Treatment of Metastatic Prostate Carcinoma with Radiolabeled Antibody CC49 Ruby F. Meredith, Anton J. Bueschen, M.B. Khazaeli, Walter E. Plott, William E. Grizzle, Richard H. Wheeler, Jeffrey Schiom, Charles D. Russell, Tiepu Liu and Albert F. LoBuglio Departments ofRadiation Oncology, Umlogy, Medicine, Patholo@, Division ofNuclear Medicine (Radiolo@'), Biostatistics, University ofAlabama at Binningham@Binningham, Alabama; and Laboratoiy of Tumor Immunolo@ and Biology, National
Cancer Institute, Bethesda,
Mwyland
generation anti-TAG-72 monoclonal reagents have been
A PhaseIItnatof 75 mCi/rn2131l-anti-TAG-72 high-affinityanti prepared (18), and one of these (CC49) has a higher binding bodyCC49was studiedin 15 patientswfthhormone-resistant affinity over B72.3 and superior localization to human can metastaticprostatecancer.Methods: Patientshad adequate cer xenografts (19). In an animal model of radioimmuno renat,liverand hematopoleticfunction.No previouscytotoxic therapy, CC49 is reported to have superior therapeutic chemotherapywas atlowedand previousradiationwas limitedto 20% of the active bone marrow. Resufts: No acute adverse reactionsoccurred, but ati patients had evidence of an immune response to CC49 by 4 wk. Six of 10 symptomatic patients
effects than B72.3 (20). Results from a Phase I trial of
‘311-CC49 in patients with metastatic colorectal cancer in dicated that a dose of 75 mCi/m2was toleratedwith 50%of patients having Grade III or IV marrow suppression (main
had bone pain relief,but no patientsmet the radiographicor was PSA criteriafor objectiveresponse.Positiveimagingof bone ly thrombocytopenia) (21). This dose of ‘311-CC49 investigated in a Phase II trial in patients with hormonally and/orsoft-tissuelesionswas notedfor 13 of the 15 patients. Conclusions: CC49hada highfrequency oftumorlocalizationunresponsive metastatic prostate cancer. withevidenceof anti-tumoreffects(painrelief). KeyWords:prostate carcinoma; radiolabeled antibody J NuclMed1994;35:1017—1022
MATERIALS AND METhODS
Clinical Protocol Eligible patients had histologically confirmed adenocarcinoma of the prostate and had failed standardhormonaltherapy. Eligi
biity criteriaincludedTAG-72positivetumorby immunoperox idase staining, Karnofsky performance status iffuse metastatic
bone lesions from prostate cancer
unresponsive to hormone manipulation have been treated with systemic radionuclide therapy for more than a decade. Bone-seeking agents such as 32P, 89Sr and ‘53Sm have been useful for palliation of pain in patients with widespread
bony metastases where conventional external beam radia tion was not feasible (1—3).
A potential alternative to systemic therapy with bone seeking radionuchides is the conjugation of radionucides to antibodies reactive with prostate cancer-associated anti gens. TAG-72 is a tumor-associated mucin of high molec ular weight present in a variety of adenocarcinomas, in cluding colon, breast, pancreas and prostate carcinomas
60, adequate he
matologic, renal and liver function. Patients were excluded for
iodine allergy, a history of cytotoxic chemotherapy, radiation to 20%of the activemarrow, other invasivemalignanciesor infec tion with HIV or hepatitis B. Concurrent chemotherapy, radia tion, immunotherapyor new hormonal therapies were not al lowed. This study was reviewed and approvedby the University of Alabama at Birmingham(UAB) Institutional Review Board, and all patients gave informedconsent. The trialdesign was an open-label Phase II study coordinated
throughthe NationalCancerInstitute.After satisfactoryprether
apy evaluation, patients (15 males, ages 54—80) received 50 @.tg Synthroid daily and 10 drops of a saturated solution of potassium iodide (SSKI, 1 g/ml) daily, beginning 2 days prior to antibody therapy and continuing for 14 days thereafter. Patients were (4). The initial anti-TAG-72 monoclonal antibody (B72.3) treated in lead-linedhospital rooms at the UAB GeneralQisKal Research Center and were confined in isolation with radiation has been studied in its original murine form (5—11) and as a precautionsuntiltheirexposure rate at one meterwas 5 mRem/ genetically engineered chimeric mouse/humanmolecule in hr. Prior to the radiolabeled dose, patients received a test dose of radioimaging and radioimmunotherapeutic trials (12—16).A unlabeled CC49 (100 j.@g) with vital signs monitored every 10 mm recentstudyhassuggested thatthisantibodycanlocalize times three. If no signs of allergic or other adverse reactions were to primary metastatic sites of prostate cancer (17). Second observed, the radioimmunoconjugate(75 mCi/rn2)was infused over 1 hr with vital signs monitored every 15 mis duringadmin istrationand for 1 hr postinfusion. ReceivedSept 21, 1993;
[email protected],1993. Subsequent to therapy, patients had serial gamma camera im Forcorrespondence orreptintscontadRubyF.Meredith, MD,PhD,University ofAlabama atBirmingham, Comprehensive Cancer Center, LB.Wallace Tumor aging, whole-body gammacounts and blood samplingdetermina Institute—i17, Birmingham, AL 35294-3300. tion of immuneresponse to the administeredantibody. Follow-up
ProstateCarcinomaRadioimmunotherapy • Meredithet at.
1017
evaluationincludedhistoryandphysicalexam,prostate-specific scale: 0 = within normal limits; 1 = probably negative; 2 = antigen(PSA),prostaticacid phosphatase,bloodcounts, liver, suspicious; 3 = positive; 4 = strongly positive. renalandthyroidfunctionstudies.A painindexwas usedwhich @@C49 Antibody was comprisedof a painscore and a narcoticscorewhichwas derivedby conversionof analgesicsto an equivalentamountof MonoclonalantibodyCC49is an IgGiwhichwas obtainedby parenteral morphine (22). The pain score was calculated by mul
immunizing mice with purified TAG-72 (18). The antibody was
tiplying the frequency and severity of pain. Tumor response was assessed 6 wk post-therapy. Toxicity grading utilized the RTOG
producedin continuousinvitrocultureandwas providedby the National Cancer Institute (NSC #620537, BB IND 3006) as a
sterile, nonpyrogenicaqueous solution for intravenoususe. Each gradingsystem(23). Responsecriteriawere adaptedandmodifiedfromthoseused 1.5-mivialcontained 10.69mg/mh CC49inpreservative-free phos in cooperative group trials (24). Response criteria were defined as
phate-buffered saline. Radiolabeing
follows for radiographically
eachadministration at 10mCi/mgantibodyutilizingstandardIo dogenmethodologyas previouslydescribed(25).
identified lesions:
• complete regression (CR): disappearanceof all evidence of tumor; •partial regression (PR): reduction in product of longest per pendicular diameter of indicator lesions by 50% without
progression in any lesion or appearance of new lesions (in the case of measurable osteolytic lesions, definite evidence of recalcification agreed upon by two independent investigators
constitutedPR); • stable:failureto qualifyforCR,PRor progression; I
progression:
an
increase
of
25%
in
the
product
of
new lesions.
ablekit. The assaywas modifiedby preabsorption of serawith mouse IgO-coated immunoaflinity beads if the patients' sera con
tamed high amounts of human anti-mouseIgG which interfered withthePSAassay(26). Statistical Analysis
Descriptivestatistics were calculatedfor each measurement.
Responsecriteriabasedon PSAchangeswere definedas fol lows:
Correlation analysis was conducted to examine the relationships among these measurements, such as age, whole-body radiation
dose, priorradiotherapy,bone marrowsuppressionindicators,
• complete response: normalizationof PSA in three successive determinations;
• partial response: decline of PSA level by >80% for three consecutive determinations; stable:
PSA Assay In order to avoid variation in processing samples at seven time pointsover a 6-wk interval, pretreatmentandweekly serumsam ples were assayed in the same batch using a commercially avail
longest
perpendiculardiametersof indicatorlesions or appearanceof
S
was performed on the day of
PSA
change
5 ng/ml. Lactic dehydrogenase levels rose in patients with progres sive disease (mean increase at 160%), whereas patients with stable disease had a mean decrease of 5%. Pretherapy PSA values rangedfrom 9 to 15,200ng/mlwith 6-wkvalues that included four patients with 50% with 17%—33%decrease;
and five patients with
ated external beam radiation or doses delivered by a
89Sr.As increase. CC49.imaging outlined in Table 1, 13/15patients had positive radio-
administration of 3 mCi of Table 3 provides the human antibody response to
aradiolabeled of at least one known tumor site, although the antibody consistently detected fewer sites
All patients had an immune response, with 14/15 having positive response by Day 14 postinfusion and 12/15 devel
than (>1000and conventional @“Tc bone scans. The two patients (#4 oping large amounts of antibody binding activity ng/ml).had #8) who failed to have positive radioimmuneimaging whereasthree 1000mg/
..
C.)
ml). This is in striking contrast to the experience with
x
@3
.
.
cyt-356, where the incidence of antibody response was < 10%
to
antibody
doses
of
0.5
mg
in
the
majority
of
patients (29). The rapid antibody response to murine CC49
2
•
U
wifi interfere with attempts at administrationof a second
I
•
.
course of therapy or to dose fractionation studies (28,36,37). Genetic engineering to decrease antigenicity, as applied to other murine antibodies, may overcome this drawback of the CC49 antibody.
0
•
I
Thus, this Phase II trial of ‘311-CC49 failed to produce
objective anti-tumor responses but did produce a high fre quency of 1311localization to tumor sites and several ex amples of symptomatic improvement in bone pain. The use FiGURE2. Compatisonof toxicityof prostatecancerpatients of alpha interferon in conjunction with ‘311-CC49 in order receMng 75 mCi/rn2131l-CC49(UAB)with a group of colorectal to increase TAG-72 expression in tumors (38) and the use cancerpatientswho receivedthe sametreatmentat anotherinsti tution (MDA)(28). The toxicitysum is the toxicitygradefor neutro of cyclosporine to allow dose fractionation (39) in patients
COLON
PROSTATE
(MDA)
(UAB)
peniaplusthetoxicitygradeforthrombocytopeniafor eachindMdual with hormone resistant metastatic prostate cancer are cur patient.Eachsymbolrepresents onepatient. rently under investigation. Other alternatives such as ad
Prostate Carcinoma Radioimmunotherapy• Meredith et at.
1021
juvant use of radiosensitizers or methods that would allow dose escalation may improve efficacy. Thyroid uptake after administration of radioactive iodine
conjugated agents occurs with both tracer and therapeutic doses. This is reduced but not eliminatedby blocking with synthroid and SSKI. Abnormal thyroid function test values have been observed after SSKI blocking for one-third of patients. The median time was 32 mo after high-dose ther
apy (40). However, to date, any clinical side effects from thyroid
injury have been inconsequential
compared
to
16. Meredith RF, Khazaeli MB, Plou G, et al. Phase I trial of ‘311-chimeric B72.3(human1g04)in metastaticcolorectalcancer.I Nuci Med 1992;33: 23—29. 17. Badalament RA, Burgers JK, Petty LR, et al. Radioimmunoguided radical
prostatectomyand lymphadenectomy.Cancer 1993;71:2268—2275. 18. MuraroR, Kuroki M, Wunderlich D, et al. Generation and characterization of B72.3 second generation monoclonal antibodies reactive with the tumor associated glycoprotein-72 antigen. CancerRes 1988;48:4588—4596. 19. Colcher D, Mmdi MF, Roselli M, Muraro R, Simpson-Milenic D, Schiom
J_Radioimmunolocalization of humancarcinoma xenografts withB72.3 second generation monoclonal antibodies. Cancer Res 1988;4&4597—4603. 20. Schlom J, Eggensperger D, Colcher D, et al. Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates. Cancer Res 199252:
other potential toxicities in the management of life-threat ening malignancies.
1067—1072. 21. Scott AM, DiVgiCR, Kemeny N, Ct al. Radioimmunotherapywith 1-131
ACKNOWLEDGMENTS
22. Grossman SA, Sheidler yR. An aid to prescribing narcotics for the relief of cancer pain. World Health Fonun 1987;8:525—527. 23. Radiation Therapy Oncolo@jr Group (RTOG). TOxicity criteiia. Copies available from RTOG Office, 1101 Market Street, 14th Floor, Philadelphia, PA 19107. 24. Schmidt JD, Gibbons RP, Johnson DE, et al. Chemotherapy of advanced prostatic cancer. Evaluation of response parameters. Urology 1976;7:602— 610. 25. Meredith RF, LoBuglio AF, Plott WE, Ct al. Pharmacokinetics, immune
labeled monoclonal antibody CC49 in colorectal cancer. EurJ Nuci Med
1992;19:709.
The authors express appreciation to Sharon Garrison and Angela Kelley for preparationof the manuscript, M.A. Mark iewicz for pharmaceutical services, Pam Dixon for nursing, and to Mark Luehmann and Gayle Elliott for technical assistance. This study was conducted under General Clinical Research Center
NIH grant#M01-RR-00032 andwas supportedby NC! contract #CM87215.
responseand biodistributionof ‘311-labeled chimericmouse/humanIgGl,k
17-lAmonoclonal antibody. I NuciMed1991;32:1162-1168.
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The Journal of Nuclear Medicine• Vol. 35 • No. 6 • June 1994
659—664.
