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Published on 1 May 2004

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Recent advances in radioimmunotherapy

teaser

Maggie Cooper
PhD

Stephen Mather
PhD
Cancer Research UK Nuclear Medicine Research Laboratory
St Bartholomew’s Hospital
London
UK

Although originally conceived in the 1940s, the concept of using radiolabelled tumour-associated antibodies for targeted therapy of cancer received a boost in the 1970s with the development of techniques for producing monoclonal antibodies.(1) The aim is to deliver radiation to the tumour in a more specific manner than is often possible with external-beam radiotherapy. The antibody, which is radiolabelled with a cytotoxic radionuclide and administered intravenously, binds to its specific complementary epitope expressed on the tumour cells. Unbound antibody gradually clears from the circulation, thus providing a degree of tumour-specific delivery of the radiation. Although the concept is attractive, results of the treatment of solid tumours with this modality have been generally disappointing. However, this method is extremely effective in some haematological malignancies, in particular lymphoma. This has resulted in the development of two new therapeutic radiopharmaceuticals, Bexxar(™) and Zevalin(™).

Bexxar (131I-tositumomab)

What is Bexxar?
Bexxar is a mouse monoclonal IgG2a antibody that reacts with an epitope of CD20, an antigen expressed in high density on normal and malignant B-cells. The antibody is radiolabelled with iodine-131 ((131)I), which is linked directly and covalently to tyrosine amino acids in the immunoglobulin protein. The product is marketed jointly by Corixa and GlaxoSmithKline, and is provided prelabelled and frozen on dry ice. Some of the characteristics of Bexxar are summarised in Table 1.

[[HPE14_table1_64]]

Indications for use
Bexxar has been mainly used in patients with non-Hodgkin’s lymphoma (NHL), alone or in combination with chemotherapy. In December 2002, the US Food and Drug Administration Oncologic Drug Advisory Committee (ODAC) decided that Bexxar had demonstrated substantial “clinical benefit” for NHL patients who have failed multiple chemotherapy or rituximab therapy,(2) and it was licensed in the USA in 2003.

Dosing schedule
The dosing schedule is outlined in Figure 1. An initial infusion of “cold” (nonradiolabelled) antibody is given to enhance favourable biodistribution of the radiolabelled antibody by blocking accessible CD20 sites in the peripheral blood and by preventing non-specific uptake of the radiolabelled antibody in the reticuloendothelial system, followed by an injection of a tracer dose of Bexxar. Imaging is carried out on a gamma-camera to assess biodistribution and measure the radiation dose received by the bone marrow in order to calculate the optimum dosage for radioimmunotherapy. Approximately one week after the imaging study, a second dose of “cold” antibody is given, followed by the therapeutic dose of Bexxar.

Before both the imaging and therapeutic doses of Bexxar, it is necessary to give potassium iodide to protect the thyroid, which will readily take up any unbound (131)I released during metabolism of the radiopharmaceutical.

In- or outpatient treatment?
Although patients suffer few side-effects from Bexxar treatment and do not require intensive nursing care, the treatment may need to be given on an inpatient basis because the radiation dose may be too high for family members and the general public to allow patients to return home immediately following treatment (although they can usually go home after the imaging study). Patients are required to remain in hospital until the radiation doses measured at the patient’s body surface reach acceptable levels. However, some data suggest that, depending on individual circumstances and local legislation, some patients could be treated on an outpatient basis.(3)

Clinical trials
Most trials were carried out in patients with relapsed indolent lymphomas or with indolent lymphomas that had transformed into a more aggressive histological classification. Response rates were high, with an overall response rate of 71% and a complete response rate of 34%.(4,5) The median time to progression was 12 months. Further studies have been conducted, combining Bexxar with chemotherapy with encouraging results.(6) In a phase II trial of a regimen consisting of six cycles of CHOP chemotherapy followed 4–8 weeks later by Bexxar in patients with previously untreated, advanced-stage follicular lymphoma, the treatment was well tolerated. The overall response rate for the entire treatment regimen was 90%, including 67% complete remissions. With a median follow-up of 2.3 years, the two-year progression-free survival (PFS) was estimated to be 81%, with a two-year overall survival of 97%.(6)

Adverse effects
Nonhaematological adverse events are usually mild and are often related to the administration of the “cold” antibody rather than the radiolabelled one.(4,5) The most common nonhaematological adverse effects are asthenia (32%), nausea (25%) and fever (22%).(7) Grade III–IV haematological side-effects include neutropenia (40%), thrombocytopenia (36%) and anaemia (11%). The nadir occurs 5–7 weeks after treatment and lasts for 2–3 weeks.

The FDA ODAC expressed concern over the incidence of myelodysplastic syndrome (MDS), which was found to be 2%,(2) but this bone marrow suppression is likely to be the result of the combination of chemotherapy and radiotherapy (including radioimmunotherapy) that these patients have received.

Zevalin ((90)Y ibritumomab tiuxetan)

What is Zevalin?
Zevalin is an yttrium-90 ((90)Y)-labelled immuno-conjugate that combines the linker–chelator tiuxetan with the monoclonal antibody ibritumomab. Ibritumomab is the murine IgG1 antibody precursor of the chimeric (mouse–human) rituximab, and also binds to the CD20 antigen expressed on B-lymphocytes, although to a different epitope than Bexxar. The chelator, tiuxetan (MX-DTPA), enables the antibody to be labelled with a radioisotope. The linker is attached to the antibody via a thiourea bond on the lysine amino acids in the immunoglobulin protein. The linker does not alter the metabolism of the antibody and does not result in measurable release of (90)Y from the antibody. The five carboxyl groups in the linker strongly chelate the (90)Y, and the methyl group in the backbone strengthens the chelate.(8) The antibody is provided in a “kit” form by Schering and must be radiolabelled before administration.

Indications for use
Zevalin was approved for use in the USA in April 2002 and licensed in Europe in summer 2003. Zevalin is currently available for compassionate use in Europe, and it should be formally launched during 2004. The main indications for use are the treatment of patients with relapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin’s lymphoma, including patients with follicular non-Hodgkin’s lymphoma refractory to rituximab.(9)

Dosing schedule
As for Bexxar, a dose of “cold” antibody is given before administration of the radiolabelled antibody (see Figure 1). Imaging studies may be conducted using (111)In-labelled immunoconjugate on day 1 in order to check biodistribution. However, unlike Bexxar, the administered dose is not calculated from the dosimetry data from the imaging studies, but is based on the patient’s weight. This is made possible by the fact that there is less interpatient variation in the radiation dose received by the bone marrow.(10) It is likely that, in the future, Zevalin will be used without the initial imaging study. On days 7–9, a further dose of rituximab is given, followed by the therapeutic dose of Zevalin.

In- or outpatient treatment?
Zevalin can be given on an outpatient basis (local legislation allowing), as the radiation dose to family members and the general public is very low.(11)

Clinical trials
Results of clinical trials in patients with relapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin’s lymphoma have been encouraging, with overall response rates in the region of 67% in multicentre trials.(7,12,13) In a trial comparing Zevalin treatment with rituximab immunotherapy, the overall response rate for Zevalin was superior, with an increased number of complete responses, a longer median duration of response and a greater time to progression.(12)

Adverse effects
As for Bexxar, the incidence of nonhaematological side-effects is low, and these effects are often related to administration of the “cold” antibody. Asthenia, nausea, infection, chills, fever and abdominal pain have been reported. Reported grade IV haematological side-effects are neutropenia (30%), thrombocytopenia (10%) and anaemia (3%).(14) The incidence of myelodysplastic syndrome is about 1% and occurs 8–34 months post-treatment. The nadir for haematological side-effects occurs between 7–9 weeks and lasts for 1–4 weeks.

As the radiation dose received by the tumour is far greater than that received by normal organs, the risk of radiation damage to normal organs is low.

Since mouse antibodies are “foreign” proteins, there is always a risk of anaphylactic reaction, and, although there have been no reported anaphylactic reactions due to Zevalin itself, it is advisable to have adrenaline, antihistamines and corticosteroids available should the need arise.(11)

Myeloablative radioimmunotherapy
The feasibility of using radiolabelled antibodies as part of a bone marrow preparative regimen for patients with haematological malignancies was introduced by Appelbaum and colleagues.(15) The aim of this type of treatment is to give targeted radiotherapy to the bone marrow as part of a conditioning regimen before bone marrow transplantation. Using this targeted approach, it is hoped that a higher dose of radiation can be administered directly to the bone marrow while causing less radiation damage to normal organs than occurs using external beam radiation.(16)

Several antigens have been targeted using this approach, including CD45 and CD33, which are expressed on leukocytes and lymphocytes. As for Bexxar and Zevalin, the antibodies are usually labelled with either (131)I or (90)Y.
Clinical trials in patients with acute myelogenous leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplastic syndrome (MDS) have been conducted. (15,17–19)

Further research in this area is being conducted using antibodies directed against several different antigen targets, including CD66, CD37 and CD22. The key will be to find antibodies that can selectively target the bone marrow, and to couple these with isotopes that will kill the tumour cells without damaging normal tissue.

Conclusion
The development of these new radioconjugates provides new opportunities for the treatment of haematological cancers and new challenges for radio- and oncology pharmacists. Due to their novelty and relatively high cost (>£10,000 per dose), it is likely that their use will be restricted to centres specialising in the treatment of these conditions, and it will be some time before they become accepted as regular members in the armamentarium of the oncologist.

References

  1. Kohler G, Milstein C. Nature 1976;256:495-7.
  2. Garber K. Natl Cancer Inst 2003;95:189.
  3. Rutar FJ, Augustine SC, Kaminski MS, et al. Clin Lymphoma 2001;2:164-72.
  4. Vose JM, Wahl RL, Saleh M, et al. J Clin Oncol 2000;18:1316-23.
  5. Rutar FJ, Augustine SC, Colcher D, et al. J Nucl Med 2001;42:907-15.
  6. Press OW, Unger JM, Braziel RM, et al. Blood 2003;102:1606-12.
  7. Dillman RO. J Clin Oncol 2002;20:3545-57.
  8. Brechbiel M, Gansow O. Bioconjugate Chem 1991;2:187-94.
  9. Crawford LM Jr. JAMA 2002;287:1640.
  10. Cheson BD. Blood 2003;101:391-8.
  11. Wagner HN Jr, Wiseman GA, Marcus CS, et al. J Nucl Med 2002;43:267-72.
  12. Witzig TE, Gordon LI, Cabanillas F, et al. J Clin Oncol 2002;20:2453-63.
  13. Wiseman GA, Gordon LI, Multani PS, et al. Blood 2002;99:4336-42.
  14. Witzig TE, White CA, Gordon LI, et al. J Clin Oncol 2003;21:1263-70.
  15. Appelbaum FR, Matthews DC, Eary JF, et al. Transplantation 1992;54:829-33.
  16. Press OW, Rasey J. Semin Oncol 2000;27:62-73.
  17. Matthews DC, Appelbaum FR, Eary JF, et al. Blood 1999;94:1237-47.
  18. Pagel JM, Hedin N, Subbiah K, et al. Blood 2003;101:2340-8.
  19. Pagel JM, Matthews DC, Appelbaum FR, et al. Bone Marrow Transplant 2002;29:807-16.
  20. Matthews DC, Appelbaum FR, Eary JF, et al. Blood 1995;85:1122-31.
  21. Witzig TE, Flinn IW, Gordon LI, et al. J Clin Oncol 2002;20:3262-9.


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