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Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies

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Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies Robert M. Sharkey, PhD; and David M. Goldenberg, ScD, MD Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey lular biology led the way with the development of mono- With the approval of 2 radiolabeled antibody products for the clonal antibodies and, more recently, with the engineering treatment of non-Hodgkin’s lymphoma (NHL), radioimmuno- of antibodies in various configurations with reduced immu- therapy (RIT) has finally come of age as a new therapeutic nogenicity. It is worth noting that antitumor antibodies modality, exemplifying the collaboration of multiple disciplines, remain one of the best means for selective binding to including immunology, radiochemistry, radiation medicine, suitable targets on cancer cells and have also stimulated the medical oncology, and nuclear medicine. Despite the many challenges that this new therapy discipline has encountered, study of other delivery forms, such as oligonucleotides or there is growing evidence that RIT can have a significant impact aptamers (6,7). However, the use of antibodies in radio- on the treatment of cancer. Although follicular NHL is currently immunotherapy (RIT) is still evolving, with the investiga- the only indication in which RIT has been proven to be effective, tion of new molecular constructs, new radionuclides and clinical trials are showing usefulness in other forms of NHL as radiochemistry, improved dosimetry, prediction of tumor well as in other hematologic neoplasms. However, the treatment response and host toxicities, and better targeting strategies of solid tumors remains a formidable challenge, because the to prevent or overcome host toxicities, particularly myelo- doses shown to be effective in hematologic tumors are insuffi- suppression. The hope is that the advances made for RIT in cient in the more common epithelial cancers. Nevertheless, there has been progress in locoregional applications and in the hematologic malignancies will translate to progress in the treatment of minimal residual disease. There is also optimism therapy of more radioresistant solid tumors. The purpose of that pretargeting procedures, including new molecular con- this article is not to review the many efforts and advances structs and targets, will improve the delivery of radioactivity to made in RIT, but to summarize our views of the current tumors, do so with less hematologic toxicity, and become the status and future prospects. Other reviews may be consulted next generation of RIT. for more comprehensive discussions of this subject (4,5,8–14). Key Words: Antibodies; colorectal cancer; non-Hodgkin’s lym- phoma; pretargeting; radioimmunotherapy HEMATOLOGIC MALIGNANCIES J Nucl Med 2005; 46:115S–127S 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuti- cals Corporation) and 131I-tositumomab (Bexxar; Corixa and GlaxoSmithKline Corporations) are currently the only At the turn of the 19th century, Paul Ehrlich conceived radiolabeled antibodies approved for treatment of cancer. the idea that “magic bullets” could effectively target com- Each is registered for therapy of chemotherapy-refractive, pounds and eradicate sites of disease, but it was not until the follicular (low-grade) NHL, with or without transformation, early 1950s that this idea was first explored with an anti- and uses an antibody that is directed to CD20, an antigen body conjugated to a radionuclide (1). Another quarter of a that is abundantly present on a high percentage of both normal and malignant B-cells. Details of the treatment century would pass before antibody-based tumor localiza- schemes for each of these approved agents are provided in tion was achieved clinically (2). This then led to the first Figure 1. Each is administered at radioactivity dose levels radioimmunodetection products in the mid-1990s (3). In the that result in severe myelosuppression that, for the most first years of the 21st century, the first agent of this type was part, is reversible. A significant portion of patients in the approved for the treatment of non-Hodgkin’s lymphoma registration trials for Zevalin and Bexxar, however, required (NHL) (4,5). The first 30 y of this process were devoted supportive therapy, including platelet transfusions (22% and mostly to the discovery and production of suitable antibod- 15%, respectively), erythropoietin or epoetin alfa (8% and ies, as well as developing radiolabeling technologies. Cel- 7%, respectively), or filgrastim (13% and 12%, respec- tively) (15,16). The overall response rate for 131I-tositu- Received Apr. 12, 2004; revision accepted Aug. 16, 2004. momab in rituximab-refractory patients was similar to that For correspondence or reprints contact: David M. Goldenberg, ScD, MD, reported with 90Y-ibritumomab tiuxetan, suggesting that the Center for Molecular Medicine and Immunology, 520 Belleville Ave., Belleville, NJ 07109. radionuclides are equally effective. However, the selection E-mail: [email protected] of the radionuclide has been shown to be more important for CANCER RADIOIMMUNOTHERAPY • Sharkey and Goldenberg 115S B1 alone has been shown to be active in animal models (37–39). Furthermore, responses were described in patients after they received a pretherapy diagnostic imaging dose (40,41). Anti-CD22 and anti-human leukocyte antigen (anti- HLA) antibodies also have been shown to be active as naked antibodies (42,43). Thus, the antibody itself is likely contributing to the antitumor responses observed with some of the radiolabeled antibodies used in NHL. In contrast, evidence for this has not been documented for the antibod- ies used in RIT of solid tumors. Although the acceptance of these approved treatment modalities appears to be slow, it is important to remember that this technology is still in the early stages of develop- ment. With several opportunities to improve the overall response and survival rates, this treatment modality should FIGURE 1. Comparison of administration conditions for 131I- become more established. For example, RIT is currently tositumomab) and 90Y-ibritumomab tiuxetan. Reprinted with used in patients in whom chemotherapy fails, but clinical permission from Goldenberg, DM. Therapeutic use of radiola- studies using 131I-tositumomab as a frontline treatment for beled antibodies: hematopoietic tumors. In: Ell PJ, Gambhir SS, eds. Nuclear Medicine in Clinical Diagnosis and Treatment. 3rd NHL were highly encouraging, not only because of the ed. London, UK: Churchill Livingstone; 2004:428–434. excellent response rate, but also because the regimen had far fewer side-effects than chemotherapy (44). Press et al. (45) reported encouraging therapeutic results when 131I-tositu- other radiolabeled antibodies being investigated as potential momab was administered as a frontline therapy 4–6 wk therapeutics for NHL, because these antibodies are internal- after standard cyclophosphamide, adriamycin, vincristine, ized and then rapidly catabolized, which favors the use of and prednisone treatment for follicular NHL. It is notable radionuclides that remain inside the cell (17–20). 90Y-ibri- that in this trial hematologic toxicity was more severe with tumomab tiuxetan and 131I-tositumomab each have unique chemotherapy than with RIT. Most of the data for RIT are requirements for use, which have been extensively reviewed based on a single treatment, yet Kaminski et al. (35) re- in several papers (21–26). ported that 9 of 16 patients re-treated with 131I-tositumomab Antitumor responses in NHL occur at very low absorbed after progression responded a second time, with 5 attaining doses (e.g., much less than 1,000 cGy). Koral et al. (27,28) a complete response. Others have reported safety and effi- reported a trend for higher absorbed doses to tumors that cacy of radioantibody treatment in patients who previously ultimately had a complete response, but others have dis- received another radioantibody therapy, and standard che- puted this relationship and even whether the lesions that motherapy can also be given after nonmyeloablative radio- responded were visualized by the radioimmunoconjugate antibody treatment without additional side effects (46–48). (29,30). Although clear evidence for a dose–response rela- Thus, not only can multiple cycles of radioantibody treat- tionship is lacking, it is likely present, but technical limita- ment be given, but RIT can also be integrated safely with tions in the way radiation dose and tumor size are measured various treatment modalities as a means of further improv- create considerable inaccuracies in these estimates. Another ing response. variable is the fact that some antibodies used in these trials Although each radioantibody treatment has established a have therapeutic activity by themselves (31,32). Evidence dosing regimen that ultimately results in a majority of suggests a role for anti-CD20 antibody in enhancing the patients experiencing severe, dose-limiting thrombocytope- therapeutic response from low-dose radiation (33,34). A nia and neutropenia, the tolerance of the therapy is related randomized trial comparing the efficacy of a full course of more to the patient’s treatment history as it affects their rituximab (375 mg/m2/week ϫ 4) with that of 90Y-ibritu- bone marrow status than is the actual radiation dose deliv- momab tiuxetan (250 mg/m2 rituximab/week ϫ 2 with the ered to the red marrow (49). Perhaps further refinement in radiolabeled murine anti-CD20) showed the radiolabeled optimizing the manner in which the radioactivity
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