Biomed Imaging Interv J 2006; 2(3):e23
© 2006 Biomedical Imaging and
Radioimmunotherapy: a brief overview
MBBS, MRCP, FAMS
Department of Nuclear Medicine and PET, Singapore General
With the advent of biotechnological advances and knowledge
of molecular and cellular biology, radioimmunotherapy (RIT) has become a highly
promising oncologic therapeutic modality with established clinically efficacy,
particularly in non-Hodgkin�s lymphomas. This paper provides a short survey of
the basic science of RIT and the various monoclonal antibodies and
radionuclides used. A brief review of the published literature on the clinical
applications of radioimmunotherapy, particularly in non-Hodgkin�s lymphoma, is
provided. New research data indicate many potential areas of development of
this modality, including haematological and solid-organ radioimmunotherapy as
well as new radionuclidic approaches and clinical protocols. � 2006 Biomedical
Imaging and Intervention Journal. All rights reserved.
Keywords: Monoclonal antibodies, oncology, ibritumomab
Radioimmunotherapy (RIT) evolved from the spectacular growth
in molecular biology and biotechnological advances that resulted in the production
of highly purified monoclonal antibodies for clinical use. Just as
radio-labelling has been very successful with organic ligands such as
bisphosphonates for bone scan, or small peptides for octreotide scanning,
highly specific and purified monoclonal antibodies are excellent targets for
radiochemical labelling for diagnostic and therapeutic purposes. It has been
more than two decades since the early reports of radio-labelled antibodies for
diagnostic purposes, such as in Tc99m-anti-CEA antibodies, for imaging of
metastatic sites of colorectal carcinoma. The current interest is more in the
potential of radio-labelled monoclonal antibodies for therapeutic purposes.
Highly specific and purified, but non-radioactive, monoclonal antibodies have
been used in clinical practice for various medical indications with good
results. For instance, ritximab (Mabthera) has been used against the CD20
antigen on B-cell non-Hodgkin�s lymphomas (NHLs), and trastuzumab (herceptin)
has been directed at the human epidermal growth factor receptor 2 (HER-2) in
Such highly specific ligands may act as targeted therapeutic
agents, delivering adequate radiation dose at specific tumour sites, �guided�
by monoclonal antibodies that are clearly antigen-specific. Conversely, this
methodology is expected to reduce radiation dose to other tissues, especially
critical organs such as the haematopoietic system.
The efficacy of RIT rests on three fundamental principles:
cellular biology, monoclonal antibody selection and radionuclide selection. It
begins with the identification of appropriate cellular targets favourable to
the creation of a potential in-vivo nuclear medicine therapy. Haematological
malignancies can exploit this methodology. They typically express various types
of antigens on their cell surface, depending on cell type and cellular
differentiation. For instance, acute lymphoblastic leukaemia (ALL) expresses
CD5, CD22 and CD45, while acute myeloid leukaemia (AML) expresses CD15, CD33.
NHLs express various antigenic types such as CD19, CD20, CD21 and CD22. Most
experience has been reported in RIT for NHLs directed at the CD20 antigen. For
NHLs, the B-cell antigen CD20 is expressed in high density on B-cell
malignancies. CD20 is a B-cell antigen present on the surface of normal B
cells, pre-B cells, and more than 90% of B-cell lymphomas, but it is not found
on B-cell precursors, plasma cells, or other non-lymphoid normal tissues. Upon
binding, the antigen-antibody complex is internalised, nor is it shed or
secreted. These favourable features allow the radio-labelled antibody to remain
on the cell surface to exert its desired therapeutic effects.
The clinical efficacy of RIT is distinct from conventional
external beam radiotherapy and systemic chemotherapy in that it involves
continuous exposure to low-dose radiation that slowly decreases over time. A
study in mice with Burkitt�s lymphoma suggests that it works through cell
apoptosis (programmed cell death), rather than by cell necrosis .
In modern molecular and cellular biotechnology, monoclonal
antibodies can be produced in significant amounts for therapy. Many studies
were conducted when only murine antibodies were available for radio-labelling.
More recently, chimeric and even humanised monoclonal antibodies have become
more widespread in clinical use.
In the literature of RIT involving NHLs, most of the
antibodies used were IgGs (Table 1). In fact, several commercially available
monoclonal antibodies have been produced and used in various clinical indications
Table 1 Antibodies developed for RIT
Table 2 Some commercially
available monoclonal antibodies and their clinical use
The selection of an appropriate radionuclide is crucial in
the overall design of a clinically useful RIT. The suitability of a
radionuclide resides in its physical and chemical properties; its capacity for
conjugation with organic ligands; its stability in-vivo after conjugation; the
nature of its radiation; and the clearance behaviour of the isotope-complex.
The choice of a radionuclide is also influenced by the clinical disease, such
as tumour size, physiological behaviour and tumour radio-sensitivity.
Nuclides with beta radiation (β) are crucial to RIT and
produce cellular damage due to the ionising properties of beta radiation. There
is the additional effect of cross-fire where surrounding bystander cells, which
did not receive enough complex binding, are also destroyed by radiation from
adjacent targeted cells. Those beta emitter nuclides, with additional
production of gamma radiation (β/γ), allow for dosimetry and imaging.
But this additional long-range gamma radiation would usually require the
isolation of the patient to reduce radiation exposure to the public.
The two most widely used radionuclides in RIT are Iodine-131
and Yttrium-90 (Table 3). Iodine-131 has a physical half-life of about 8 days
(193 hours) and produces gamma radiation for imaging. It is relatively
inexpensive and readily available. Yttrium-90 has a higher energy emission and
longer path length. It is suitable for irradiation of larger tumours, but the
absence of gamma emission prevents its use for imaging.
Table 3 Radionuclides used in RIT
Different chemical synthetic pathways have been developed
for chemically linking radionuclides to monoclonal antibodies. Zevalin links
the yttrium nuclide through a specific linker molecule, tiuxetan, to the parent
monoclonal antibody (ibritumomab) via thiourea bonds to lysine and arginine
amino acids in the Fc portion of the immunoglobulin. Bexxar directly links the
iodine nuclide to the antibody via covalent bonds to tyrosine amino acids in
the antibody molecule, tositumomab.
RIT in NHLs
Early papers on RIT for NHLs were on refractory or relapsed
NHLs that had failed conventional chemotherapy and radiation therapy. In the
late 1980s, DeNardo et al, one of the early groups working on RIT,
treated 18 patients of B-cell NHL with Iodine-131 conjugated-Lym-1. Since then,
many papers on RIT for NHLs have been published involving Phase I/II or II
trials. Several papers have also been published in which high dose
marrow-ablative RIT has been used in conjunction with bone marrow transplant
Phase II clinical trials were performed for pre-registration
of both the commercial preparations of I-131 tositumomab and Y-90 ibritumomab
in patients with indolent lymphoma (follicular), whose disease had become
refractory to conventional therapy. The results of these trials were highly
promising, with a reported response rate of 70% for I-131 tositumomab and 74%
for Y-90 ibritumomab tiuxetan, and a complete response rate of 32% for I-131
tositumomab and 16% for Y-90 ibritumomab tiuxetan. There was median response
duration of 15.4 months in I-131 tositumomab and in excess of 7.7 months in
Y-90 ibritumomab. The group of patients that received Y-90 ibritumomab tiuxetan
had a higher proportion of bulky disease, which may account for the apparent
difference in the complete response rate and duration of response between the
The main adverse effect reported was marrow suppression,
with neutropenia and thrombocytopenia being the most common haematological
events. In a small proportion of patients, red cell and platelet transfusions
were necessary. There was a small risk of infection requiring hospitalisation.
Non-haematological adverse effects, which were generally of minor significance,
included nausea, chills, fever, headache and rashes. The development of HAMA
(human anti-mouse-antibodies) was low and was reported as 8% for I-131
tositumomab and 1% for Y-90 ibritumomab.
A serious potential concern is the risk of the development
of myelodysplasia and/or acute myeloid leukaemia. Although this has been
observed in a few treated patients, it is currently not clear whether it is due
to the effects of RIT or prior chemotherapy.
Of significance is a recent paper, following up on 1,071
patients who had enrolled in seven studies using I-131 tositumomab for RIT of
NHL, which showed that out of 25 confirmed cases of treatment-related
myelodysplastic syndromes and acute myeloid leukaemia, 52% developed after RIT
with I-131 tositumomab. This represents a crude incidence of 2.3% and an
annualised incidence of 1.1% per year, which compares favourably with reported
rates following chemotherapy used in the treatment of low-grade NHL. For a
small group of patients that received I-131 tositumomab as the initial therapy,
the median follow-up approaching five years showed no case of treatment-related
myelodysplastic syndromes and acute myeloid leukaemia. These findings are
encouraging, although longer follow-up studies are needed .
Other than Zevalin and Bexxar, I-131 rituximab RIT has also
been developed and results of a Phase II clinical trial has shown high
radiochemical purity and preservation of immunoreactivity. In such studies,
pre-therapeutic loading of unlabelled rituximab was followed by administration
of I-131 rituximab, calculating dosing based on dosimetric studies to deliver a
whole body radiation absorbed dose of 75 cGy. Rituximab is a commercially
available chimeric IgG1 anti-CD20 monoclonal antibody, with similarities to the
murine antibodies used in Bexxar. The objective response rate (ORR) was 71% in
35 patients with median follow-up of 14 months. Complete remission was achieved
in 54% of patients with median duration of 20 months .
Schedule of Y-90 ibritumomab tiuxetan therapy and clinical
The schedule for Y-90 ibritumomab tiuxetan RIT includes
several steps. A �cold� therapeutic dose of rituximab (250 mg/m2) is given one
week prior to the treatment to optimise tumour targeting. This is to deplete
circulating CD20+ B cells and thus maximise binding of the radioisotope-bearing
antibody to CD20+ malignant cells. If required (depending on local
regulations), the surrogate complex 111In-ibritumomab tiuxetan (5 mCi [185
MBq]) is infused for gamma imaging to assess biodistribution and for dosimetric
Dosimetry and imaging studies using 111In-ibritumomab
tiuxetan show generally low uptake of radioactivity by organs throughout the
body (in particular, the bone marrow), with rapid appearance and concentration
in the tumour. Dosimetry does not correlate with toxicity, and is no longer
considered necessary in most centres in the standard use of Y-90 ibritumomab
The treatment therapeutic component, Y-90 ibritumomab
tiuxetan is calculated based on body weight (0.4 or 0.3 mCi/kg [14.8 or 11.1
MBq/kg]; maximum dose 32mCi [1184MBq]) and infused after a �cold� therapeutic
dose of rituximab (250 mg/m2). This sub-therapeutic dose of unlabelled
rituximab administered (250 mg/m2) is about three quarters of that used when
rituximab is given as a treatment for low-grade NHLs (375 mg/m2).
In a Phase I/II dose-escalation trial in 51 patients with
low-grade, intermediate-grade, or mantle-cell NHL, Y-90 ibritumomab tiuxetan
given at 0.2 to 0.4 mCi/kg (7.4-14.8 MBq/kg) produced an overall response rate
of 67% (26% CR), with response durations ranging from 10.8 to 14.4 months. The
response rate was highest in patients with low-grade NHL, with an overall
response rate of 82% (27% CR, 56% PR) compared with 43% in patients with
intermediate-grade NHL (29% CR, 14% PR) .
A Phase III study involving 143 patients compared Y-90
ibritumomab tiuxetan with single-agent rituximab in patients with relapsed or
refractory low-grade, follicular, or transformed CD20+ NHL. The Y-90
ibritumomab tiuxetan treatment resulted in a response rate of 80% (30% CR) compared
with an overall response rate of 56% (16% CR) for rituximab therapy (p=.002).
The highest response rate was obtained in patients with follicular lymphomas
(86% vs. 67% in non-follicular NHL). Rituximab produced a response rate of 55%
in patients with follicular lymphomas (p<.001 vs. Y-90 ibritumomab
tiuxetan) and 50% in non-follicular NHLs .
Long-term data have been reported from the Phase I/II
dose-escalation trial of Y-90 ibritumomab tiuxetan in 51 patients with
low-grade, diffuse large-cell, or mantle-cell NHLs, up to a median follow-up of
28.5 months with up to 63 months for ongoing responders. The response rate was
73%, (51% CR/CRu) in all patients, 85% (58% CR/CRu) in patients with FL, and
58% (50% CR/CRu) in patients with diffuse large cell lymphoma (DLCL). Median
time to progression for all patients, treated at the recommended dose of 0.4
mCi/kg (14.8 MBq/kg), was 28.3 months with those ongoing responders having a
median time to progression of 45.0 months .
Schedule of I-131 tositumomab therapy and clinical efficacy
The standard schedule for I I-131 tositumomab involves a
dosimetric dose of 185 MBq of I-131 tositumomab given with pre-administration
of unlabelled antibody, followed by total body imaging for dosimetry
calculations. The dosimetric scans are performed over the next few consecutive
days. This enables the estimation of the radiopharmaceutical clearance time and
the therapeutic dose required to deliver a fixed total body radiation dose
(usually 65 or 75 cGy). The therapy dose is administered one week
post-dosimetric dose, again with pre-medication with unlabelled antibody.
Thyroid blockage with Lugols� iodine is necessary for at least three weeks from
the dosimetric dose. In view of the gamma emissions of I-131, in most centres,
the infusion of the therapeutic dose is conducted with hospital isolation of
the patient until the radiation exposure has dropped to acceptable levels.
A Phase I/II single centre study trial of I-131 tositumomab
found that chemotherapy-relapsed or chemotherapy-refractory low-grade or
transformed low grade NHLs with a median of 4 prior to chemotherapy regimes had
a response rate of 83% and a complete response rate of 48%. The median
progression-free survival was 14 months for responders and 20 months for complete
responders. Seven of 20 complete responders continued CR for 3 to 5.7 years
A Phase II multi-centre study also showed an overall
response rate of 57% and a complete response rate of 32%. A Phase III
clinical trial of Bexxar in chemotherapy-refractory low-grade or transformed
low grade B-cell NHLs gave a response rate of 65% and a complete response rate
of 20% compared to 28% response rate and 3% complete response rate in the
patients� last qualifying chemotherapy regimens .
Other RIT for haematological indications
Apart from the anti-CD20 monoclonal antibody, the anti-CD22
antibody (epratuzumab) with various radiolabels including Y-90, has also been
used in RIT in non-Hodgkin�s lymphoma with promising results .
In therapeutic options for acute leukaemia, research on RIT
largely focussed on the myeloid antigen CD33. Monoclonal antibodies M195 and
HuM195 raised against this target, radio-labelled with I-131, have been used in
the conditioning regime for allogenic bone marrow transplantation together with
busulfan and cyclophosphamide. There was good targeting of radiotracer to the
marrow, liver and spleen with absorbed marrow doses of 272-1470 cGy .
Another group working with anti-CD66 RIT recently published
a Phase I/II study where Rhenium-188 or Y-90 labelled anti-CD66 antibody was
used a part of a dose-reduced conditioning regimen for patients with acute
leukaemia or myelodysplastic syndrome. The authors concluded that RIT using the
anti-CD66 antibody was feasible and safe in their elderly patient group and
provided a high marrow dose .
RIT for solid tumours
The results of RIT for several solid tumour types have also
been published. The tumour types included ovarian, colorectal and glioma
tumours [15-17]. Currently, there is no sufficient evidence to suggest good
clinical activity for advanced metastatic disease of these tumour types,
although the potential for future development of these agents for early or
adjuvant therapy for micro-metastases remains bright. Solid organ RIT may become
useful in an adjuvant setting, where primary surgical resection of the tumour
has been successfully performed.
RIT is a promising new radioisotope oncological therapy. New
ways to improve the efficacy of these treatments should be sought. One of the
ways in which this can be achieved is through the use of combination therapy,
i.e., adding chemotherapy to RIT, perhaps as frontline or in salvage
chemotherapeutic regimes. An attractive combination, particularly for clearing
circulating cells or bone marrow cells in preparation for the administration of
the radiation, is the addition of a radiosensitiser, such as fludarabine or
paclitaxel. In three different mouse models (lymphoma, breast, prostate)
paclitaxel has been shown to enhance the effects of RIT . Athymic mice
bearing Raji xenografts were treated with Y-90-Lym-1 alone; paclitaxel alone;
Y-90-Lym-1 plus paclitaxel; or given no treatment. The addition of the
radiosensitiser to RIT markedly improved survival compared with either treatment
alone. Survival was 71% for Y-90-Lym-1 plus paclitaxel; 29% for paclitaxel
alone; 6% for Y-90-Lym-1 alone; and 14% in the untreated group. The average
tumour volume in the RIT plus radiosensitiser group was reduced by 89% compared
with RIT alone; and by 99% compared with radiosensitiser alone .
The role of RIT in the overall sequence of therapeutic
interventions and clinical treatment protocols for non-Hodgkin�s lymphomas
(such as in the neo-adjuvant setting or adjuvant setting) should be examined in
the context of randomised prospective trials. New work on molecular and
cellular biology will provide further impetus to the development of new areas
of RIT in the future.
Another recent development is the use of a-emitting radionuclides, such as bismuth-212
and bismuth-213 in RIT . They are used because of the highly ionising
nature of their particulate radiation. (a-radiation
are relatively heavier helium nuclei, compared to b-radiation which are electrons). These heavier nuclei transfer
larger amounts of energy per unit path-length in tissues and are stopped much
earlier by tissue than electrons. Based on these considerations, a-isotopes would be highly relevant when
targeting dispersed but small volume tumours.
RIT is a highly promising oncological therapeutic modality,
with good reported efficacy for refractory or relapsed NHLs. Future randomised,
prospective trials involving RIT will further determine and almost certainly
expand the scope of this useful therapeutic modality in the clinical management
of NHL and other tumours.
Kroger LA, DeNardo GL, Gumerlock PH, et al. Apoptosis-related gene and protein expression in human lymphoma xenografts (Raji) after low dose rate radiation using 67Cu-2IT-BAT-Lym-1 radioimmunotherapy. Cancer Biother Radiopharm 2001;16(3):213-25.
Bennett JM, Kaminski MS, Leonard JP, et al. Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 2005;105(12):4576-82.
Turner JH, Martindale AA, Boucek J, et al. 131I-Anti CD20 radioimmunotherapy of relapsed or refractory non-Hodgkins lymphoma: a phase II clinical trial of a nonmyeloablative dose regimen of chimeric rituximab radiolabeled in a hospital. Cancer Biother Radiopharm 2003;18(4):513-24.
Witzig TE, White CA, Wiseman GA, et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol 1999;17(12):3793-803.
Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002;20(10):2453-63.
Gordon LI, Molina A, Witzig T, et al. Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study. Blood 2004;103(12):4429-31.
Kaminski MS, Zasadny KR, Francis IR, et al. Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med 1993;329(7):459-65.
Kaminski MS, Zasadny KR, Francis IR, et al. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14(7):1974-81.
Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000;96(4):1259-66.
Vose JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2000;18(6):1316-23.
Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2001;19(19):3918-28.
Linden O, Hindorf C, Cavallin-Stahl E, et al. Dose-fractionated radioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab. Clin Cancer Res 2005;11(14):5215-22.
Burke JM, Caron PC, Papadopoulos EB, et al. Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant 2003;32(6):549-56.
Ringhoffer M, Blumstein N, Neumaier B, et al. 188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol 2005;130(4):604-13.
van Zanten-Przybysz I, Molthoff CF, Roos JC, et al. Radioimmunotherapy with intravenously administered 131I-labeled chimeric monoclonal antibody MOv18 in patients with ovarian cancer. J Nucl Med 2000;41(7):1168-76.
Behr TM, Salib AL, Liersch T, et al. Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study. Clin Cancer Res 1999;5(10 Suppl):3232s-42s.
Paganelli G, Grana C, Chinol M, et al. Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin. Eur J Nucl Med 1999;26(4):348-57.
Denardo SJ, Richman CM, Kukis DL, et al. Synergistic therapy of breast cancer with Y-90-chimeric L6 and paclitaxel in the xenografted mouse model: development of a clinical protocol. Anticancer Res 1998;18(6A):4011-8.
O'Donnell RT, DeNardo SJ, Miers LA, et al. Combined modality radioimmunotherapy with Taxol and 90Y-Lym-1 for Raji lymphoma xenografts. Cancer Biother Radiopharm 1998;13(5):351-61.
McDevitt MR, Sgouros G, Finn RD, et al. Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med 1998;25(9):1341-51.
|Received 28 November 2005; received in revised form 25 March
2006; accepted 26 March 2006
Department of Nuclear Medicine and PET, Singapore General Hospital, Outram Road, Singapore 169608 Tel: (65) 63266040; Fax: (65) 62240938; E-mail: email@example.com (David Chee-Eng Ng).
Please cite as: Ng DCE, Radioimmunotherapy: a brief overview, Biomed Imaging Interv J 2006; 2(3):e23
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