Abstract
TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-α and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25ng/mL to 100 with a 40mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.
Similar content being viewed by others
References
Legler JM, Ries LA, Smith MA, Warren JL, Heineman EF, Kaplan RS, Linet MS: Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst 91: 1382–1390, 1999
Howe HL, Wingo PA, Thun MJ, Ries LA, Rosenberg HM, Feigal EG, Edwards BK: Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93: 824–842, 2001
Burger PC, Vogel FS, Green SB, Strike TA: Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer 56: 1106–1111, 1985
Dandy WE: Removal of right cerebral hemisphere for certain tumors with hemiplegia. JAMA 90: 823–825, 1928
Imperato JP, Paleologos NA, Vick NA: Effects of treatment on long-term survivors with malignant astrocytomas. Ann Neurol 28: 818–822, 1990
Galanis E, Buckner J: Chemotherapy for high-grade gliomas. Br J Cancer 82: 1371–1380, 2000
Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17: 2572, 1999
Pastan IH, Archer GE, McLendon RE, Friedman HS, Fuchs HE, Wang Q-C, Pai LH, Herndon J, Bigner DD: Intrathecal administration of single-chain immunotoxin, LMB-7 (B3(Fv)-PE38), produces cures of carcinomatous meningitis in a rat model. Proc Natl Acad Sci USA 93: 2765–2769, 1995
Pai LH, Pastan I: Immunotoxins and recombinant toxins. In: DeVita VT, Jr., Hellman S, Rosenberg SA (eds) Biologic Therapy of Cancer, 2nd edn, JB Lippincott Company, Philadelphia, 1995, pp 521–533
Pastan I: Targeted therapy of cancer with recombinant immunotoxins. Biochim Biophys Acta 1333: C1–6, 1997
Pastan I, FitzGerald D: Recombinant toxins for cancer treatment. [Review] [90 refs]. Science 254: 1173–1177, 1991
Phillips PC, Levow C, Catterall M, Colvin OM, Pastan I, Brem H: Transforming growth factor-alpha–Pseudomonas exotoxin fusion protein (TGF-alpha–PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice. Cancer Res 54: 1008–1015, 1994
Hall WA, Fodstad O: Immunotoxins and central nervous system neoplasia. J Neurosurg 76: 1–12, 1992
Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, Pastan I: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 345: 241–247, 2001
Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Jaffe ES, Giardina S, Waldmann TA, Pastan I: Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18: 1622–1636, 2000
LeMaistre CF, Craig FE, Meneghetti C, McMullin B, Parker K, Reuben J, Boldt DH, Rosenblum M, Woodworth T: Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers. Cancer Res 53: 3930–3934, 1993
LeMaistre CF, Meneghetti C, Rosenblum M, Reuben J, Parker K, Shaw J, Deisseroth A, Woodworth T, Parkinson DR: Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor. Blood 79: 2547–2554, 1992
LeMaistre CF, Rosenblum MG, Reuben JM, Parkinson DR, Meneghetti CM, Parker K, Shaw JP, Deisseroth AB, Woodworth T: Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia. Lancet 337: 1124–1125, 1991
Kuzel TM, Rosen ST, Gordon LI, Winter J, Samuelson E, Kaul K, Roenigk HH, Nylen P, Woodworth T: Phase I trial of the diphtheria toxin/interleukin-2 fusion protein DAB486IL-2: efficacy in mycosis fungoides and other non-Hodgkin's lymphomas. Leuk Lymphoma 11: 369–377, 1993
Tepler I, Schwartz G, Parker K, Charette J, Kadin ME, Woodworth TG, Schnipper LE: Phase I trial of an interleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies: complete response in a patient with Hodgkin's disease refractory to chemotherapy. Cancer 73: 1276–1285, 1994
Joshi BH, Kawakami K, Leland P, Puri RK: Heterogeneity in interleukin-13 receptor expression and subunit structure in squamous cell carcinoma of head and neck: differential sensitivity to chimeric fusion proteins comprised of interleukin-13 and a mutated form of Pseudomonas exotoxin. Clin Cancer Res 8: 1948–1956, 2002
Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK: Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in 35 patients with high-grade glioma. Clin Cancer Res 6: 2157–2165, 2000
Pai LH, Bookman MA, Ozols RF, Young RC, Smith JW, Longo DL, Gould B, Frankel A, McClay EF, Howell S: Clinical evaluation of intraperitoneal Pseudomonas exotoxin immunoconjugate OVB3-PE in patients with ovarian cancer [see comments]. J Clin Oncol 9: 2095–2103, 1991
Pai LH, Wittes R, Setser A, Willingham MC, Pastan I: Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin. Nat Med 2: 350–353, 1996
Lorimer IAJ, Wikstrand CJ, Batra SK, Bigner DD, Pastan I: Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res 1: 859–864, 1995
Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B: Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84: 6899–6903, 1987
Wickstrand CJ, Fung K-M, Trojanowski JQ, et al: Russell & Rubenstein's Pathology of Tumors of the Nervous System. Antibodies and Molecular Immunology: Immunohistochemistry and Antigens of Diagnostic Significance, 6th edn. Arnold: Oxford University Press, 1998, Vol 1
Humphrey PA, Wong AJ, Vogelstein B, Friedman HS, Werner MH, Bigner DD, Bigner SH: Amplification and expression of the epidermal growth factor receptor gene in human glioma xenografts. Cancer Res 48: 2231–2238, 1988
Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H: Expression of epidermal growth factor receptors in human brain tumors. Cancer Res 44: 753–760, 1984
Torp SH, Helseth E, Dalen A, Unsgaard G: Epidermal growth factor receptor expression in human gliomas. Cancer Immunol Immunother 33: 61–64, 1991
Wikstrand CJ, Stenzel T, McLendon RE, Bigner DD: Correlation of EGFRwt RNA transcript levels and patient biopsy protein expression by immunohistochemistry. J Neuro-Oncol 2002 (in press)
Pastan I, Chaudhary V, FitzGerald DJ: Recombinant toxins as novel therapeutic agents. [Review] [155 refs]. Ann Rev Biochem 61: 331–354, 1992
Kunwar S, Pai LH, Pastan I: Cytotoxicity and antitumor effects of growth factor-toxin fusion proteins on human glioblastoma multiforme cells. J Neurosurg 79: 569–576, 1993
Laske DW, Youle RJ, Oldfield EH: Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3: 1362–1368, 1997
Zalutsky MR, Moseley RP, Coakham HB, Coleman RE, Bigner DD: Pharmacokinetics and tumor localization of 131I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies. Cancer Res 49: 2807–2813, 1989
Zalutsky MR, Moseley RP, Benjamin JC, Colapinto EV, Fuller GN, Coakham HP, Bigner DD: Monoclonal antibody and F(ab')2 fragment delivery to tumor in patients with glioma: comparison of intracarotid and intravenous administration. Cancer Res 50: 4105–4110, 1990
Bullard DE, Bourdon M, Bigner DD: Comparison of various methods for delivering radiolabeled monoclonal antibody to normal rat brain. J Neurosurg 61: 901–911, 1984
Bigner D, Brown M, Friedman AH, Coleman RE, Akabani G, Friedman HS, Thorstad WL, McLendon RE, Bigner SH, Zhao X-G, Pegram CN, Wikstrand CJ, Herndon IJE, Vick NA, Paleologos NA, Cokgor I, Provenzale JM, Zalutsky MR: Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J Clin Oncol 16: 2202–2212, 1998
Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91: 2076–2080, 1994
Morrison PF, Laske DW, Bobo H, Oldfield EH, Dedrick RL: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266: R292–R305, 1994
Laske DW, Morrison PF, Lieberman DM, Corthesy ME, Reynolds JC, Stewart-Henney PA, Koong SS, Cummins A, Paik CH, Oldfield EH: Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging. J Neurosurg 87: 586–594, 1997
Lieberman DM, Laske DW, Morrison PF, Bankiewicz KS, Oldfield EH: Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82: 1021–1029, 1995
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sampson, J.H., Akabani, G., Archer, G.E. et al. Progress Report of a Phase I Study of the Intracerebral Microinfusion of a Recombinant Chimeric Protein Composed of Transforming Growth Factor (TGF)-α and a Mutated form of the Pseudomonas Exotoxin Termed PE-38 (TP-38) for the Treatment of Malignant Brain Tumors. J Neurooncol 65, 27–35 (2003). https://doi.org/10.1023/A:1026290315809
Issue Date:
DOI: https://doi.org/10.1023/A:1026290315809