|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.01.903 on April 18 2005 © 2005 American Society of Clinical Oncology.
Radioimmunotherapy of Prostate Cancer: Does Tumor Size Matter?Ludwig Institute for Cancer Research, and Department of Nuclear Medicine and Centre for Positron Emission Tomography, Austin Hospital, Heidelberg, Victoria, Australia Monoclonal antibody–based therapeutics for cancer patients has recently proven to be highly successful.1 A number of these new treatments have been based on the ability of monoclonal antibodies to modulate receptor-based intracellular signaling (such as trastuzumab, rituximab, cetuximab, and bevacizumab), as well as tumor cell cytotoxicity mediated by immune effector function initiated by the Fc portions of these antibodies. The combination of monoclonal antibodies with other therapies, including chemotherapy and other biologics, and using monoclonal antibodies to deliver toxins and radioisotopes to tumor sites, have also emerged as mechanisms of increasing response rates and duration of response. The selection of suitable antigens on the surface of cancer cells for targeting with monoclonal antibodies,2 and the biology of cellular function related to cognate antigens, remain critical factors in the success of this type of therapy, as well as in identifying new strategies for antibody-based treatment. The identification of candidate antigens expressed on prostate cancer for monoclonal antibody–based therapy has been extensively studied, and prostate-specific membrane antigen (PSMA) has emerged as one of the most promising targets.3 PSMA has many of the ideal characteristics as an antigen for antibody-based therapy: it is a stable cell surface glycoprotein with minimal shedding or secretion; it is abundantly expressed on prostate cancer, and this expression increases with high-grade tumors and hormone refractory disease. While PSMA is expressed in some normal tissues (most notably small intestine, proximal renal tubule cells, and salivary glands) this expression is low compared with tumor; and there is little phenotypic variation in expression in prostate cancer metastases. Interestingly, PSMA expression in endothelial cells of tumor-associated neovasculature, including colon, breast, melanoma, and kidney cancer has also been reported.3 The functional role of PSMA in prostate cancer is, however, still unclear. The development of successful monoclonal antibody therapeutics for prostate cancer has been challenging. The humanized monoclonal antibody J591, which targets the extracellular domain of PSMA, has emerged as one of the most promising candidates. J591 has been shown to selectively target prostate cancer in human trials, including bone and soft tissue metastases, and, importantly, is nonimmunogenic.4 In an initial phase I trial, J591 was found to be well tolerated, though no tumor or prostate-specific antigen (PSA) responses were seen after four weekly infusions (up to 200 mg/m2). In a subsequent phase II trial of J591 (25 mg/m2) with daily low-dose subcutaneous interleukin-2 (1.2 x 106 U/m2), some stabilization of PSA was observed.4 Based on the excellent targeting characteristics of radiolabeled J591, a study of 90Y-J591 was recently reported,5 and this treatment regime was found to be well tolerated, with an MTD established at 17.5 mCi/m2, with some biologic activity seen, including objective responses and reduction in PSA. In this issue of the Journal of Clinical Oncology, Bander et al6 extend their experience with J591 and report on a phase I trial of 177Lutetium-labeled J591 (177Lu-J591) in patients with hormone refractory prostate cancer. While radioimmunotherapy has shown success in hematologic malignancy (such as 131I-tositumomab [131I] and 90Y-ibritumomab [90Y] tiuxetan in non-Hodgkin's lymphoma), responses in solid tumors have been infrequent. This is due in part to the inability to deliver sufficient radiation dose to tumor cells, the relative lack of sensitivity of solid tumors to radiation compared with lymphoma, and the size of metastatic lesions combined with physiologic barriers to uniform tumor penetrance by antibodies.7 The physical properties of isotopes, particularly the path length and energy of emission, and physical half-life, need to be selected based on the size of lesion and the targeting and internalization properties of the antibody. For solid tumors, beta emitters remain the principal choice for effective therapy for lesions greater than 2 to 3 mm in size, while alpha emitters may be best suited to micrometastatic disease.8 90Y has a higher beta particle energy and longer range compared with 177Lu; however, this does increase potential normal tissue toxicity. Both 90Y and 177Lu are well suited to internalizing antigens like PSMA compared with radiohalides (such as 131I), due to superior tumor retention. 177Lu radioimmunotherapy has also been demonstrated in computational models and animal experiments to be more effective in treating small lesions compared with 90Y radioimmunotherapy.9,10 Based on these observations, what were the tumor biologic responses in this study following 177Lu-J591 treatment, and how did they compare to the prior study of 90Y-J591? In the trial by Bander et al,6 four (11%) of 35 patients had a decrease in PSA following treatment with 177Lu-J591, and 16 (46%) of 35 had stabilization of PSA, which is an encouraging result for a phase I trial. This result compares favorably to two (7%) of 29 patients having PSA decrease and six (21%) of 29 with PSA stabilization after 90Y-J591.5 In contrast, none of 35 patients had objective responses in the 177Lu-J591 trial, compared with two of 29 patients with objective responses from 90Y-J591 treatment. Although both trials had similar patient eligibility criteria, a distinct variable was the smaller number of patients with measurable lesions in the 177Lu-J591 trial compared to the 90Y-J591 trial (seven of 35 patients compared with 12/29 patients). Overall, these results suggest that 177Lu-J591 may be better suited to treatment of small volume prostate cancer lesions (< 5 mm), whereas 90Y-J591 may be more effective in larger-volume (> 1 cm) disease. These results will clearly need to be confirmed in larger phase II trials. Dose-limiting toxicity in the Bander et al trial was principally hematologic, with the MTD of a single infusion established at 70 mCi/m2, related to the effects of radiation on red marrow. Similar to other radioimmunotherapy trials, no clinical or diagnostic parameter (including past therapy, and marrow involvement by tumor) could predict toxicity in individual patients. The need for patient specific dosimetry, which has been successfully utilized for anti-CD20 radioimmunotherapy (such as 131I),11,12 was not explored in this trial, and while this may assist in predicting hematologic toxicity, a similar approach for radioimmunotherapy in other solid tumors has not shown encouraging results. In light of these findings, how can the toxicity of radioimmunotherapy potentially be predicted? Serum levels of FMS-like tyrosine kinase–3 (FLT-3) ligand as a biomarker of red marrow functional reserve have been shown to assist in predicting hematologic toxicity following radioimmunotherapy13; however, this assay was not performed in this trial. Dosimetry calculations in the Bander trial showed normal organs to have received doses well below those normally associated with toxicity, although some liver transaminase elevations were observed following treatment, and one episode of an hepatic dose-limiting toxicity was reported at the highest dose level (75 mCi/m2). These results indicate that 177Lu-J591 does target liver parenchymal cells at levels that may cause toxicity, albeit manageable at the doses studied in this trial. An important observation in the Bander trial was the excellent targeting characteristics of 177Lu-J591 to soft tissue and bony metastases of prostate cancer. Interestingly, the pharmacokinetics of 177Lu-J591 show a T1/2ß of 44 ± 16 hours, which is remarkably short compared to most humanized antibodies.14 The authors provide no clear explanation for this finding; however, the fast clearance of the antibody would reduce red marrow exposure and therefore minimize radiation exposure and hematologic toxicity associated with 177Lu-J591 treatment. The excellent targeting characteristics of J591 to tumor, and internalization into tumor cells, do raise the possibility of delivery of other toxic molecules to prostate cancer, already explored by the authors in preclinical studies.15,16 The actual radiation dose delivered to tumor remains the principal factor affecting efficacy of radioimmunotherapy. How can the targeted delivery of radiation to metastatic tumor be improved with monoclonal antibody-based approaches? One option is to consider multiple treatments, with dose and scheduling predicated on red marrow toxicity and recovery.17 In the Bander trial this was approached by administering two or more treatments of 177Lu-J591. However, the toxicity of this approach was high, with repeat infusions well tolerated only at 30 mCi/m2, and progression of disease often seen before subsequent treatments could be administered. The theoretical advantages of such fractionated radioimmunotherapy have been demonstrated in animal model studies, though recent human trials have not confirmed these results.18 Pretargeting of antibodies19 may also improve tumor to normal tissue ratios and possible therapeutic efficacy. The success of any new therapeutic for prostate cancer will be predicated on the response rate and duration of responses, particularly in comparison to the 40% to 60% responses seen with taxane-based therapy. For radioimmunotherapy with J591, combination treatment with chemotherapy, including taxanes, may be one approach to achieve optimal results.20 The Bander et al trial provides important information on the potential for 177Lu-J591 in the therapy of hormone refractory prostate cancer, and the efficacy of this therapy in metastatic prostate cancer remains to be determined in phase II trials. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. von Mehren M, Adams GP, Weiner LM: Monoclonal antibody therapy for cancer. Annu Rev Med 54:343-369, 2003[CrossRef][Medline] 2. Van den Eynde B, Scott AM: Tumor antigens, in: Encyclopedia of Immunology (ed 2). London, UK, Academic Press, 2424-2431, 1998 3. Chang SS: Monoclonal antibodies and prostate-specific membrane antigen. Curr Opin Investig Drugs 5:611-615, 2004[Medline] 4. Nanus DM, Milowsky MI, Kostakoglu L, et al: Clinical use of monoclonal antibody HuJ591 therapy: Targeting prostate specific membrane antigen. J Urol 6:S84-S88, 2003
5. Milowsky MI, Nanus DM, Kostakoglu L, et al: Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 22:2522-2531, 2004
6. Bander NH, Milowsky MI, Nanus DM, et al: Phase I trial of 177Lutetium-labeled J591, a monoclonal antibody to prostate specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 23:4591-4601, 2005
7. Christiansen J, Rajasekaran AK: Biological impediments to monoclonal antibody-based cancer immunotherapy. Mol Cancer Ther 3:1493-1501, 2004
8. O'Donoghue JA, Bardies M, Wheldon TE: Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med 36:1902-1909, 1995
9. Smith-Jones PM, Vallabhajosula S, Navarro V, et al: Radiolabeled monoclonal antibodies specific to the extracellular domain of prostate-specific membrane antigen: Preclinical studies in nude mice bearing LNCaP human prostate tumor. J Nucl Med 44:610-617, 2003
10. Brouwers AH, van Eerd JE, Frielink C, et al: Optimization of radioimmunotherapy of renal cell carcinoma: Labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med 45:327-337, 2004 11. Hernandez MC, Knox SJ: Radiobiology of radioimmunotherapy: Targeting CD20 B-cell antigen in non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 59:1274-1287, 2004[CrossRef][Medline] 12. Wahl RL: The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab. Semin Oncol 30:31-38, 2003 (2 suppl 4)[Medline]
13. Siegel JA, Yeldell D, Goldenberg DM, et al: Red marrow radiation dose adjustment using plasma FLT3-L cytokine levels: Improved correlations between hematologic toxicity and bone marrow dose for radioimmunotherapy patients. J Nucl Med 44:67-76, 2003
14. Scott AM, Lee FT, Hopkins W: Specific targeting, biodistribution and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma: Results of a phase I trial. J Clin Oncol 19:3976-3987, 2001 15. Li Y, Tian Z, Rizvi SM, et al: In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. Prostate Cancer Prostatic Dis 5:36-46, 2002[Medline] 16. Patri AK, Myc A, Beals J, et al: Synthesis and in vitro testing of J591 antibody-dendrimer conjugates for targeted prostate cancer therapy. Bioconjug Chem 15:1174-1181, 2004[CrossRef][Medline] 17. DeNardo GL, Schlom J, Buchsbaum DJ, et al: Rationales, evidence, and design considerations for fractionated radioimmunotherapy. Cancer 94:1332-1348, 2002 (suppl 4)[CrossRef][Medline]
18. Divgi CR, O'Donoghue JA, Welt S, et al: Phase I clinical trial with fractionated radioimmunotherapy using 131I-labeled chimeric G250 in metastatic renal cancer. J Nucl Med 45:1412-1421, 2004
19. Boerman OC, van Schaijk FG, Oyen WJ, et al: Pretargeted radioimmunotherapy of cancer: Progress step by step. J Nucl Med 44:400-411, 2003 20. O'Donnell RT, DeNardo SJ, Miers LA, et al: Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90yttrium-DOTA-peptide-ChL6. Prostate 50:27-37, 2002[CrossRef][Medline] Related Article
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
