dose. The authors
concluded that intraperitoneal RIT with 131I-OC125 was
safe and feasible in this patient population.
MOv18 is a murine or chimeric monoclonal antibody directed against a folate-binding protein present
on the surface of nearly all ovarian carcinomas.113,114
Although the antibodies specifically target the folatebinding protein, significant heterogeneity was found
between patients and even between tumor foci within
patients following RIT, perhaps owing to differences
in folate-binding protein in the tumors.115 The same
group examined differences between intravenous and
intraperitoneal administration of the 131I-labeled antibody and found no targeting benefits to intraperitoneal delivery but possibly less hematologic toxicity.116
Another intriguing potential target for RIT in
OC is the cell-surface sodium-dependent phosphate
transport protein 2b, recognized by the murine IgG
MX35.117,118 A Swedish group119 has performed extensive preclinical studies on intraperitoneal delivery of
the alpha-emitter-labeled antibody, 211At-MX35 F(abʹ)2.
Nude mice inoculated intraperitoneally with OC xenografts were treated with either the targeted agent
211At-MX35 F(abʹ) or the nonspecific 211At-rituximab
2
F(abʹ)2. The alpha-labeled MX35 was significantly
more effective at tumor kill, with a relatively higher
mean absorbed dose (> 22 Gy) than is typically seen
with beta-emitter–labeled antibodies. In a murine
dose-escalation study,120 absorbed doses of up to 400
January 2013, Vol. 20, No. 1
Gy were intraperitoneally given, with posttherapy tumor-free fractions up to 61% with 211At-MX35 F(abʹ)2.
An experiment that treated mice with one infusion
vs repeated weekly infusions showed a significant
improvement in tumor-free status with repeat therapy.121 In the one published clinical trial of this agent,
9 women with recurrent OC who were in complete
remission following salvage systemic therapy were
enrolled into a phase I study of intraperitoneal 211AtMX35 F(abʹ)2.122 No toxicity was observed, and only
6% of the infused dose was measurable in the serum,
so the authors concluded that intraperitoneal therapy
with 211At-MX35 F(abʹ)2 was both feasible and safe for
patients with recurrent OC.
Several other potential targets for RIT in OC have
been described, but with little or no clinical experience.123-131 RIT for OC appears to be a potentially
promising option, particularly in patients who have
been optimally debulked following surgery and chemotherapy but who still are at high risk for microscopic intraperitoneal disease. Alpha-emitting radionuclides hold particular promise in nonbulky disease,
given the higher linear energy transfer and shorter
path length compared with beta particles. Therefore,
the accrual of ongoing clinical trials of these novel
agents should be encouraged.
Pancreatic Cancer
In general, pancreatic cancer (PanC) carries a poor
prognosis. In 2012, approximately 43,920 new cases
were diagnosed and 37,390 deaths occurred due to
this disease.15,16 Particularly for unresectable cases,
the median survival is shorter than 1 year, with few
long-term survivors. The vast majority of PanC cases
are mucin-producing adenocarcinomas, making MUC1 an attractive target for RIT.132 PAM4 is a murine
monoclonal antibody directed against MUC-1, and
early preclinical work demonstrated efficient targeting of PanC xenografts in athymic mice.133 Initial
human studies of patients going for surgical resection used immunoscintigraphy to demonstrate the
targeting of the 131I-radiolabeled PAM4 to PanC tumor
cells.134 Both 131I-PAM4 and 90Y-PAM4 showed significant anti-PanC tumor effects in animal models, particularly when given concurrently with gemcitabine
as a radiosensitizer.135-137
The first human therapeutic trial of the humanized version of the antibody (hPAM4) treated 20
patients with escalating single doses of 90Y-hPAM4
(15-25 mCi/m2).138 Objective responses were seen
in 3 patients, and PFS was seen up to 5.6 months
following treatment. However, most patients progressed within 1 month following RIT. The MTD
was determined to be 20 mCi/m2 for a single infusion. In a phase I/II follow-up study of 100 patients,
investigators examined the role of fractionated RIT
concurrent with escalating doses of gemcitabine for
radiosensitization.139 They found that the administration of multiple cycles of fractionated RIT was both
Cancer Control 65
feasible and safe in patients with advanced PanC.
Escalated doses of gemcitabine did not appear to
improve responses. SD or objective responses were
seen in 58% of the treated patients. Nearly one-half
of patients treated with 1 or more cycles of RIT had
an OS of longer than 1 year. A randomized trial of
90Y-hPAM4 with or without gemcitabine is currently
in development to determine the role of the addition
of the radiosensitizing agent.140
Hepatocellular Carcinoma
Primary liver cancer is diagnosed in more than 500,000
people worldwide each year, including 25,000 in the
United States.15,16 More than 90% of these are hepatocellular carcinomas (HCCs).141 Few patients are diagnosed at an early, resectable stage, making long-term
survival for most patients poor, with a median survival
shorter than 1 year.142 Early attempts at RIT for unresectable HCC using 131I–anti-alpha-fetoprotein (AFP)
and 131I–anti-ferritin have yielded mixed results.2,143,144
131I–Hepama-1 was the first RIT agent developed
to bind to a HCC membrane antigen, and early preclinical studies of human HCC xenografts in nude mice
demonstrated that injections of the antibody led to
objective responses and improved survival compared
with controls.145 A phase I dose-escalation trial146
of the antibody in patients with unresectable HCC
examined doses from 20 to 100 mCi. The treatments
were well tolerated by all patients, and the 1-year OS
rate was reported to be 31% (60% for patients without
metastases). Three-fourths of patients with elevated
AFP levels exhibited a 50% or greater reduction in
the tumor marker.
The HCC-associated membrane antigen HAb18G/
CD147 has also been identified as a potential RIT target, using the monoclonal antibody F(abʹ)2 fragment
131I-metuximab as a hepatic artery infusion. A phase
I/II study determined the MTD to be 0.75 mCi/kg
body weight per cycle and, of the 73 patients receiving 2 cycles of RIT, 20 had objective responses and
43 exhibited SD in response to therapy.147 Median
OS was 19 months. In a separate report, the group
demonstrated highly specific tumor-to-normal-tissue
absorbed doses.148
Central Nervous System
The blood–brain barrier hinders the transport of most
large molecules such as proteins from entering the
central nervous system (CNS). Although tumor-initiated angiogenesis may result in more permeable microvasculature, this is typically not sufficient to allow for
significant delivery of antibodies and antibody fragments to the CNS.149 The addition of external beam
radiotherapy can further disrupt the blood–brain barrier by increasing the vascular permeability.150-152 Most
attempts at RIT for CNS malignancies have focused
on direct intratumoral or intracavitary administration.
Perhaps the target most investigated for CNS tumors is tenascin, a glycoprotein concentrated within
66 Cancer Control
the extracellular matrix of malignant gliomas.153 Riva
et al154 first reported on antitenascin RIT in a study
of 10 patients with recurrent glioblastoma (GBM)
who received intratumoral administration of 131I-BC2, a murine monoclonal antibody directed against
tenascin. The mean specific activity per injection was
approximately 15 mCi, and most patients received
multiple injections. Cumulative tumor doses ranged
from 70 to 410 Gy. The injections were well tolerated without systemic effects. Responses included 1
patient with CR, 2 with PRs, and 3 with SD, and all
responders were relapse-free for at least 11 months.154
In a separate report by the same group of 24 patients
with relapsed gliomas, antitenascin RIT was given
in doses from 15 to 57 mCi, with up to 4 repeated
doses.155 No significant toxicities were observed, and
the median survival was 16 months. Of 17 evaluable
patients, 3 reported a CR, 3 had a PR, and 5 had SD.
Riva et al156 also examined the role of 131I antitenascin RIT in patients with newly diagnosed malignant
gliomas following surgical resection and chemoradiotherapy in a study of 50 patients: 26 had recurrent
disease and 24 had been newly diagnosed. Patients
received up to 6 repeated infusions, with doses up to
300 Gy per infusion. The median OS was 20 months
for all patients (18 for relapsed disease and 23 for the
newly diagnosed), with a 40% overall response rate.
The group later performed a phase I study of 90Y-BC-4,
another antitenascin murine antibody, in 20 patients
with recurrent high-grade gliomas.157 Doses ranged
from 5 to 30 mCi with an MTD of 25 mCi. The mean
tumor dose was 3200 cGy/mCi, and no systemic toxicity was seen. The use of 90Y demonstrated improved
responses compared with 131I for bulky residual disease and with fewer radioprotection concerns due to
the lack of gamma emissions.158
Another antitenascin radiolabeled monoclonal
antibody, 131I-81C6, was evaluated in a phase 1 study
in 34 patients with previously irradiated glioma who
also had surgically created resection cavities.159 Doses
ranged from 20 to 120 mCi, with the MTD determined
to be 100 mCi. Neurologic toxicity was dose limiting,
with significant hematologic toxicity seen only at the
120 mCi level, and median survival for all treated patients was 60 weeks. The same group reported the
results of a phase I study in patients who were newly
diagnosed with malignant glioma following surgery
and had not received additional adjuvant therapy.160
Doses ranged from 20 to 180 mCi with, an MTD of
120 mCi. DLT was primarily delayed neurotoxicity.
One patient required surgery for symptomatic radiation necrosis. Median survival for all patients was
79 weeks. In a follow-up phase II trial in 33 patients
with newly diagnosed high-grade glioma receiving
120 mCi 131I-81C6 followed by adjuvant chemoradiation, the median OS was 86.7 weeks for all patients
and 79.4 weeks for those with GBM.161 A dosimetric
analysis from this trial suggested that the tumor cavity
absorbed a dose of 44 Gy provided optimal clinical
January 2013, Vol. 20, No. 1
outcomes.162 A phase II study in 43 patients with
recurrent disease receiving 100 mCi 131I-81C6 showed
median survivals of 99 and 64 weeks for anaplastic
and GBM patients, respectively.163 A phase I study
of a chimeric construct of 131I-81C6 reported an MTD
of 80 mCi and suggested greater hematologic toxicity
than was seen with the murine antibody.164
The epidermal growth factor receptor (EGFR), a
transmembrane glycoprotein, is expressed in a variety
of tissues and its expression in gliomas increases in
conjunction with grade, and it is present in a majority
of cases of GBM.165 Early evidence of the efficacy of
anti-EGFR RIT was reported in a pilot study by Brady
et al.166 A total of 15 patients with recurrent malignant
glioma were treated with 125I-labeled anti–EGFR-425,
given intra-arterially via either the carotid or vertebral
arteries. They reported 1 CR, 2 PRs, and 5 patients
with SD in response to treatment. The same group
performed a phase II trial of 125I-425 in 25 patients
with multiple infusions and cumulative doses, ranging from 40 to 224 mCi, following surgical resection
and adjuvant external beam radiotherapy.167 Median
survival was reported to be 15.6 months, with more
than 60% of patients alive at 1 year. Recently, Li et
al168 published the results of a phase II trial of 125I-425,
with or without temozolomide, in 192 patients with
GBM following surgical resection. Median survival
following RIT alone was 14.5 months vs 20.2 months
for the temozolomide arm, representing a 38% reduction in the risk of death with the addition of concurrent chemotherapy.
Leptomeningeal disease (LMD) represents a
unique form of CNS malignancy, and intraventricular
administration of RIT has been investigated in several
studies. Kramer et al169 reported on the use of 131I3F8, a murine monoclonal antibody directed against
disialoganglioside (GD2). Five patients with LMD
expressing GD2 received intraventricular administration of 1 to 2 mCi of 131I-3F8. Single-photon emission
computed tomography imaging predicted doses of
15 to 56 cGy/mCi to the cerebral spinal fluid (CSF)
compared with less than 2 cGy/mCi to extracranial
tissues. In a formal phase I study of intraventricular
131I-3F8, 15 patients with GD2+ LMD received from
10 to 20 mCi after acceptable CSF flow was demonstrated with a dosimetric dose.170 The total dose to
the CSF ranged from 1 to 13 Gy. DLT was seen at the
higher dose level, including chemical meningitis, and,
of the 13 assessable patients, 3 exhibited a CR and 2
remained in remission for at least 3.5 years.
Antitumor Necrosis Therapy
Although most RIT approaches have endeavored to
target specific tumor membrane antigens, one alternative is to target regions of tumors undergoing necrosis,
either secondary to therapy or to degeneration. These
dead and dying cells exhibit increased permeability of
the cell membrane, and previous studies have shown
increased uptake of circulating proteins.171,172 Epstein
January 2013, Vol. 20, No. 1
et al173 reported on the development of monoclonal
antibodies directed against the DNA-histone H1 complex seen in dying cells. Tumor-bearing nude mice
were injected with 131I–TNT-1, an F(abʹ)2 IgG fragment,
and necrotic tumor-to-blood ratios were greater than
100:1, showing highly specific accumulation in areas
of tumor necrosis. Since that early report, radiolabeled TNT-1 has been investigated in a number of
malignancies, including cervical, colon, brain, and
lung cancers as well as hepatic metastases.174-179 The
antibody was approved by the Chinese State Food
and Drug Administration in 2003 for the treatment
of advanced lung cancer, and it appears to have little
immunogenicity in clinical practice.180
Conclusions
Significant advancements have been made in the development of RIT during the last 60 years. Progress
in chimerization and humanization of monoclonal
antibodies, the use of antibody fragments, pretargeting methods, improved dosimetric models, and novel
radionuclides — including alpha-emitters — have
opened the field beyond simply B-cell non-Hodgkin
lymphomas. Several new RIT agents are under active clinical investigation for many solid tumor types.
Many of these are entering phase II and III clinical
trials, and physicians and their patients with cancer
should be encouraged to consider participating in
these important endeavors.181
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