Radioimmunotherapy of Prostate Cancer: Does Tumor Size Matter?

Abstract

Monoclonal antibody– based therapeutics for cancer patients has recently proven to be highly successful. A number of these new treatments have been based on the ability of monoclonal antibodies to modulate receptorbased 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, 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. 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. 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. 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/m). In a subsequent phase II trial of J591 (25 mg/m) with daily low-dose subcutaneous interleukin-2 (1.2 106 U/m), some stabilization of PSA was observed. Based on the excellent targeting characteristics of radiolabeled J591, a study of Y-J591 was recently reported, and this treatment regime was found to be well tolerated, with an MTD established at 17.5 mCi/m, with some biologic activity seen, including objective responses and reduction in PSA. In this issue of the Journal of Clinical Oncology, Bander et al extend their experience with J591 and report on a phase I trial of Lutetium-labeled J591 (Lu-J591) in patients with hormone refractory prostate cancer. While radioimmunotherapy has shown success in hematologic malignancy (such as I-tositumomab [I] and Y-ibritumomab [Y] 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. 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, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 21 JULY 2