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Clinical Cancer Research Vol. 6, 3855-3863, October 2000
© 2000 American Association for Cancer Research

Clinical Trials

A Phase I Radioimmunotherapy Trial Evaluating 90Yttrium-labeled Anti-Carcinoembryonic Antigen (CEA) Chimeric T84.66 in Patients with Metastatic CEA-producing Malignancies1

Jeffrey Y. C. Wong2, David Z. Chu, Dave M. Yamauchi, Lawrence E. Williams, An Liu, Sharon Wilczynski, Anna M. Wu, John E. Shively, James H. Doroshow and Andrew A. Raubitschek

Divisions of Radiation Oncology and Radiation Research [J. Y. C. W., A. A. R.], Radioimmunotherapy [A. A. R., J. Y. C. W., A. L.], Radiology [L. E. W., D. Y.], Surgery [D. Z. C.], Medical Oncology [J. H. D.], Pathology [S. W.], Molecular Biology [A. M. W.], and Immunology [J. E. S.], Beckman Research Institute and City of Hope National Medical Center, Duarte, California 91010


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chimeric T84.66 (cT84.66) is a genetically engineered human/murine chimeric IgG1 with high affinity and specificity to carcinoembryonic antigen (CEA). The purpose of this Phase I dose escalation therapy trial was to evaluate the toxicities, biodistribution, pharmacokinetics, tumor targeting, immunogenicity, and organ and tumor absorbed dose estimates of cT84.66 labeled with 90Y. Patients with metastatic CEA-producing malignancies were first administered 5 mCi 111In-labeled DTPA-cT84.66 (5 mg), followed by administration of the therapy dose of 90Y-labeled DTPA-cT84.66 1 week later. The therapy infusion was immediately followed by a 72-h administration of DTPA at 250 mg/m2/24 h. Dose levels of administered activity ranged from 5 to 22 mCi/m2 with three to six patients per level. Serial nuclear scans, blood samples, and 24-h urine collections were performed out to 5 days after infusion. Human antichimeric antibody response was assayed out to 6 months. Patients were administered up to 3 cycles of therapy every 6 weeks. Radiation absorbed doses to organs were estimated using a five compartment model and MIRDOSE3. Twenty-two patients received at least one cycle of therapy, with one individual receiving two cycles and two receiving three cycles of therapy. All were heavily pretreated and had progressive disease prior to entry in this trial. Reversible leukopenia and thrombocytopenia were the primary dose-limiting toxicities observed. Maximum tolerated dose was reached at 22 mCi/m2. In general, patients with liver metastases demonstrated more rapid blood clearance of the antibody. Thirteen patients developed an immune response to the antibody. Average radiation doses to marrow, liver, and whole body were 2.6, 29, and 1.9 cGy/mCi 90Y, respectively. Dose estimates to tumor ranged from 66 to 1670 cGy (8.7 to 52.2 cGy/mCi 90Y) for each cycle of therapy delivered. Although no major responses were observed, three patients demonstrated stable disease of 12–28 weeks duration and two demonstrated a mixed response. In addition, a 41–100% reduction in tumor size was observed with five tumor lesions. 90Y-labeled cT84.66 was well tolerated, with reversible thrombocytopenia and leukopenia being dose limiting. Patients with extensive hepatic involvement by tumor demonstrated unfavorable biodistribution for therapy with rapid blood clearance and poor tumor targeting. Average tumor doses when compared with red marrow doses indicated a favorable therapeutic ratio. Stable disease and mixed responses were observed in this heavily pretreated population with progressive disease. This trial represents an important step toward further improving the therapeutic potential of this agent through refinements in the characteristics of the antibody and the treatment strategies used. Future trials will focus on the use of peripheral stem cell support to allow for higher administered activities and the use of combined modality strategies with radiation-enhancing chemotherapy drugs. Further efforts to reduce immunogenicity through humanization of the antibody are also planned. Finally, novel engineered, lower molecular weight, faster clearing constructs derived from cT84.66 continue to be evaluated in preclinical models as potential agents for radioimmunotherapy.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Systemic targeted delivery of radiation therapy using monoclonal antibodies directed against tumor-associated antigens continues to be actively investigated (1, 2, 3, 4, 5, 6, 7, 8) . Several groups have evaluated antibodies directed against CEA3 as agents for radioimmunoimaging (9, 10, 11, 12, 13, 14) and radioimmunotherapy (15) . CEA provides an attractive tumor antigen target, because it is expressed by a wide variety of tumor types, particularly adenocarcinomas of the gastrointestinal tract, lung, and breast (16, 17, 18, 19, 20, 21) . Radioimmunoimaging trials have demonstrated tumor targeting and imaging of tumors using anti-CEA antibodies radiolabeled with 131I or 111In. At this institution, Beatty et al. (22) demonstrated imaging of 69% of primary colorectal carcinomas using an 111In-labeled, high-affinity, anti-CEA murine monoclonal antibody, murine T84.66 (mT84.66).

Murine antibodies have the disadvantage of being recognized as foreign by the patient’s immune system, which can lead to the formation of HAMAs in 30–50% of patients (23, 24, 25, 26) . The formation of HAMA can hasten blood clearance and therefore compromise the imaging or therapeutic efficacy of subsequently administered antibody (25 , 27) . Investigators have recently evaluated human/mouse chimeric and humanized antibodies, which have demonstrated decreased immunogenicity (28, 29, 30, 31, 32) . cT84.66 is a human/murine chimeric IgG1 monoclonal antibody developed at the City of Hope with high affinity (KA = 1.16 x 1011 M-1) and specificity to CEA (33) . cT84.66 was initially evaluated at this institution, conjugated to isothiocyanatobenzyl DTPA, and radiolabeled with 111In in a pilot biodistribution trial that entered patients with metastatic CEA-producing malignancies of various histologies (34) . 111In-labeled DTPA-cT84.66 was further evaluated in an antibody protein dose escalation trial in 15 patients with colorectal cancer (35) . Results from these two studies demonstrated targeting to CEA-producing metastatic sites, imaging sensitivity comparable with other intact anti-CEA monoclonals, no allergic reactions, decreased immunogenicity compared with murine monoclonals, and no significant changes in biodistribution or tumor localization with escalation of antibody protein doses from 5 to 105 mg. In addition, antibody uptake determined from biopsy samples demonstrated that cT84.66, if labeled with 90Y, could potentially deliver therapeutic radiation doses to tumor and regional lymph nodes in a subset of patients. On the basis of the results of these trials, a Phase I therapy trial with 90Y-labeled DTPA-cT84.66 was initiated. In the following text, we report the results of 22 patients treated in this trial.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Antibody Production and Conjugation.
Human/murine cT84.66 is an anti-CEA intact IgG1, with high affinity (KA = 1.16 x 1011 M-1) and specificity to CEA. Details of its production, characterization, purification, conjugation, and radiolabeling have been reported previously (33 , 34 , 36, 37, 38) . Briefly, for this study cT84.66 was conjugated to isothiocyanatobenzyl DTPA. Preparation of the radiolabeled dose involved incubation of 111In at a ratio of 1 mCi to 1 mg and 90Y at a ratio of 10 mCi to 1 mg, followed by size exclusion HPLC purification. All administered doses demonstrated radiolabeling >90%, endotoxin levels <1 unit/ml, and immunoreactivity >95%. The final vialed lot of purified conjugated antibody met standards set by the Food and Drug Administration. Investigational New Drug application for 111In-labeled DTPA-cT84.66 and 90Y-labeled DTPA-cT84.66 are currently on file with the Food and Drug Administration.

Clinical Trial Design.
cT84.66, radiolabeled with 111In or 90Y, was evaluated in a Phase I dose escalation radioimmunotherapy trial. The primary objective of this trial was to determine the MTD of 90Y-labeled cT84.66 when administered i.v. and to characterize the associated toxicities. Biodistribution, tumor targeting, absorbed radiation dose estimates, and clearance of the antibody were also evaluated through serial blood samples, 24-h urine collections, and nuclear scans performed at time points out to 7 days after antibody infusion.

Patients were eligible if they were 18 years of age or older and had evidence of metastatic disease that was CEA-producing and refractory to conventional therapies. Tumor CEA production was documented by either an elevated serum CEA and/or positive CEA immunohistochemistry staining of tumor biopsy specimens. All patients had to demonstrate a Karnofsky performance status of >60%, a predicted life expectancy of at least 3 months, completion of any previous therapy 4 weeks prior to antibody therapy, and adequate renal, pulmonary, and hepatic function. Patients with a history of previous antibody exposure and a positive HAMA or HACA response were excluded from the study. In addition, patients with active brain or leptomeningeal metastatic disease, previous radiotherapy to >50% of the bone marrow, or previous exposure to nitrosoureas or mitomycin C were excluded. The following studies were performed prior to antibody administration: complete blood count and platelet count, SMA-18, creatinine clearance, electrocardiogram, pulmonary function tests, urinalysis, serum HIV testing, serum pregnancy testing if indicated, plasma CEA levels, serum HACA response, chest X-ray, and computed tomography scans of relevant anatomical locations corresponding to areas of metastatic or suspected metastatic disease. If clinically indicated, bone scans or magnetic resonance imaging scans were performed to assess disease location and extent. All blood studies were done within 2 weeks and all radiological studies within 6 weeks of antibody infusion.

Each patient first received an imaging dose of 111In-labeled DTPA-cT84.66, which was radiolabeled at a ratio of 5 mCi of 111In to 5 mg of protein. Initially, a test dose of 100 µg of radiolabeled antibody was administered i.v. over 5 min. After 15 min, if there were no side effects, the remainder of the antibody was administered. Serial blood samples were taken for pharmacokinetics at 30 min and 1, 2, and 6 h and at each scan time after antibody infusion. Urine collections (24 h) were done daily for 5 consecutive days after antibody administration for pharmacokinetic analysis. Blood and urine samples were counted for 111In activity on a Packard gamma counter (Model 5530; Packard, Inc., Downers Grove, IL) with a window setting of 150–500 keV and were processed on a size exclusion HPLC Superose 6 column. Planar and whole body imaging studies were performed at 6, 24, and 48 h and 4–7 days after antibody administration using a Toshiba dual head 7200 camera with single photon emission tomography capability. In all cases, 20% energy windows were set over each of the two {gamma}-ray energies of 111In. A medium energy high resolution collimator was used throughout. Scan speed of 20 cm/min over a distance of 200 cm was used for the whole body imaging. Single photon emission computed tomography scans were performed of relevant areas at 48 h and 4–7 days after antibody administration. A bowel cathartic was administered to patients prior to each scan to reduce normal bowel uptake, unless it was felt that the patient could not tolerate such a preparation.

If at least one known tumor site imaged with 111In-labeled antibody, the therapy dose, consisting of 5 mg of cT84.66 labeled with the therapeutic amount of 90Y and 5 mCi of 111In, was administered 1 week later. An exception was made for patients with disease confined to the liver, who received the therapy dose even if activity in hepatic metastases did not exceed that of surrounding normal liver. Immediately after the therapy infusion, Ca-DTPA (Fluka Biochemika, Berlin, Germany) was administered by continuous i.v. infusion for 3 days at 250 mg/m2 /24 h. As with the pretherapy imaging dose, blood samples, 24-h urine collections, and nuclear scans were performed at serial time points after therapy infusion. Patients were followed weekly with differential blood counts, serum electrolytes, liver function studies, serum calcium, blood urea nitrogen, and serum creatinine.

Radiological studies, including computed tomography scans, were repeated at 5–6 weeks after therapy to assess tumor response. Response criteria were defined as follows: complete response, disappearance of all measurable and evaluable disease and no new lesions; partial response, >=50% decrease from baseline in the sum of the products of perpendicular diameters of all measurable lesions, with no progression of evaluable disease and development of new lesions; stable disease, does not qualify for complete response, partial response, or progression; and progressive disease, 25% increase in the sum of products of measurable lesions over the smallest sum observed, or reappearance of any lesion that had disappeared, or appearance of any new lesion/site.

For this trial, a maximum of three therapy cycles at 6-week intervals was planned for each patient. Toxicity was scored using the Southwest Oncology Group toxicity criteria. Informed written consent was obtained for each patient prior to protocol entry. This protocol had full review and approval from the Institutional Review Board.

HACA Response.
Serum HACA response to cT84.66 and cT84.66-DTPA was assayed prior to infusion and at ~2 weeks and 1, 3, and 6 months after infusion using a double capture solid phase quantitative RIA, as described previously (34) . Serum samples incubated with 111In-labeled DTPA-cT84.66 were also examined by size exclusion HPLC using two tandem Superose 6 columns to detect possible immune responses not found by RIA. Patients were felt to have an anti-id response if serum samples were positive by HPLC assay but were negative by RIA.

Pharmacokinetic Analysis and Absorbed Dose Estimates.
Blood and urine samples were counted for 111In activity on a gamma counter and were processed on a HPLC size-exclusion Superose 6 column. Samples containing both 111In and 90Y were counted sequentially in gamma and beta well counters. In the latter case, Cerenkov radiation was used, with quench correction, to determine the amount of 90Y present. Samples were homogenized in aqueous media and bleached prior to counting. Standards were used to calibrate the absolute accuracy of the counting systems.

For those organs seen in both projections, 111In activity in normal organs was estimated using parallel-opposed nuclear images to construct the geometric mean uptake as a function of time. Otherwise, single view images were acquired. All resultant curves demonstrating 111In activity versus time were corrected for background and patient attenuation. Attenuation was estimated using a separate series of experiments involving gamma camera efficiency in counting a planar 111In phantom source as a function of tissue-equivalent absorber thickness. Given the geometric mean or single-view uptake values and measured blood and urine activity, a five-compartment modeling analysis was performed to estimate residence times for 111In and 90Y activity in blood, urine, liver, and whole body. Details of this compartmental model have been published previously (39) . 90Y radiation doses to normal organs based on biodistribution of 111In-labeled cT84.66 were estimated with the MIRD method (40) using the MIRDOSE3 program (41) . As reported previously, 90Y-labeled DTPA-cT84.66 and 111In-labeled DTPA-cT84.66 biodistributions were comparable in the mouse model (42) . Red marrow radiation dose estimates were performed using the AAPM algorithm (43) based on blood residence times determined from the five-compartment model.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The primary objective of this Phase I dose escalation trial was to define the MTD and dose-limiting toxicities of 90Y-labeled DTPA-cT84.66. Data were also collected to evaluate biodistribution, pharmacokinetics, and immunogenicity of the agent. Twenty-eight patients with progressive CEA-producing malignancies of various histologies were entered into this study and were administered cT84.66. Five patients (four colorectal adenocarcinomas and one gastric adenocarcinoma) failed to demonstrate antibody targeting to tumor and did not receive therapy. An additional patient with esophageal cancer demonstrated targeting to focal sites in the brain. A subsequent magnetic resonance imaging scan confirmed brain metastases, making him ineligible for therapy. The remaining 22 patients went on to receive therapy with 90Y-labeled DTPA-cT84.66 and formed the basis for this analysis (Table 1)Citation . Fifteen were male and seven female. Eighteen patients presented with metastatic colorectal cancer, 2 with adenocarcinoma of the lung, 1 medullary thyroid cancer, and 1 pseudomyxoma peritonei. All patients were heavily pretreated, with 18 patients having received prior chemotherapy (one to four regimens) and 6 prior radiation therapy. Seventeen presented with elevated serum CEA levels ranging from 14.8 to 1027 ng/ml.


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  		Table 1 %Patient summary

 
Patients were treated at five dose levels: 5, 7.5, 12.5, 16.6, and 22 mCi/m2 administered activity per cycle (Table 2)Citation . Two of the first 3 patients entered on this trial at dose level 1 (5 mCi/m2 ) had extensive liver metastases and demonstrated unusually rapid clearance of the antibody (38) . This was consistent with an earlier biodistribution trial evaluating 111In-labeled DTPA-cT84.66, in which there was faster clearance in patients with extensive liver metastases (35) . In an attempt to evaluate a group of patients with a more uniform range of antibody clearance characteristics, the eligibility criteria were amended after these initial 3 patients to exclude patients with over one-third of the liver volume involved with tumor.


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  		Table 2 %Radiation dose estimates to marrow and liver correlated with observed toxicities for each patient

 
Total administered activity ranged from 7.5 to 42.6 mCi. Nineteen patients received one cycle, 1 patient received two cycles, and 2 patients received three cycles of therapy. An MTD of 22 mCi/m2 was reached. Dose-limiting toxicities were reversible leukopenia and/or thrombocytopenia. Two patients demonstrated a transient grade 1–2 rise in liver transaminases after one cycle at 5 mCi/m2 and after three cycles at 7.5 mCi/m2 . However, changes in liver transaminases were not observed in patients administered higher levels of activity and receiving higher radiation doses to liver. Headache and nausea resulted in two patients that immediately responded to a 50% reduction in the amount Ca-DTPA infused after therapy. Other side effects observed included fatigue in 4 patients, anemia in 3 patients, flu-like symptoms in 2 patients, and transient diarrhea and pleuritic pain in 1 patient. Finally, 1 patient developed a skin rash 24 h after antibody infusion identical to a skin rash after previous 5-FU.

A summary of estimated radiation doses to liver, marrow, and whole body is presented in Table 3Citation . Although the trial was amended to exclude patients with extensive liver metastases, a broad range of clearance rates was observed, with an inverse linear relationship (R2 = 0.79) observed between 111In residence times in liver and blood (Fig. 1)Citation . Patients with liver metastases demonstrated greater liver residence times and lower blood residence times, indicative of faster blood clearance rates. No correlation was seen between 111In blood residence times and serum CEA levels (Fig. 2)Citation .


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  		Table 3 %Organ dose estimates

 


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  		Fig. 1. 111In residence time in liver (L) versus blood. A strong linear correlation (R2 = 0.79) was observed. Patients with liver metastases demonstrated shorter residence times in blood and greater residence times in liver, indicating faster clearance of activity from blood to liver.

 


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  		Fig. 2. Serum CEA as a function of 111In residence time in blood. No correlation was seen between serum CEA and circulating time of activity in blood.

 
HACA response was assayed in 21 patients out to 1 month and 10 patients out to 6 months. Eleven patients developed a HACA response after one cycle, 1 patient after two cycles, and 1 patient after three cycles of therapy. Four of the 13 patients were felt to have an anti-id response.

Dose estimates were possible for five tumor sites and ranged from 66 to 1670 cGy (8.7–52.2 cGy/mCi 90Y) delivered for each cycle of therapy (Table 4)Citation . No objective responses were observed. However, in five patients, antitumor effects were observed. Three patients demonstrated stable disease of 12–28 weeks duration (S. A., M. M., and T. H.), with one of these patients demonstrating 54 and 68% decrease in size of two lesions (S. A.) and another patient demonstrating a 41% shrinkage of one lesion (M. M.). Two patients (A. M. and K. C.) demonstrated a mixed response after one cycle, with each having one lesion reduce in size by 44 and 100%, but developing progressive disease at other sites. In addition, 7 patients demonstrated stable disease after the first cycle but did not receive subsequent therapy because of development of HACA.


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  		Table 4 %Tumor radiation dose estimates

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Monoclonal antibodies continue to be actively investigated as vehicles to selectively deliver therapeutic doses of radiation to tumors. Antibodies to CEA are some of the most studied, because CEA is expressed by a wide variety of common malignancies, including colon, rectal, and breast carcinomas. Initial clinical radioimmunotherapy efforts evaluated intact murine monoclonal antibodies. These antibodies proved immunogenic in the majority of patients after single administration, limiting opportunities for multiple cycles (44, 45, 46, 47, 48, 49) . Recent efforts have successfully reduced immunogenicity through chimerization or humanization of the antibody (50 , 51) Antitumor effects have been comparable for the different radiolabeled anti-CEA intact and fragment constructs studied, with primarily maintenance of stable disease, mixed responses, and minor responses observed (44, 45, 46, 47, 48, 49 , 52, 53, 54) .

The majority of clinical trials have evaluated antibodies radiolabeled with 131I. 131I has potential disadvantages of in situ dehalogenation, a relatively long half-life of 8 days, and gamma emissions that contribute to normal organ radiation dose and personnel exposure. 90Y has potential advantages for radioimmunotherapy. Its half-life is shorter (2.7 days), linkage chemistry to the antibody is more stable in situ, and its pure ß emissions limit radiation dose to normal organs and personnel.

The objective of this Phase I trial was to evaluate the toxicities, immunogenicity, and antitumor effects of a high-affinity anti-CEA chimeric IgG1 anti-CEA radiolabeled with 90Y and to determine the MTD of the agent. As with other radioimmunotherapy constructs, dose-limiting toxicities with 90Y-labeled DTPA-cT84.66 were primarily hematological, in the form of transient leukopenia and thrombocytopenia (44, 45, 46, 47, 48, 49 , 52 , 55) . The MTD reached was 22 mCi/m2 . This is comparable with the MTD reached with other 90Y-labeled intact antibody constructs evaluated in a Phase I setting (56, 57, 58) .

Results presented in Table 2Citation suggest a correlation between marrow dose and observed hematological toxicity, with grade 3 and 4 changes seen with marrow doses >120 cGy. A recent study in this same group of patients (59) also demonstrated a correlation between the degree of platelet/WBC count depression and marrow dose (R2 = 0.28–0.43). An even stronger correlation was observed between marrow dose and chromosomal translocations, another biological indicator of marrow radiation effects (R2 = 0.67–0.89). Taken together, these data indicate that the methodology for marrow dosimetry used in this study is appropriate and predictive of marrow radiation effects for a given patient. Future trials should allow for individualized radioimmunotherapy treatment based on patient marrow dose estimates.

In two patients treated at 5 and 7.5 mCi/m2 , a transient rise in liver transaminases was observed. However, signs of hepatotoxicity were not observed in patients treated at higher dose levels and receiving higher radiation doses to liver. A dose-response relationship was therefore not observed. The data do suggest that hepatotoxicity may be the likely dose-limiting toxicity in marrow transplant trials using this agent. No other acute or long-term organ toxicities were observed.

As seen with other anti-CEA antibodies, antibody trafficking and tumor targeting were influenced by tumor burden (35 , 47 , 51) . In this study, the presence and extent of liver metastases were particularly important and were associated with increased blood clearance of the activity. The reason for this observed correlation is unclear. It does not appear to be related to an increase in antibody uptake by liver metastases, because liver metastases were seen on nuclear scans as photopenic lesions relative to surrounding normal liver. We hypothesize that an increase in tumor burden in liver and the associated increase in local production of CEA may have resulted in an increase of normal liver clearance and retention of serum CEA and CEA/antibody complexes. Unlike other groups (45 , 47 , 51) , no correlation between serum CEA levels and antibody biodistribution or clearance was observed (Fig. 2)Citation .

A previous report, based on data from 19 patients in this trial (60) , showed a strong concordance between 111In blood, liver, and total body residence times with the pretherapy imaging infusion versus 111In residence times with the therapy infusion. A strong correlation was also observed between blood residence times for 90Y and 111In for the therapy infusion. This supports the feasibility of using the pretherapy 111In-labeled DTPA-cT84.66 infusion to estimate biodistribution and organ doses of a subsequent therapy infusion of 90Y-labeled DTPA-cT84.66.

In this study, Ca-DTPA was administered after infusion of 90Y-labeled DTPA-cT8.46, with the purpose of capturing any 90Y activity disassociating from the antibody, thereby preventing its deposition in bone. As reported previously, Ca-DTPA infusion did appear to increase urinary excretion of 90Y activity in the form of a Mr 5,000 metabolite seen on HPLC (38) . The effect was small, however, and not sufficient enough to significantly alter organ biodistribution and blood pharmacokinetics of the therapy infusion.

Radiation dose estimates to tumor ranged from 66 to 1670 cGy (8.7–52.2 cGy/mCi 90Y) for each cycle of therapy administered, indicating a favorable therapeutic ratio when compared with marrow dose estimates (Table 4)Citation . Tumor dose estimates from this trial were comparable with those determined from tumor biopsy data on previous trials evaluating cT84.66 (35 , 61) . Stable disease and mixed responses were observed, which was encouraging, and are comparable with results reported for other radiolabeled anti-CEA constructs (44, 45, 46, 47, 48, 49 , 52, 53, 54) .

Immunogenicity was more frequent than anticipated. Earlier trials with 111In-labeled DTPA-cT84.66 observed a HACA response in only 1 of 30 patients administered a single administration (35 , 61) . In this study, 13 of 21 patients assayed developed a HACA response, with 11 developing the response after the first therapy cycle. The reasons for this are not clear but may relate to the fact that all patients received a tandem infusion of antibody at the beginning of the trial (pretherapy imaging infusion, followed by the therapy infusion 1 week later).

In conclusion, this Phase I trial reports the initial clinical evaluation of a genetically engineered, high-affinity 90Y-labeled anti-CEA construct for radioimmunotherapy. Biodistribution and tumor targeting were as predicted from previous imaging trials, and no unexpected toxicities were seen. Although no major responses were observed, the reduction in tumor size in a subset of patients and the favorable tumor dose estimates are encouraging, especially given the large tumor burden in this heavily pretreated, poor-prognosis patient population. This trial therefore represents an important step toward further improving the therapeutic potential of this agent through refinements in the characteristics of the antibody and the treatment strategies used. Future efforts will focus on further decreasing the immunogenicity of the antibody through humanization of the molecule. Novel engineered, lower molecular weight, faster clearing constructs derived from cT84.66 with improved therapeutic ratios will continue to be evaluated in preclinical models as potential agents for radioimmunotherapy. Finally, strategies will be evaluated to improve the therapeutic potential through the use of stem cell support to permit higher administered activities and through the use of combined modality strategies with radiation-enhancing chemotherapy drugs. In the stem cell supported setting, dosimetry estimates predict that hepatotoxicity will be dose-limiting and that tumor doses will approach that of tolerance doses to liver. Tumor doses in this range have been shown to be clinically important alone or in combination with radiation-enhancing chemotherapy drugs for solid tumors (62, 63, 64, 65) .


   ACKNOWLEDGMENTS
 
We thank Lupe Ettinger (protocol nurse); Gina Farino and Jennifer Rimmer (data managers); Anne-Line Anderson and Randall Woo (radiopharmacy); George Lopatin (dose estimation); and Kathleen Thomas, Ron Fomin, and Joy Bright (nuclear medicine) for their contributions.


   FOOTNOTES
 
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 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Grants NIH PO1 43904 and NIH Cancer Center Core Grant 33572. Presented at the 39th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 19–23, 1997, Orlando, FL. Back

2 To whom requests for reprints should be addressed, at Division of Radiation Oncology and Radiation Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010. Phone: (626) 301-8247; Fax: (626) 930-5334. Back

3 The abbreviations used are: CEA, carcinoembryonic antigen; cT84.66, chimeric T84.66; HAMA, human antimurine antibody; HACA, human antichimeric antibody; DTPA, diethylenetriaminepentaacetic acid; MTD, maximum tolerated dose; HPLC, high-performance liquid chromatography; 5-FU, 5-fluorouracil. Back

Received 5/23/00; revised 7/ 3/00; accepted 7/ 5/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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