Blocking interleukin-6 activity with chimeric anti-IL6 monoclonal antibodies in multiple myeloma: effects on soluble IL6 receptor and soluble gp130

Interleukin-6 (IL6) plays a major role in the pathogenesis of multiple myeloma. In patients with monoclonal gammopathy serum levels of sIL6R have been found to be increased. The role of IL6 in the regulation of soluble receptors is still unclear. In a phase I/II study we treated 12 myeloma patients with high-affinity chimeric anti-IL6 monoclonal antibodies. This treatment resulted in a total in vivo blockage of IL6 activity and as a result we had an unique opportunity to gain insight into the possible regulation effects of IL6 on these soluble IL6 receptors. Pre-treatment sIL6R levels were elevated in 9 of the 12 patients; pre-treatment sgp130 levels were significantly increased in all patients. Total blockage of IL6 activity by the high-affinity cMab did not influence sIL6R in 10 of these 12 patients and sgp130 levels remained stable in all patients. Of the 2 patients whose sIL6R levels increased during therapy, one had progressive disease and the other developed an acute infection. We conclude that in most end-stage myeloma patients sIL6R and sgp130 serum levels are elevated, but that there is no relation between IL6 activity and sIL6R or sgp130 levels.     

A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas

OBJECTIVE: Epidermal growth factor receptor (EGFR) is an operationally specific antigen in malignant gliomas; it is overexpressed in > 60% of these tumors, whereas its expression is very low in normal brain. This study aimed to evaluate whether an adequate amount of an anti-EGFR monoclonal antibody (MAb) could reach a tumor after a single intravenous administration. METHODS: This study was open, nonrandomized, and uncontrolled. Single doses (20, 40, 100, 200, or 400 mg) of the murine MAb EMD55900 (MAb 425) were administered intravenously before surgery to 30 patients with malignant brain tumors. Serum samples were taken at defined time intervals during infusion, to determine EMD55900 concentrations, and 10, 21, and/or 42 days after infusion, to evaluate the development of human anti-mouse antibodies. Tumor samples were investigated for EGFR and EMD55900 contents. RESULTS: Tolerance to EMD55900 was good. Increased liver transaminase levels were noted for three patients with Grade 1 toxicity. Twenty patients developed significant human anti-mouse antibody titers, without correlation with the administered dose. The median half-life of EMD55900 in serum ranged from 6 hours for 20 mg to 24 hours for 400 mg. In the membrane fractions of the tumors, EGFR saturation by EMD55900 varied with the injected dose of MAb. No binding was detected after a 20-mg dose. After doses of 40, 100, 200, and 400 mg, the mean saturation levels were 33, 73, 89, and 71%, respectively. CONCLUSION: This study indicates that a single intravenous administration of EMD55900 is well tolerated and produces substantial in vivo tumor binding with doses > 100 mg.     

Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study

PURPOSE: Standard therapy for multiple myeloma consists of cytotoxic chemotherapy plus glucocorticoids. Interferon (IFN) alfa maintenance is reported to prolong chemotherapy-induced remissions and survival. This study evaluates induction chemotherapy, glucocorticoids, and interferon maintenance in myeloma. PATIENTS AND METHODS: Five hundred twenty-two previously untreated myeloma patients were randomized to three chemotherapy regimens with differing glucocorticoid intensities. Patients who achieved remission were randomized to receive IFN or observation until relapse. Patients who failed to respond to chemotherapy received IFN alfa plus dexamethasone (DEX). RESULTS: Five hundred nine patients were eligible for induction chemotherapy. Chemotherapy with higher dose-intensity glucocorticoids yielded higher response rates and improved survival (P = .02 for the three-group comparison; P < .05 for each higher glucocorticoid arm v vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine [BCNU], doxorubicin, and prednisone [VMCP/VBAP]). One hundred ninety-three patients who achieved remission were randomized to receive IFN alfa 3 MU three times weekly or observation. IFN was not superior to observation for relapse-free (P = .95) or overall survival (P = .39) from start of maintenance. Eighty-eight induction failures received 5 MU of IFN three times weekly plus DEX. Patients who received IFN/DEX had a median survival duration of 48 months from start of IFN/DEX. CONCLUSION: Higher-dose glucocorticoids increases frequency of response to chemotherapy and prolong survival in myeloma. IFN maintenance with the dose schedule used in this trial did not prolong relapse-free or overall survival. We cannot exclude a small effect of IFN, as most individual trials do not have sufficient statistical power. Meta-analysis of randomized trials evaluating IFN maintenance in myeloma might be of value. While IFN appeared ineffective, addition of higher-dose glucocorticoids improved outcome in myeloma.     

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.     

Dosimetry of rhenium-186-labeled monoclonal antibodies: methods, prediction from technetium-99m-labeled antibodies and results of phase I trials

Rhenium-186 is a beta-emitting radionuclide that has been studied for applications in radioimmunotherapy. Its 137 keV gamma photon is ideal for imaging the biodistribution of the immunoconjugates and for obtaining gamma camera data for estimation of dosimetry. Methods used for determining radiation absorbed dose are described. We have estimated absorbed dose to normal organs and tumors following administration of two different 186Re-labeled immunoconjugates, intact NR-LU-10 antibody and the F(ab')2 fragment of NR-CO-02. Tumor dose estimates in 46 patients varied over a wide range, 0.4-18.6 rads/mCi, but were similar in both studies. Accuracy of activity estimates in superficial tumors was confirmed by biopsy. Prediction of 186Re dosimetry from a prior 99mTc imaging study using a tracer dose of antibody was attempted in the NR-CO-02 (Fab')2 study. Although 99mTc was an accurate predictor of tumor localization and the mean predicted and observed radiation absorbed doses to normal organs compared favorably, 186Re dosimetry could not be reliably predicted in individual patients. The methods described nevertheless provide adequate estimates of 186Re dosimetry to tumor and normal organs.     

Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.     

The role of interferon-alpha in the treatment of multiple myeloma

Interferon-alpha (IFN-alpha) is an active therapeutic agent in multiple myeloma. IFN-alpha alone may induce complete or partial responses in approximately 20% of previously untreated patients. However, it remains less effective than conventional chemotherapy. Recently, it proved to be beneficial in some but not all studies, in combination with conventional chemotherapy, to improve the overall response rate and prolong the plateau phase in patients in remission. The Hanshin Hematological Neoplasia Study Group developed a regimen consisting of DMVM (dexamethasone, MCNU, VCR, melphalan) with IFN-alpha. This regimen yields an 69% response rate, including 26% complete remissions defined by disappearance of M-protein and morphological normalization of the bone marrow. The most effective strategy of administration has yet to be established.     

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.     

Liposomal daunorubicin in advanced Kaposi's sarcoma: a phase II study

We report a non-randomized Phase II clinical trial to assess the efficacy and safety of liposomal daunorubicin (DaunoXome) in the treatment of AIDS related Kaposi's sarcoma. Eleven homosexual men with advanced Kaposi's sarcoma were entered in the trial. Changes in size, colour and associated oedema of selected 'target' lesions were measured. Clinical, biochemical and haematological toxicities were assessed. Ten subjects were evaluated. A partial response was achieved in four, of whom two subsequently relapsed. Stabilization of Kaposi's sarcoma occurred in the remaining six, maintained until the end of the trial period in four. The drug was generally well tolerated, with few mild symptoms of toxicity. The main problem encountered was haematological toxicity, with three subjects experiencing severe neutropenia (neutrophil count < 0.5 x 10(9)/l). There was no evidence of cardiotoxicity. In this small patient sample, liposomal daunorubicin was an effective and well tolerated agent in the treatment of Kaposi's sarcoma.     

A phase I study of paclitaxel and 5-fluorouracil in advanced gastric cancer

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of paclitaxel and 5-Fluorouracil (5-FU) in advanced gastric cancer patients. The patients, refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin), received weekly 5-FU at the fixed dose of 500 mg/m2, and escalating doses of paclitaxel every 3 weeks with a starting dose of 150 mg/m2 given as in 3-h infusion. The dose was escalated by 25 mg/m2 every 3 patients. Fifteen patients entered the study. The upper paclitaxel dose (225 mg/m2) was given to 6 patients. Up to this dose, no severe toxicity (grade 3-4) was recorded. Apart from alopecia, grade 1-2 leukopenia occurred in 5 patients and grade 1-2 neurotoxicity in 2 patients. All patients were evaluable for response (at least 2 cycles): 2 patients achieved an objective response (200 and 225 mg/m2). In 6 patients, treatment resulted in notable relief from symptoms. Out-patient paclitaxel given over 3 h and 5-FU may be combined safely for the treatment of patients with advanced gastric cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and 5-FU 500 mg/m2.     

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group

PURPOSE: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS: Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.     

High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.     

Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer

PURPOSE: To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression. PATIENTS AND METHODS: Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery. RESULTS: Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels. CONCLUSION: PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.     

Detection by a solid phase independent enzyme immunoassay of monoclonal anti-idiotypic antibodies against monoclonal antibodies neutralizing Semliki Forest virus and encephalomyocarditis virus

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) is the rate limiting step in the mevalonate pathway that produces isoprenoids and cholesterol. Inhibitors of HMG-CoA reductase are teratogenic in vivo and induce neural tube defects in rat embryo culture, effects which appear unrelated to cholesterol deficiency. This study is the first to localize HMG-CoA reductase mRNA by in situ hybridization (ISH). Expression of reductase mRNA was examined in post-implantation rat embryos, and for control purposes in rat liver and UT-1 cells, using a digoxigenin-11 (dig-11) labelled cRNA probe. Eighteen-day fetal liver showed heavy but patchy hybridization, and adult rat liver showed strong hybridization only on some periportal hepatocytes, which was absent in livers of fasted animals. UT-1 cells stimulated to overexpress HMG-CoA reductase mRNA were strongly positive with the same probe. Control hybridizations with sense strand RNA probe, or with cRNA probe on pre-RNased tissue were negative. Strong hybridization signal for HMG-CoA reductase mRNA was observed in all tissues of the post-implantation rat embryo, from egg cylinder to 30 somite stages (7 to 12 days). Heavy signal was noted in primitive ectoderm and neural tube. The wide embryonic and extraembryonic distribution and abundance of HMG-CoA reductase mRNA may reflect developmental requirements for products of the mevalonate pathway, e.g., isoprenoids for post-translational farnesylation of p21ras.     

Observations following Corynebacterium parvum administration to patients with advanced malignancy. a phase I study

There has been increasing interest regarding the use of Corynebacterium parvum (CP) with other modalities in the management of primary cancer. Due to the paucity of specific information available relative to CP toxicity, a Phase I study was carried out in patients with advanced disease. The purpose of the investigation was not to evaluate the effect of CP on tumor growth. from 273 injections of CP in 40 patients it was observed that following intravenous (i.v.) infusion of CP: a) a febrile response and chills of considerable severity occured in almost all patients and did not appreciably diminish in intensity following repetitive administrations; b) nausea, vomiting, headache, and confusion were not infrequent; c) a "flu-like" syndrome lasting 24 to 48 hours occurred following almost all courses of CP; d) blood pressure elevations occurred on occasion and were related to the severity of other-side-effects; hyper- or hypo- tension was not a problem; e) ther were no anaphalactic reactions. Pretreatment with a single administration of 100 mg of hydrocortisone prior to CP infusion markedly and in some instances dramatically diminished the toxicity and made acceptable the use of i.v. CP on an outpatient basis. The use of i.v. CP in patients with cerebral metasteses may be hazardous. Subcutaneously administered CP resulted in a significant number of undesirable local reactions. Evaluation of delayed cutaneous hypersensitivity response, immunoglobulins, complement, and E- and EAC-rosette-forming cells during CP administration failed to demonstrate significant change from injection values. Results were similar whether hydrocortisone pretreatment was or was not employed. From the standpoint of toxicity it now seems appropriate to use i.v. CP, particularly following pretreatment with hydrocortisone, in a controlled clinical trial to evaluate its therapeutic effectiveness in the management of primary cancer.     

The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study

Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with malignant mesothelioma, a new mode of treatment is desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-tk). By virtue of their expression of HSV-tk, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.     

Immunotherapy of multiple myeloma with a monoclonal antibody directed against a plasma cell-specific antigen, HM1.24

Multiple myeloma remains an incurable malignancy because of marked resistance of tumor cells to conventional chemotherapeutic agents. Alternative strategies are needed to solve these problems. To develop a new strategy, we have generated a monoclonal antibody (MoAb), which detects a human plasma cell-specific antigen, HM1.24. In this report, we evaluated the in vivo antitumor effect of unconjugated anti-HM1.24 MoAb on human myeloma xenografts implanted into severe combined immunodeficiency (SCID) mice. Two models of disseminated or localized tumors were established in SCID mice by either intravenous or subcutaneous injection of human myeloma cell lines, ARH-77 and RPMI 8226. When mice were treated with a single intraperitoneal injection of anti-HM1.24 MoAb 1 day after tumor inoculation, the development of disseminated myeloma was completely inhibited. In mice bearing advanced tumors, multiple injections of anti-HM1.24 MoAb reduced the tumor size and significantly prolonged survival, including tumor cure, in a dose-dependent manner. The proliferation of cultured human myeloma cells was inhibited in vitro by anti-HM1.24 IgG-mediated complement-dependent cytotoxicity, but not by the antibody alone. Moreover, spleen cells from SCID mice mediated antibody-dependent cell cytotoxicity against RPMI 8226 cells. These results indicate that anti-HM1.24 MoAb can be used for immunotherapy of multiple myeloma and related plasma cell dyscrasias.     

Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma

CC49, a murine monoclonal antibody that recognizes the tumor-associated glycoprotein 72, was conjugated to the chemical chelate 1,4,7,10-tetraaza-1-(1-carboxy-3-(4-aminophenyl) propyl)-tris-4,7,10- ((carboxy)methyl)cyclododecane that had been labeled with a beta emitter, Lu. Preclinical studies had shown that Lu-labeled CC49 caused regression of human colon adenocarcinoma xenografts in nude mice. Patients with advanced adenocarcinoma who had failed standard treatment and whose tumors expressed the tumor-associated glycoprotein 72 antigen were eligible for treatment to determine the maximum tolerated dose of Lu-labeled CC49. The starting dose of Lu was 10 mCi/m2 given i.v. with the dose of CC49 held constant at 20 mg. Pharmacokinetic sampling and immunoscintigraphy were performed over the ensuing 3 weeks. The dose of radioactive Lu was escalated by 15 mCi/m2 for each successive dose level. Unexpected bone marrow toxicity developed in patients treated at the second dose level with 25 mCi/m2 Lu; two patients developed grade 4 thrombocytopenia, while the third patient developed grade 3 thrombocytopenia. Pharmacokinetic studies showed that the plasma half-life of the immunoconjugate was 67 h; whole-body retention, however, was prolonged with a biological half-life of 258 h. Serial gamma camera imaging localized known tumor in all patients, and also demonstrated prolonged Lu retention in the reticuloendothelial system (RES). Bone marrow dosimetry estimates ranged from 4 to 5 REMS/mCi Lu based on imaging and biopsy data. Analysis of bone marrow biopsies demonstrated that most of the Lu was localized in the cellular compartment and not in the bone. No antitumor responses were observed. Intravenous administration of 15 mCi/m2 Lu-labeled CC49 to previously treated advanced cancer patients was associated with acceptable hematological toxicity and was the maximum tolerated dose. However, prolonged retention of Lu in the RES, including the bone marrow, was observed and limited the dose of Lu that could be given. Additional studies are indicated to reduce RES uptake and retention of this immunoconjugate.