Jean-Claude Saccavini

Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(ab')2 in patients with non-resectable liver metastases from colorectal cancer.

Experimental studies in nude mice with human colon‐carcinoma grafts demonstrated the therapeutic efficiency of F(ab′)2 fragments to carcinoembryonic antigen (CEA) labeled with a high dose of 131Iodine. A phase I/II study was designed to determine the maximum tolerated dose of 131I‐labeled F(ab′)2 fragments (131I‐F(ab′)2) from anti‐CEA monoclonal antibody F6, its limiting organ toxicity and tumor uptake. Ten patients with non‐resectable liver metastases from colorectal cancer (9 detected by CT scan and 1 by laparotomy) were treated with 131I‐F(ab′)2, doses ranging from 87 mCi to 300 mCi for the first 5 patients, with a constant 300‐mCi dose for the last 5 patients. For all the patients, autologous bone marrow was harvested and stored before treatment. Circulating CEA ranged from 2 to 126 ng/ml. No severe adverse events were observed during or immediately following infusion of therapeutic doses. The 9 patients with radiologic evidence of liver metastases showed uptake of 131I‐F(ab′)2 in the metastases, as observed by single‐photon‐emission tomography. The only toxicity was hematologic, and no severe aplasia was observed when up to 250 mCi was infused. At the 300‐mCi dose, 5 out of 6 patients presented grade‐3 or ‐4 hematologic toxicity, with a nadir for neutrophiles and thrombocytes ranging from 25 to 35 days after infusion. In these 5 cases, bone marrow was re‐infused. No clinical complications were observed during aplasia. The tumor response could be evaluated in 9 out of 10 patients. One patient showed a partial response of one small liver metastasis (2 cm in diameter) and a stable evolution of the other metastases, 2 patients had stable disease, and 6 showed tumor progression at the time of evaluation (2 or 3 months after injection) by CT scan. This phase‐I/II study demonstrated that a dose of 300 mCi of 131I‐F(ab′)2 from the anti‐CEA Mab F6 is well tolerated with bone‐marrow rescue, whereas a dose of 200 mCi can be infused without severe bone‐marrow toxicity. Int. J. Cancer 75:615–619, 1998.

Adjuvant radioimmunotherapy trial with iodine-131-labeled anti-carcinoembryonic antigen monoclonal antibody F6 F(ab')2 after resection of liver metastases from colorectal cancer

Purpose: To evaluate the feasibility of radioimmunotherapy (RIT) with radiolabeled anti–carcinoembryonic antigen antibodies after complete resection of liver metastases (LM) from colorectal cancer. Patients and Methods: Twenty-two patients planned for surgery of one to four LM received a preoperative diagnostic dose of a 131I-F(ab′)2–labeled anti-carcinoembryonic antigen monoclonal antibody F6 (8-10 mCi/5 mg). 131I-F(ab′)2 uptake was analyzed using direct radioactivity counting, and tumor-to-normal liver ratios were recorded. Ten patients with tumor-to-normal liver ratios of >5 and three others were treated with a therapeutic injection [180-200 mCi 131I/50 mg F(ab′)2] 30 to 64 days after surgery. Results: Median 131I-F(ab′)2 immunoreactivity in patient serum remained at 91% of initial values for up to 96 hours after injection. The main and dose-limiting-toxicity was hematologic, with 92% and 85% grades 3 to 4 neutropenia and thrombocytopenia, respectively. Complete spontaneous recovery occurred in all patients. No human anti-mouse antibody response was observed after the diagnosis dose; however, 10 of the 13 treated patients developed human anti-mouse antibody ∼3 months later. Two treated patients presented extrahepatic metastases at the time of RIT (one bone and one abdominal node) and two relapsed within 3 months of RIT (one in the lung and the other in the liver). Two patients are still alive, and one of these is disease-free at 93 months after resection. At a median follow-up of 127 months, the median disease-free survival is 12 months and the median overall survival is 50 months. Conclusion: RIT is feasible in an adjuvant setting after complete resection of LM from colorectal cancer and should be considered for future trials, possibly in combination with chemotherapy, because of the generally poor prognosis of these patients.

A monoclonal antibody (Po66) directed against human lung squamous cell carcinoma immunolocalization of tumour xenografts in nude mice.

SummaryPo66, a mouse IgG1 monoclonal antibody, was produced by immunization against a patient lung squamous cell carcinoma. The tissue reactivity of the antibody was measured by a radioimmunological assay with enzymatically dissociated cells, by an immunofluorescence test on frozen tissue sections and by peroxidase-staining of paraffin sections. The antibody bound to lung squamous cell carcinoma, oesophagous carcinoma and, inconsistantly to lung adenocarcinoma but not to the other tumours tested. Some normal tissues also reacted positively, in particular bronchial serous glands, oesophagus epithelium and renal distal and collecting tubules. In normal and malignant tissues showing epithelioid differentiation, Po66 bound to the intermediate maturation area. The antigen immunoprecipitated by Po66 from lung squamous cell carcinoma appeared as a single band with a molecular weight 47000 to 50000 daltons. Purified monoclonal antibody Po66 and an unrelated IgG1 immunoglobulin were labelled with radioactive iodine and injected i. v. into nude mice bearing subcutaneous xenografts of human lung squamous cell carcinoma. The localization index in the tumour was 3.3. Antibody labelled with 131I allowed gamma-scintigraphic imaging of the xenografts which were clearly outlined by days 9 to 11.

Potential contribution of 131I-labelled monoclonal anti-CEA antibodies in the treatment of liver metastases from colorectal carcinomas : pretherapeutic study with dose recovery in resected tissues

20 patients with liver metastases from colorectal carcinoma undergoing laparotomy received 15-60 mg intravenously, either intact or fragments of, anti-carcinoembryonic antigen (anti-CEA) monoclonal antibodies labelled with 0.55-1.48 GBq (15-40 mCi) of 131I, 3-8 days prior to operation. The uptake measured per gram of metastases ranged from 0.33 to 6.6 x 10(-3%) of injected dose. Tumour to liver uptake ratios ranged from 2 to 33. The radiation dose, estimated in 6 patients (3 of each group), for an extrapolated dose of 3.7 GBq (100 mCi) of 131I ranged from 0.3 to 0.8 Gy in normal liver or spleen (an acceptable estimate for bone marrow radiation dose) and from 3.4 to 8.2 Gy to the hepatic metastases, indicating that probably other therapeutic modalities should be associated with radioimmunotherapy.

755 Radioimmunotherapy of metastatic colon cancer: Phase I study with anti-CEA F(AB)′2 fragments labeled with escalating dose OD iodine 131

Experimental studies demonstrated efficiency of F(ab)′2 antibody fragments to CEA labeled with Iodine 131 (131-I-F(ab)′2 A phase I study was designed to determine the maximum tolerated dose (MTD) of 131-I- F(ab)′2. Ten patients with liver metastases (LM) from colorectal cancer were treated with 13l-I-F(ab)′2 ranging from 87 mCi to 300 mCi. No adverse event was observed during and just after infusion. The only toxicity was hematologic and no aplasia was observed up to 300 mCi infused. At this dose, the five patients presented grade 3 or 4 hematologic toxicity, the nadir for neutrophils and thrombocytes ranged from 25 to 35 days after infusion and bone marrow rescue was infused. In conclusion, this study demonstrated that MTD of 131-I-F(ab)′2 is 300 mCi with bone marrow rescue.