No abstract

Purpose: Endosialin/CD248/tumor endothelial marker 1is expressed in stromal cells, endothelial cells, and pericytes in various tumors; however, few studies have focused on expression in malignant cells. Experimental Design: We studied expression of endosialin in clinical specimens, cell culture, and animal models and designed an anti-endosialin therapeutic prototype. Results: Fifty human tumor cell lines and 6 normal cell types in culture were assayed by reverse transcription-PCR and/or flow cytometry for endosialin. Cell surface protein was found on 7 sarcoma lines, 1neuroblastoma, and 4 normal cell types in culture. A fully human anti-endosialin antibody bound to human A-673 Ewing's sarcoma cells and SK-N-AS neuroblastoma cells but not HT-1080 cells. Exposure of cells to an anti-human IgG conjugated to saporin resulted in growth inhibition only of endosialin-expressing cells. Endosialin expression was assessed by immunohistochemistry in 250 clinical specimens of human cancer including 20 cancer subtypes. Endosialin is frequently found in human cancers. Endosialin expression is mainly a perivascular feature in carcinomas, with some expression in stromal cells. In sarcomas, endosialin is expressed by malignant cells, perivascular cells, and stromal cells. Development and characterization of experimental models for studying endosialin biology in sarcomas and evaluating anti-endosialin therapies is presented. Conclusions: Findings suggest that an anti-endosialin immunotoxin might be a promising therapeutic approach for endosialin-positive neoplasia, especially synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, and osteosarcoma. Thus, a diagnostic/therapeutic targeted therapeutic approach to treatment of endosialin-expressing tumors may be possible.

Diffuse or multifocal invasion of the leptomeninges by malignant glioma (meningeal gliomatosis) is believed to be rare. From 1971 through 1977, 11 of 52 patients with intracranial malignant gliomas examined at autopsy were found to have meningeal gliomatosis, and 1 additional patient was diagnosed clinically without autopsy (12 cases total). Eight of the 12 patients were diagnosed antemortem with positive cerebrospinal fluid (CSF) cytology, while the other 4 patients were diagnosed at autopsy only. All 11 autopsied patients had multifocal or diffuse meningeal tumor distant from the primary site; 8 patients had spinal subarachnoid seeding with tumor encroachment of cauda equina and spinal nerve roots, and 9 patients had tumor invasion into the lateral ventricles. Three patients had symptomatic spinal cord compression at the thoracic or lumbar level, and 10 patients had hydrocephalus. These 12 patients with meningeal gliomatosis were compared with the other 41 autopsied malignant glioma patients without the complication (controls); the patients with meningeal gliomatosis were significantly younger (mean age, 40 versus 57 years; p less than 0.005). Patients with meningeal gliomatosis lived somewhat longer (median, 49 weeks) compared to controls (35 weeks), but the difference was not statistically significant. With the advance of chemotherapy, patients with malignant glioma are living longer and the incidence of meningeal gliomatosis may rise. The diagnosis of meningeal gliomatosis can be suspected, especially if hydrocephalus is present, and can often be confirmed by CSF cytology.

Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-positive cells in vitro and achieved profound and durable antitumor efficacy in preclinical human tumor xenograft models of endosialin-positive disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE molecules per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the antiendosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors.

Five meningeal neoplasms grossly resembling meningiomas but histologically containing meningothelial cells together with abundant plasma cells and lymphocytes are reported. These masses are regarded as meningiomas with extensive plasma cell--lymphocytic infiltrates.