Interferon-.y and Monoclonal Antibody 1311-labeled CC49: Outcomes in Patients with Androgen-independent Prostate Cancer1

To assess the tumor targeting, safety, and efficacy of monocbonal antibody ‘311-labeled CC49 in patients with androgen-independent prostate cancer, 16 patients received 75 mCi/m2 of the radiolabeled antibody after 7 days of IFN-y pretreatment. Sequential tumor biopsies in three patients showed a median 5-fold (range, 2-6-fold) increase in the proportion of cells staining positively for the TAG-72 antigen, whereas one showed a decrease in staining. Fourteen patients received ‘311-labeled CC49, whereas 2 showed a disease-related decrease in performance status, precluding antibody treatment. The antibody localized to sites of metastatic androgen-independent prostate cancer in 86% (12 of 14; 95% confidence interval, 57-95%) of cases. Both osseous and extraosseous sites were visualized, and in six (42%) patients, more areas were visible when the radioimmunoconjugate was used than were apparent when conventional scanning techniques were used. The localization of the conjugate in the marrow cavity was usually a site not visualized by the radionuclide bone scan, in which the isotope localizes Received 10/9/97: revised 12/5/97: accepted 12/I 1/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 1 8 U.S.C. Section 1734 solely to indicate this fact. I This work was supported by NIH Grants CA095 I 2 and CA05826 and by the PepsiCo Foundation. 2 To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, I 275 York Avenue, New York, NY 10021. Phone: (212) 639-2364; Fax: (212) 794-5813. primarily to the tumor-bone interface. The dose-limiting toxicity was thrombocytopenia because five (36%) patients showed grade IV and seven (50%) showed grade III effects. In addition, six (42%) patients, four of whom were hospitalized, showed a flare in baseline pain, and four showed a decrease in pain. No patient showed a >50% decline in prostate-specific antigen, although radionuclide bone scans remained stable in four cases for a median of 4 months. The results are consistent with dosimetry estimates showing that the delivered dose to tumor was subtherapeutic and suggest that approaches that exclusively target the bone tumor interface or the marrow stroma may be unable to completely eradicate disease in the marrow cavity. For CC49, improving outcomes would require repetitive dosing, which was precluded by the rapid development of a human antimouse antibody response. INTRODUCTION Bone metastases develop from single cells or clumps of cells that are “seeded” through the blood to the sinusoids in the medubbary cavity, where they adhere to specific receptors on endothelial cells (I, 2). Once attached, growth is facilitated by a bidirectional interaction between the malignant epithelial cells, which secrete factors that result in osteoblast proliferation, and bone marrow stroma-derived factors, which stimulate malignant epithelial cell growth. One feature of the process is that tumors can metastasize to the marrow without spreading to cortical bone (3). Left untreated, bone metastases can result in significant morbidity, including pain. spinal cord compression. and marrow compromise. Bone metastases are often multiple and diffuse, which limits the long-term efficacy of external beam radiation, although significant palliation can be provided to selected sites. Therapeutic radiopharmaceuticals that preferentially localize to sites of osseous spread have the potential to treat all sites of osseous spread simultaneously. These agents reside in the bonetumor interface and may not distribute throughout a tumor mass uniformly. Consequently, the delivered radiation doses to tumor are often subtherapeutic. which may explain why overall clinical benefits have been limited to pain relief, with modest tumoricidal effects. An alternative approach is to use a radiolabeled MoAb3 that localizes directly to tumor and to treat marrow metastases before an osteoblastic response has been observed. 3 The abbreviations used are: MoAb, monoclonal antibody: ‘ ‘ ‘ I-CC49. ‘31I-labeled CC49; CEA, carcinoembryonic antigen: KPS, Karnofsky performance status; PSA. prostate-specific antigen: HAMA. human antimouse antibody: CT. computed tomography: BSI. bone scan index: SPECT. single-photon emission CT. Research. on June 3, 2017. © 1998 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 644 IFNy and MoAb CC49 in Prostate Cancer TAG-72 antigen is a high molecular weight glycoprotein related to the sialyted In antigen that is expressed on adenocarcinomas of the breast (4), colon (5), and lung (6). CC49 is a murine IgG 1 MoAb that reacts with the TAG-72 antigen (7). In clinical trials, ‘311-CC49 has been shown to be safe and well tolerated and to localize to sites of disease in patients with breast and colon cancer, consistent with reported results using imniunohistochemistry (7). Immunohistochemicab studies of prostate cancers show that tumors from different sites (primary, lymph nodes, or bone) and of different hormone sensitivities (naive or androgen-independent) express the TAG-72 antigen in varied amounts (8-10). In general, despite different definitions of a “positive” result, the proportion of cells staining with the antibody and the intensity of staining are higher in the primary than in metastatic lesion and higher for hormone-naive than for androgen-independent tumors (8-10). In the clinic, a Phase II trial of ‘I-CC49 in patients with androgen-independent disease showed antibody localization to at least one known tumor site in all cases, with reversible myebosuppression as the dose-limiting toxicity. No objective responses or consistent declines in PSA were observed; however, six of nine (67%) patients with pain showed palliation ( 1 1). The current trial was designed to exploit the observation in several tumor systems that pretreatment with IFN-’y can upregulate the expression of tumor differentiation antigens. For example, the expression of CEA in colon cancer cell lines increased after IFN--y exposure and returned to baseline 4-S days after the treatment was stopped. The up-regulation was associated with an antiproliferative effect in cells showing maximal antigen expression ( 12). In human testing, pretreatment with IFN-’y resulted in an increased uptake of the melanoma antibody B96.5 (1 3), the expression of both TAG-72 and CEA on tumor cells isolated from patients with ovarian cancer and malignant ascites (14), and the expression ofTAG-72 in plasma (15). On the basis of these observations, we designed a trial in which IFN-’y was administered for a period of 7 days prior to treatment with 1I-CC49 in patients with progressive androgenindependent prostate cancer. In doing so, we sought to determine the safety and efficacy of the combination, to assess tumor localization and the delivered radiation dose to tumor, and to study the effect of IFN-y on TAG-72 expression on human prostate cancers in vitro and in vivo. PATIENTS AND METHODS Patient Eligibility Patients with progressive androgen-independent prostate cancer were considered. Entry required histological confirmation of disease, a KPS of >60%, a WBC count of >3500 cells/mm3, an absolute neutrophil count of > 1500 cells/mm3, platelets at > 100,000 cells/mm3, and normal coagulation parameters (prothrombin time and partial thromboplastin time). Additional requirements included a testosterone bevel of <30 ng/ml and adequate renal (creatinine of <2.0 mg/dl or creatinine clearance of >40 mL/min) and hepatic (bilirubin of <2.0 mg/dl and aspartate aminotransferase of <3 times the upper limit of normal) reserve. Patients must have recovered from the toxicity of any prior therapy and not received chemotherapy or radiation for at least 4 weeks prior to entry. No prior therapy with a murine MoAb was permitted. Due to the potential risk of thrombocytopenia, anticoagulants were omitted, and patients were advised to avoid aspirin and nonsteroidab anti-inflammatory drugs. Additional requirements included the documentation of progression of disease by at beast one of the following criteria: (a) an increase in PSA of more than 50% from baseline on three successive occasions, (b) new metastatic lesions on bone scan, or (c) a >25% increase in a bidimensionally measurable tumor mass. Those patients who had not undergone a surgical orchiectomy were maintained on a gonadotropin-releasing hormone agonist, whereas those concurrently taking flutamide were required to show progression of disease off of this medication before entry. Written informed consent was also required. The pretreatment evaluation included a complete history and physical examination with a baseline KPS. Laboratory studies included an automated blood cell and platelet count, serum electrolytes, screening profile (alkaline phosphatase, lactate dehydrogenase, aspartate transglutaminase, blood urea nitrogen, creatinine, calcium, phosphorus, uric acid, total protein, albumin, total bilirubin, and glucose), PSA (Tandem-E; Hybritech, San Diego, CA; upper limit of normal range, 4.0 ng/mb), acid phosphatase, CEA, testosterone, triiodothyronine uptake, 14, and thyrotropin. Prestudy TAG-72 antigen and HAMA levels were also performed. Because HAMA may interfere with PSA measurements, the serum for PSA was batched at the time of measurement, and 10 p.1 of 10 jig/mi of CC49 were added to the assay to offset any false elevations of the tumor marker by the mouse antibody. A urinalysis and urine culture were likewise tested. Imaging studies included a radionuclide bone scan and either an abdominal and pelvic CI scan or magnetic resonance imaging. A baseline electrocardiogram was also performed. To assess the effect on IFN, on TAG-72 expression in vivo and on hematopoietic precursors, selected patients were asked to undergo a preand post-IFN--y bone marrow aspirate and biopsy. Treatment Plan IFN-y. IFN--y was administered at a dose of 0.017 mg/m2 s.c. daily for 7 days prior to administration of ‘31I-CC49 MoAb. Radiolabeling of CC49 MoAb. Twenty mg of MoAb CC49 were radiobabeled with ‘ “I to achieve a final administered activity of 75 mCi/m2 per patient. lodination was carried out by the iodogen method, as outlined in the Investigational New Drug application, on the day of infusion and stored in 1 % human serum albumin. For treatment, the labeled antibody dose was diluted in 100 ml of 5% human serum albumin. ‘311-CC49 Administration. Two days prior to MoAb administration (day 6), the patient’s thyroid was blocked with 10 drops of oral supersaturated potassium iodide. This was continued for 14 days. On the day of antibody treatment (day 8), patients were admitted to hospital and given a 0.5-mg test dose of unlabeled CC49 by an iv. bolus, followed by a 30-mn observation period. If the test dose was tolerated without signs of an immediate hypersensitivity reaction, the full 75 mCi/m2 1 3 ‘I-CC49 dose was then administered iv. over 60 mm. Folbowing the infusion, patients were maintained in isolation until Research. on June 3, 2017. © 1998 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Clinical Cancer Research 645 the surface radiation levels were 50% or >80%) of decline required a minimum of three measurements, taken at a minimum of monthly intervals. The duration of the decline was measured from the start of therapy to the date of the first rise, which was confirmed by a subsequent value (16). Measurable Disease. Standard Phase II response criteria were used (17). Radionuclide Bone Scan. Posttherapy bone scans were classified as showing improvement, stability, or progression relative to the baseline scan on the basis of a visual inspection (18) by a blinded independent reviewer (S. M. L.). Progression required the appearance of new lesions. The initial bone scan was also evaluated using a semiquantitative technique, the BSI (19). This method evaluates the involvement of individual bones by a visual estimation of the fraction of each bone that is abnormal on the scan. A total of 125 individual bones, based on a reference man bone weights, are used (20). The BSI is the percentage involvement of total bone by tumor. Tumor Localization All patients underwent anterior and posterior whole-body scans using conjugate view methodology with whole-body imaging, using a dual-headed ADAC Genesys gamma camera prior to discharge. These were repeated on day 8 or 15 postinjection. SPECT imaging of areas deemed to have disease by bone scan, CT, or magnetic resonance imaging were performed at the late imaging times. Radionuclide antibody scans were interpreted as positive if there were focal, persistent areas of increased tracer concentration that did not correspond to known areas of blood poo1 activity. Nodal areas of increased radiotracer concentration were interpreted as positive only if the uptake was intense and persistent (see Table 3). The delivered dose to tumor was estimated from the SPECT images after correction for tumor volumes and are reported separately (2 1 ). The ‘ ‘ I scan appearance was graded on a semiquantitative scale from 0 to 4, as follows: 0, absence of uptake in sites that were positive using conventional imaging; 1 +, antibody uptake at most of the known sites but at fewer sites than were apparent on conventional imaging; 2+, mismatch in which some areas that were positive with conventional imaging were not visualized by the antibody and vice versa; 3 + , match between the conventional and antibody images; and 4+, more sites were positive with the antibody than with conventional imaging modalities.