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Antibody Delivery and Effector Cell Activation in a Phase II Trial Of [CANCER RESEARCH 48, 2568-2573, May 1, 1988] Antibody Delivery and Effector Cell Activation in a Phase II Trial of Recombinant 7-Interferon and the Murine Monoclonal Antibody CO 17-1A in Advanced Colorectal Carcinoma1 Louis M. Weiner,2 Philip J. Moldofsky, Robert A. Gatenby, Joyce O'Dwyer, Jacqueline O'Brien, Samuel Litwin, and Robert L. Comis Departments of Medical Oncology [L. M. W., J. O. D., J. O. B., R. L. C.J, Radiology (P. J. M., R. A. GJ, and Biostatistics [S. L.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 ABSTRACT when labeled with n'I, can concentrate in colorectal carcinoma lesions in these nude mice and in many patients (8, 9). Murine monoclonal antibodies of the immunoglobulin G2a isotype These characteristics formed the basis for a series of clinical interact with human effector cells to mediate antibody-dependent cellular trials, initiated in 1980, using this antibody. Hundreds of pa cytotoxicity (ADCC) directed against malignant cells which express antigens recognized by these antibodies. f-Interferon enhances these tients have been treated worldwide; while occasional objective effects in vitro. In a Phase I trial of murine monoclonal antibody CO17- clinical responses have been reported in patients with metastatic 1A and recombinant -y-interferon (r!FN--y), we demonstrated that low colorectal or pancreatic carcinomas, no consistent patterns of doses of rIFN-7 were superior to high doses in augmenting ADCC response have been identified (10-17). These results have fo mediated by treated patients' monocytes. These results formed the basis cused our attention on the obstacles to success of this therapy, for a Phase II trial of CO17-1A combined with low dose rlFN-f. Nineteen with emphasis upon evaluating therapeutic antibody delivery patients with metastatic colorectal carcinoma were treated with four and potentiating the cellular effector mechanisms mediated by consecutive daily infusions of 1.0 x 1(1"II /nr rIFN-T, with 150 mg of this antibody. CO17-1A administered on days 2, 3, and 4. Therapy was tolerated well. rIFN-7 enhances CO17-lA-directed ADCC mediated by hu Peripheral blood mononuclear cells were purified from patient samples man monocytes against the SW1116 colorectal carcinoma cell obtained at baseline and at 1, 4, or 24 h following the start of the first rIFN-7 infusion and were tested for their ability to lyse '"In-labeled cells line (5, 18). These results led to a Phase I clinical trial of combined therapy with rIFN-7 and CO17-1A in patients with of the SW1116 colorectal line. Enhancement of monocyte ADCC was seen by 24 h, while lymphocyte ADCC and natural killer activity directed advanced gastrointestinal carcinoma. In this study, it was de against K562 cells were enhanced to a lesser extent. Nonspecific lysis of termined that peripheral blood monocytes from patients treated SVVII16 cells by effectors was not seen at the time points examined. with low doses of this cytokine (<1.0 x IO6 IU/m2/day for 4 While CO17-1A antigen expression was observed in most biopsies, ' "I- consecutive days) augmented ADCC directed against SW1116 labeled CO17-1A imaged positively in less than one-half of the organs cells significantly more than monocytes from patients treated known to harbor métastases,and therapeutic antibody delivery was not with higher doses (19). High dose interferon therapy caused always demonstrated by immunoperoxidase staining techniques of tissue more nonspecific monocyte cytotoxicity than low dose therapy, obtained following therapy. In antigen-positive lesions, tissue p<>.•levels thus partially offsetting this ADCC advantage (20). However, appear to identify lesions which would image positively. No objective the enhanced target cell specificity and minimal toxicity seen responses were seen. Our findings suggest that prolonged therapy with low doses of rIFN--x potentiates ADCC but that physiological obstacles with low dose therapy formed the rationale for the current to therapeutic antibody delivery are significant. In order to evaluate the clinical study, a Phase II trial of low dose rIFN-7 therapy validity of this therapeutic approach, measures to enhance antibody administered with CO 17-1A in patients with advanced colorec delivery are needed, starting with systematic evaluations of therapy with tal carcinoma. escalating doses of CO17-1A combined with low dose rIFN--x therapy. In addition to efficacy, we studied the effects of rIFN--y on the cellular effector mechanisms of monocyte and lymphocyte ADCC and lymphocyte NK activity. We also examined the INTRODUCTION relationship of antigen expression to labeled antibody imaging, The murine monoclonal antibody CO 17-1A binds to a cell tumor oxygen tension, and therapeutic antibody delivery. surface glycoprotein expressed preferentially by adenocarcino- mas of the gastrointestinal tract (1-3). This antibody, which is MATERIALS AND METHODS of the IgG2a isotype, does not fix complement but participates in ADCC3 mediated by human monocytes and lymphocytes Patients. Nineteen patients with histologically documented met directed against carcinoma cells which express the target anti astatic colorectal carcinoma were treated. All patients had measurable gen (4-6). Injection of the antibody into nude mice bearing disease and Eastern Cooperative Oncology Group performance status appropriate human tumor xenografts induces significant of 0 (n = 14) or 1 (n = 5). Five had received no prior systemic therapy, growth delays of the grafts and under selected conditions may while 14 had been treated with one regimen, but not for at least 4 cure the animals (7). The antibody or its F(ab')2 fragments, weeks. The biperpendicular products of all measurable lesions in each patient were added to yield an estimate of relative tumor burden; the values ranged from 2.2 to 181.3 cm2 with the median sum of these Received 6/9/87; revised 1/14/88; accepted 2/3/88. The costs of publication of this article were defrayed in part by the payment products being 66.6 cm2 in the 19 patients. Pertinent features are of page charges. This article must therefore be hereby marked advertisement in described in Table 1. accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ' This study was supported by funds from the Frank Strick Foundation. Treatment. Patients were hospitalized for treatment. Recombinant 2 Recipient of a National Cancer Institute Clinical Investigator Award. To 7-interferon (Biogen, Cambridge, MA), 1.0 x IO6 IU/m2, was admin whom requests for reprints should be addressed, at Department of Medical istered by a 4-h i.v. infusion daily for 4 consecutive days. The murine Oncology, Fox Chase Cancer Center, Central and Shelmire Avenues, Philadel monoclonal antibody CO 17-1A (Centocor, Malvern, PA) was admin phia, PA 19111. 3The abbreviations used are: ADCC, antibody-dependent cellular cytotoxicity; istered at a dose of ISO mg over 2 h at the conclusion of each interferon rIFN-f, recombinant -y-interferon; NK, natural killer cell; CT, computer-assisted infusion on days 2, 3, and 4 (cumulative dose, 450 mg). One 4-day tomography. course of therapy was given to each patient. 2568 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1988 American Association for Cancer Research. PHASE II TRIAL OF rIFN-, AND MONOCLONAL ANTIBODY 17-IA Table 1 Patient characteristics of all In perpendicular products of all Patient measurable le code28293031323334353637383940414243444546Age(yr)44394963583650645753645753446057444956SexMFMMFFMMMFFMFFMFMFFECOGP.S."000001000111000000!PriortherapyNoneNoneXRTIL-2métastasesLungsLiverLiver(L)of sions(cm2)2.21877.019.962.572.0*181.34.066.640.761.4104.829.27.049.2135.284.6140.4105.6 IFN-05-FUraXRT5-FUraXRT5-FUraNone5-FUraNone5-FUra5-FUraTMX+ Supraclavicu-lar and (L) axil nodesLiverPeripancreaticnodesLungs,lary (L)supraclavicularnodesLiverLiverLiverPeriaorticliver, nodesLiver, abdominalwall, supra-clavicular(L) node(R) LungLungs, 5FUraNoneNoneFdUrd+ liverLiverLiver, nodesPeripancreaticnodesLiver,celiac +MMC5-FUra +MMCNoneIL-2 nodesLiverLiverLungsLiverSumpelvic IFN-0TMX+ 5-FUraXRTIL-2+ IFN-0TMX+ 5-FUraSites+ * XRT, radiation therapy; IL-2, recombinant interleukin 2; IFN-/J, recombinant (i-interferon; 5-FUra, 5-fluorouracil; TMX, trimetrexate; FdUrd, floxuridine; MMC, miteirmein C; ECOG P.S., performance status criteria of the Eastern Cooperative Oncology Group; L, left; R. right. * Multiple small pulmonary métastasesnot included in this sum. Monitoring Studies. Whole blood (100 ml) was drawn from all The midsection of a tumor and all sites of measurements were localized patients at the start of therapy and at two or three other time points with CT scanning using 8-mm sections. The sensing electrode is nega during the first and second days of the treatment course. Normal control tively polarized (—0.75V) with a reference electrode which is placed samples were obtained for each day of assay. Five ml of plasma were just under the skin near the area of interest to allow electrical continuity obtained at baseline, 30 min, 1 h, 2 h, and 4 h following the start of with the sensing electrode. the first interferon infusions and at the beginning and end of the The sensing electrode is then inserted into the tumor, using CT interferon infusions of the subsequent day. Daily complete blood counts guidance for approximately 5 min to form a "tissue membrane" over and blood chemistries were performed, as were baseline electrocardi the platinum wire. Current readings are obtained by passing the elec ographs, and chest X-rays. Tumor measurements were obtained by trode through the tumor at approximately 5-mm increments. To pre physical examination, X-rays, or CT scans and were obtained monthly vent artifact from tissue damage, measurements are taken only when until there was evidence of progressive disease. the needle is being inserted and never while being withdrawn. Because Immunohistochemistry. Fine needle aspirations of accessible tumor the electrode motion creates artifact, the probe remains in position at deposits were performed in a number of patients and sent for cytological each site until the current output is stable (this rarely requires more evaluation; all demonstrated adenocarcinoma.
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