Tumor targeting with monoclonal antibody B72.3: experimental and clinical results.
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Animals↗
Biomedical subjects
P Sugarbaker
Publications and source records attributed to P Sugarbaker.
Binding of radiolabeled MAb B72.3 administered intravenously and intraperitoneally in colorectal cancer patients. An overview.
Monoclonal antibody (MAb) B72.3 coupled to 131I is currently being used in clinical trials for the diagnostic imaging of gastrointestinal, ovarian, and breast carcinomas. The MAb has also been used extensively in immunohistochemical studies and in the development of radioimmunoassays to define antigen levels in tissues and sera of cancer patients. When administered intravenously, the radionuclide-conjugated MAb has localized tumor in over 70 percent of patients. When intraperitoneal administration was studied, the MAb-radionuclide conjugate successfully imaged peritoneal lesions; moreover, in 3 of 10 patients, B72.3 detected lesions not found by conventional methods. Concomitant administration of 131I labeled B72.3 intraperitoneally and 125I labeled B72.3 intravenously showed that the intraperitoneal route localized peritoneal implants at least two times better than the intravenously administered MAb. Conversely, hematogenously borne or non-implant lesions were better localized with intravenously administered B72.3.
Antibodies, Monoclonal↗
Tumor targeting with monoclonal antibody B72.3.
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Antibodies, Monoclonal↗
A monoclonal antibody (B72.3) to adenocarcinoma of the colon and related tumors.
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Adenocarcinoma↗
Differences in biodistribution of indium-111-and iodine-131-labeled B72.3 monoclonal antibodies in patients with colorectal cancer.
We have compared the biodistributions of [131I]B72.3 and 111In-SCN-Bz-DTPA B72.3 monoclonal antibody (MoAb) in patients with metastatic colon cancers. B72.3 is an IgG1 that recognizes a mucin-like colon cancer associated antigen. Eight patients were infused with 3-5 mCi and 0.36-20 mg of 111In-labeled B72.3 prepared with a bifunctional chelate, isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA). The biodistribution was compared with that of 13 patients previously studied as part of a separate trial, with 1-10 mCi and 0.16-1.35 mg of [131I]B72.3. The Beta T1/2 in serum was 63 +/- 5 hr for 111In-SCN-Bz-DTPA B72.3 and 52 +/- 10 hr for [131I]B72.3. Whole-body retention of the 111In (T1/2 = 11.8 days) was significantly longer than for [131I]B72.3 (T1/2 = 3.3 days), p less than 0.000001. The 131I was excreted primarily through the urine. Urinary excretion of 111In was low and gamma camera images confirmed that some 111In was excreted in the bowel. Tumor localization was seen in one of seven evaluable patients receiving 111In-SCN-Bz-DTPA B72.3. Gamma camera images showed that the liver concentrates 111In but not 131I. We conclude that 111In-SCN-Bz-DTPA B72.3 is metabolized in a different manner from the iodinated B72.3. The high concentration and prolonged retention of 111In by the liver interferes with tumor imaging of metastases.
Antibodies, Monoclonal↗
Peritoneal carcinomatosis: imaging with intraperitoneal injection of I-131-labeled B72.3 monoclonal antibody.
Monoclonal antibody (MoAb) B72.3 is reactive with a variety of carcinomas such as colorectal and ovarian carcinoma and not reactive with a range of normal tissues in adults. Twelve patients, ranging in age from 16 to 63 years, with metastatic colorectal or appendiceal carcinoma were studied by means of radioimmunoscintigraphy after injection of 5-10 mCi (185-370 MBq) of iodine-131-labeled B72.3 immunoglobulin G (IgG). Eight of the 12 patients had positive scans. In three of these patients the MoAb scan depicted tumors that were not found by other means. Positive scans had excellent correlation with surgical findings in seven patients and caused underestimation of the extent of disease in one patient. In one patient the scan was technically inadequate and could not be evaluated. In three patients the scan was negative. No adverse reactions were associated with the infusions.
Adenocarcinoma↗
Radioimmunoscintigraphy of colon cancer with iodine-131-labeled B72.3 monoclonal antibody.
The monoclonal antibody B72.3 is a murine IgG1 that is reactive with a wide range of carcinomas while demonstrating little or no reactivity to normal adult tissues. We have shown (27) quantitative analyses demonstrating selective targeting of [131I]B72.3 IgG to metastatic colorectal cancer. We have also shown (28) that (a) B72.3 localization in metastases correlated with the percentage of tumor cells in the biopsy specimen; (b) B72.3 could localize in carcinomas of various degrees of differentiation with best localization in well-differentiated tumors and (c) [131I]B72.3 could penetrate tumor masses, as determined by autoradiographic studies. We report here the various parameters effecting radioimmunoscintigraphy with [131I]B72.3 IgG. Sixteen of 35 patients with colorectal carcinoma had positive scans (without blood-pool subtraction). High circulating TAG-72 antigen levels correlated with positive scans. No dose dependent differences were seen in biodistribution or tumor imaging. The plasma clearance and urinary excretion of [131I]B72.3 and [125I]BL-3 (nonspecific control) were not significantly different. No toxicity was noted. Approximately one-half of patients developed human anti-mouse immune response.
Adolescent↗
Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma.
Monoclonal antibody (MAb) B72.3 has been shown to have selective reactivity for a wide range of carcinomas (colorectal, ovarian, breast, lung, gastric, and endometrial) versus normal adult tissues. 131I-Labeled B72.3 IgG has recently been shown to selectively bind carcinoma lesions when administered i.v. in patients with metastatic colorectal cancer. We report here the first direct comparison of i.p. administered [131I]B72.3 IgG to specifically localize metastatic carcinoma. Three of 10 patients studied were negative for tumor detection by both CAT scan and X-ray but were positive for tumor localization via gamma scanning i.p. administered 131I-labeled MAb B72.3 IgG. Direct analyses of biopsy specimens of carcinoma and normal tissues demonstrated ratios of greater than 70:1 (based on percentage of injected dose/mg) for tumor MAb localization versus normal tissues. Specificity of [131I]B72.3 tumor targeting was demonstrated by the concomitant administration of an equal dose of an 125I-labeled isotype identical (IgG1) control MAb. Simultaneous i.p. administration of [131I]B72.3, and i.v. administration of [125I]B72.3 in individual patients demonstrated: peritoneal implants are targeted more efficiently via i.p. MAb administration, and hematogenously spread and lymph node metastases as well as local recurrences are targeted more efficiently by i.v. administered MAb. No antibody toxicity was observed in any patients. Pharmacokinetics of MAb clearance demonstrated that only 10 to 30% of the i.p. administered MAb was found in plasma. These studies thus demonstrate the efficacy of intracavitary MAb administration as well as the advantage of the concomitant use of intracavitary and i.v. administered MAbs for tumor targeting and for potential MAb guided therapy of metastatic carcinoma.
Adolescent↗
Quantitative analyses of selective radiolabeled monoclonal antibody localization in metastatic lesions of colorectal cancer patients.
We have previously demonstrated, using in vitro assays, a high degree of selective binding of monoclonal antibody (MAb) B72.3 for carcinomas of the colon, ovary, and breast versus normal adult tissues using in vitro assays. We report here a demonstration of selective tumor localization in colorectal cancer patients of i.v. administered 131I-labeled MAb B72.3 immunoglobulin G prior to surgery. Radiolocalization indices (RI) were obtained by direct analyses of biopsy materials (i.e., cpm of 131I-labeled MAb per g of tumor versus cpm per g of normal tissues). Using as a "positive" localization, RI of 3 times greater than normal tissue (i.e., RI greater than 3.0), tumor lesions in various sites from 17 of 20 patients scored positive. In eight of these patients, all tumor lesions demonstrated RIs of greater than 3, while in five patients RIs of some lesions were greater than 10 and as high as 30 to 46. Seventy % (99 of 142) of tumor lesions showed RIs of greater than 3, while only 12 of 210 histologically confirmed normal tissues examined showed RIs of greater than 3. These tissues, moreover, were either adjacent to tumor or draining tumor masses, or, as in the case of two patients, apparently due to high levels of circulating immune complexes that were deposited in the spleen. Positive gamma scans (confirmed at surgery) were observed in 14 of 27 patients. An isotype-identical control immunoglobulin G was coinjected and showed RIs considerably lower than that of B72.3. No toxicity or adverse reaction was observed with either MAb. These studies are among the most comprehensive to date concerning the definition of the actual delivery of radiolabeled MAb to carcinoma lesions versus a wide range of adjacent and distal normal tissues and lead the way for other diagnostic and potential therapeutic applications of this antibody either alone, or in combinations with other monoclonal antibodies.
Antibodies, Monoclonal↗
Quantitative and qualitative aspects of radiolocalization in colon cancer patients of intravenously administered MAb B72.3.
Monoclonal antibody (MAb) B72.3 has been previously shown, by in vitro assays, to have a high degree of specificity for carcinomas of the colon, ovary and breast versus normal adult tissues. B72.3 IgG was labelled with 131I and injected i.v. into 20 patients with known or suspected colorectal cancer. All patients subsequently underwent surgical exploration, with tumor and selected normal tissues removed for staging purposes. The selective localization of 131I-MAb B72.3 IgG was demonstrated in biodistribution studies in which the % ID/g of each tumor was compared with that of the normal tissues, thus providing a relative RI for each lesion. Of the tumor lesions, 70% (99/142) had an RI of at least 3 (i.e., 3 times greater uptake per gram than normal tissues), and 31% of the tumor lesions had RIs of over 10. Only 12 of 210 (6%) histologically normal tissues had RIs of greater than 3; either these tissues were adjacent to or draining tumor masses or, as in the case of 2 patients, the high RI values were apparently due to deposition of immune complexes in the splenic tissues. Several parameters were studied to determine factors that might influence MAb localization. Whereas tumors of all histologic types localized the MAb, 31% of the well-differentiated mucinous carcinomas displayed tumor-to-normal ratios greater than 10, while less than 5% of the lesions of other tumor types demonstrated similar localization. The expression of the antigen (TAG-72) detected by MAb B72.3 in these tumors, as studied by immunohistochemical techniques using tissue sections, did not always correlate with the outcome of the MAb distribution. No differences in MAb uptake were observed among the carcinoma lesions from numerous anatomic locations, demonstrating the ability of i.v. administered B72.3 to reach all the tumor sites. Furthermore, autoradiographic studies of tumors showed good penetration of the MAb into the medial areas of the tumors, regardless of their size.
Adolescent↗
Radiolabeled monoclonal antibody B72.3 localization in metastatic lesions of colorectal cancer patients.
We have previously demonstrated a high degree of selective binding of monoclonal antibody (MAb) B72.3 to carcinomas of the colon, ovary, and breast in contrast to normal adult tissues using in vitro assays. In this report we demonstrate selective tumor localization in colorectal cancer patients after intravenously administering 131I-labeled MAb B72.3 IgG. Radiolocalization Indices (RI) (i.e. cpm 131I-labeled MAb per gram of tumor vs cpm per gram of normal tissues), were obtained by direct analyses of biopsy materials. Using an RI of greater than or equal to 3 as a positive localization, tumor lesions in various sites from 17/20 patients scored positive. In eight of these patients, all tumor lesions demonstrated RIs of greater than 3, while in five patients RIs of some lesions were greater than 10 and as high as 30-46. Seventy percent (99/142) of the tumor lesions showed RIs of greater than 3, while only 12 of 210 histologically confirmed normal tissues examined showed RIs of greater than 3. These tissues were either adjacent to the tumor or the draining tumor masses or, as in the case of two patients, was caused by high levels of circulating immune complexes that deposited in the spleen. Positive scintigraphic images (confirmed at surgery) were observed in 14/27 patients. No toxicity or adverse reactions were observed with either MAb. These studies provide absolute quantitative analyses of the actual delivery of radiolabeled MAb to carcinoma lesions vs a wide range of adjacent and distal normal tissues and establishes the means for other diagnostic and potential therapeutic applications of this antibody alone, or in combinations with other monoclonal antibodies.
Antibodies, Monoclonal↗
A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk.
Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high-grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000-6300 rads over 7-8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (less than or equal to 550 mg/m2), cyclophosphamide (less than or equal to 5500 mg/m2), and methotrexate (less than or equal to 1000 mg/kg). Three-year actuarial disease-free survival in the chemotherapy arm was 77%, compared to 49% in the no-chemotherapy arm (P = 0.075). Three-year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3-year actuarial disease-free survival in the chemotherapy arm was 92%, compared to 47% in the no-chemotherapy arm (P = 0.006). Actuarial 3-year overall survival in the chemotherapy arm was 82%, compared to 61% in the no-chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow-up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3-year actuarial disease-free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease-free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease-free survival (P less than or equal to 0.001). The most significant toxicity associated with chemotherapy was doxorubicin-induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease-free survival, but additional patients and longer follow-up are necessary to determine if improved overall survival will result.
Actuarial Analysis↗
Results of multimodality therapy of resectable soft-tissue sarcomas of the retroperitoneum.
Thirty-seven patients with resectable retroperitoneal sarcomas were studied prospectively to determine the efficacy of aggressive multimodality treatments. No patients was lost to follow-up, which ranged from 11 to 85 months (median 29 months). All patients received radiotherapy and some received postoperative chemotherapy (doxorubicin, cyclophosphamide, and high-dose methotrexate). A subset of 15 patients were entered into a prospective, randomized study testing the efficacy of adjuvant chemotherapy (eight received chemotherapy; seven did not). Two-year actuarial survival rates were inferior in the chemotherapy arm (100% versus 47%; p = 0.06), but the small number of patients precluded drawing definitive conclusions from this randomized study alone. Among the entire 37 patients (21 received chemotherapy; 16 did not) the actuarial 3-year survival rate was 43% and appeared unaffected by chemotherapy. Two patients suffered doxorubicin infiltration, three sustained cardiac toxicity, two developed cyclophosphamide-induced cystitis, and three withstood transient, severe bone marrow suppression. Eight patients suffered severe radiation enteritis, and one patient died after bowel resection for this problem. Thus the chemotherapy regimen we administered did not appear to improve survival but was associated with major morbidity. Radiotherapy was also associated with major complications, and since all patients received radiotherapy, it remains to be established if this modality is beneficial in improving survival.
Actuarial Analysis↗
Segmental hyperlucent defects in the liver.
When lucent defects in the liver have a segmental configuration, they may be on an ischemic basis and related to decreased vascular perfusion. Portal venous inflow, by virtue of its low pressure, is particularly susceptible to diversion by focal intrahepatic masses, intravenous thrombi, or external compression. Innovative operative techniques for tumor enucleation may also result in lucent defects that can be confused with, or conceal, pathology. A hypothesis relating such defects to diminished portal inflow and reduced glycogen content is proposed.
Female↗
Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities.
Sixty-five patients with high-grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high-dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow-up of 653 days revealed an advantage in continuous disease-free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one-sided Mantel-Haenszel test). The continuous disease-free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty-eight percent of patients had limb-sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease-free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four-year follow-up, reveals an improvement in disease-free and overall survival due to chemotherapy (P less than 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment adult patients with soft tissue sarcomas of the extremities.
Adult↗
The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.
Between May 1975 and April 1981, 43 adult patients with high-grade soft tissue sarcomas of the extremities were prospectively randomized to receive either amputation at or above the joint proximal to the tumor, including all involved muscle groups, or to receive a limb-sparing resection plus adjuvant radiation therapy. The limb-sparing resection group received wide local excision followed by 5000 rads to the entire anatomic area at risk for local spread and 6000 to 7000 rads to the tumor bed. Both randomization groups received postoperative chemotherapy with doxorubicin (maximum cumulative dose 550 mg/m2), cyclophosphamide, and high-dose methotrexate. Twenty-seven patients randomized to receive limb-sparing resection and radiotherapy, and 16 received amputation (randomization was 2:1). There were four local recurrences in the limb-sparing group and none in the amputation group (p1 = 0.06 generalized Wilcoxon test). However, there were no differences in disease-free survival rates (71% and 78% at five years; p2 = 0.75) or overall survival rates (83% and 88% at five years; p2 = 0.99) between the limb-sparing group and the amputation treatment groups. Multivariate analysis indicated that the only correlate of local recurrence was the final margin of resection. Patients with positive margins of resection had a higher likelihood of local recurrence compared with those with negative margins (p1 less than 0.0001) even when postoperative radiotherapy was used. A simultaneous prospective randomized study of postoperative chemotherapy in 65 patients with high-grade soft-tissue sarcomas of the extremities revealed a marked advantage in patients receiving chemotherapy compared with those without chemotherapy in three-year continuous disease-free (92% vs. 60%; p1 = 0.0008) and overall survival (95% vs. 74%; p1 = 0.04). Thus limb-sparing surgery, radiation therapy, and adjuvant chemotherapy appear capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremity.
Adolescent↗
The use of preoperative plasma CEA levels for the Stratification of patients after curative resection of colorectal cancers.
One hundred forty-five patients with colorectal cancer were analyzed in order to correlate the preoperative plasma carcinoembryonic antigen (CEA) levels with the sites and times of disease recurrence. The median follow-up periods of these patients was 50 months (range 36-72 months). Twenty-one patients were found to have metastases at the time of their operation. None of the seven patients whose primary tumors were classified as Dukes/Kirklin A have had tumor recurrence. Seventeen per cent of the patients with Dukes/Kirklin B tumors have had tumor recurrences, and 63% of the patients with Dukes/Kirklin C colorectal primary tumors have had tumor recurrence. No correlation was found between preoperative CEA values and subsequent risk of tumor recurrence or times to recurrence among the patients with Dukes/Kirklin B colorectal primary cancers. In Dukes/Kirklin C patients, however, elevated preoperative CEA values predicted a higher risk of tumor recurrence. Ninety per cent of the patients (19/21) with preoperative CEA levels greater than 5.0 ng/ml have had relapses, with a median time of 17 months before disease recurrence. Only 39% (9/23) of the patients with Dukes/Kirklin C lesions and CEA levels less than 5 ng/ml have had relapses and there is insufficient follow-up data as yet to determine the median survival time. If those patients whose Dukes/Kirklin C primary tumors were poorly differentiated on histologic examination are excluded, the contrast between patients having CEA levels greater than 5.0 ng/ml and those having CEA levels less than 5 ng/ml is even more marked. Sixteen of the 18 remaining patients whose CEA levels were greater than 5.0 ng/ml prior to curative resection have had relapses as compared with only three of 15 patients whose preoperative CEA values were less than 5. We conclude, therefore, that CEA is an important factor in stratifying patients after curative resection of their Dukes/Kirklin C colorectal tumors.
Carcinoembryonic Antigen↗
Use of liposoluble contrast material to separate left renal and splenic parenchyma on computed tomography.
A lobulated or accessory spleen lying against the upper pole of the left kidney may simulate renal tumor on computed tomograms. Water soluble contrast material is usually of little help in the differential diagnosis, since it increases the attenuation of both the kidney and the spleen. Intravenous liposoluble contrast material preferentially increases the attenuation of the liver and spleen and thus permits clear separation of the enhanced lobulated or accessory spleen from the unopacified renal parenchyma.
Adult↗