Abstract
Human malignant glioma cell lines, primary cell cultures, and tumor specimens derived from surgical samples have been shown to overexpress high-affinity receptors (R) for interleukin-4 (IL-4) in vitro and in situ. The significance of IL-4R expression on malignant glioma cells is still unclear. However, IL-4 has been reported to mediate functional effects in several solid tumor cell lines. These activities include inhibition of cell proliferation, regulation of adhesion molecules, and induction of signal transduction through the JAK/STAT pathway. To target IL-4Rs on tumor cells, we have produced a chimeric recombinant fusion protein consisting of a binding ligand, circularly permuted IL-4 and a mutated form of Pseudomonas exotoxin. This molecule is termed IL4(38–37)-PE38KDEL, cpIL4-PE, or IL-4 cytotoxin. Recombinant cpIL4-PE is highly and specifically cytotoxic to glioma cell lines in vitro, while it is not cytotoxic or less cytotoxic to hematopoietic and normal brain cells. In a nude mouse model, cpIL4-PE showed significant antitumor activity and partial or complete regression of small or large established human glioblastoma tumors. Encouraging preclinical efficacy, safety, and tolerability studies lead to testing of this agent in patients with recurrent glioblastoma. Based on these pilot studies, an extended Phase I/II clinical trial is currently ongoing to determine safety, tolerability, and efficacy of cpIL4-PE when injected stereotactically directly into the recurrent glioma by convection enhanced delivery. Preliminary clinical results suggest that cpIL4-PE can cause pronounced necrosis of recurrent glioma tumors without systemic toxicity. The central nervous system toxicities observed were attributed to the volume of infusion and/or nonspecific toxicity. Ongoing clinical trials will reveal antitumor activities of IL-4 cytotoxin in recurrent malignant glioma.
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References
Paul WE: Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 77: 1859–1870, 1991
Puri RK, Siegel JP: Interleukin-4 and cancer therapy. Cancer Invest 11: 473–486, 1993
Puri RK: Structure and function of interleukin-4 and its receptor In: Kurzrock R, Talpaz M (eds) Cytokines: Interleukins and their Receptors. Kluwer Academic Publishers, Norwell, MA, 1995, pp 143–185
Toi M, Bicknell R, Harris AL: Inhibition of colon and breast carcinoma cell growth by interleukin-4. Cancer Res 52: 275–279, 1992
Topp MS, Koenigsmann M, Mire-Sluis A, Oberberg D, Eitelbach F, von Marschall Z, Notter M, Reufi B, Stein H, Thiel E, Berdel WE: Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo. Blood 82: 2837–2844, 1993
Puri RK, Leland P, Kreitman RJ, Pastan I: Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the cytotoxic effect of IL4-Pseudomonas exotoxin chimeric protein. Int J Cancer 58: 574–581, 1994
Husain SR, Kreitman RJ, Pastan I, Puri RK: Interleukin-4 receptor directed cytotoxin therapy of AIDS-associated Kaposi's sarcoma tumors in xenograft model. Nat Med 5: 817–822, 1999 (Enrique A Mersi: News and Views Targeting AIDS-Kaposi's Sarcoma, pp 738, 739)
Leland P, Taguchi J, Husain SR, Kreitman RJ, Pastan I, Puri RK: Human breast carcinoma cells express type II IL-4 receptors and are sensitive to antitumor activity of a chimeric IL-4-Pseudomonas exotoxin fusion protein in vitro and in vivo. Mol Med 6: 165–178, 2000
Joshi BH, Leland P, Asher A, Prayson RA, Varricchio F, Puri RK:Advances in Brief: in situ expression of interleukin-4 receptors in human brain tumors and cytotoxicity of a recombinant interleukin-4 (IL-4) cytotoxin in primary glioblastoma cell cultures. Cancer Res 61: 8058–8061, 2001
Puri RK, Leland P: Tumor necrosis factor upregulates interleukin-4 receptors on murine sarcoma cells. Biochem Biophys Res Commun 197: 1424–1430, 1993
Kawakami K, Leland P, Puri RK: Structure, function, and targeting of interleukin 4 receptors on human head and neck cancer cells. Cancer Res 60: 2981–2987, 2000
Kawakami K, Kawakami M, Husain SR, Puri RK: Advances in brief: targeting interleukin-4 receptors for effective pancreatic cancer therapy. Cancer Res 62: 3575–3580, 2002 (Profiled on the Cover).
Puri RK, Hoon DS, Leland P, Snoy P, Rand RW, Pastan I, Kreitman RJ: Preclinical development of a recombinant toxin containing circularly permuted interleukin-4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. Cancer Res 56: 5631–5637, 1996
Joshi BH, Plautz GE, Puri RK: Advances in brief: interleukin-13 receptor ? chain: a novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. Cancer Res 60: 1168–1172, 2000
Liu H, Prayson RA, Estes ML, Drazba JA, Barnett GH, Bingaman W, Liu J, Jacobs BS, Barna BP: In vivo expression of the interleukin 4 receptor alpha by astrocytes in epilepsy cerebral cortex. Cytokine 12: 1656–1661, 2000
Idzerda RL, March CJ, Mosley B, Lyman SD, Vanden Bos T, Gimpel SD, Din WS, Grabstein KH, Widmer MB, Park LS, Cosman D, Beckman MP: Human interleukin-4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med 171: 861–873, 1990
Eyckerman S, Verhee A, derHeyden JV, Lemmens I, Ostade XV, Vandekerckhove J, Tavernier J: Design and application of a cytokine-receptor-based interaction trap. Nat Cell Biol 3: 1114–1119, 2001
Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Freidman MC, Miyajima A, Puri RK, Paul WE, Leonard WJ: Interleukin-2 receptor ? chain: a functional component of the interleukin-4 receptor. Science 262: 1880–1882, 1993
Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K: Sharing of interleukin-2 (IL-2) receptor ?c chain between receptors for IL-2 and IL-4. Science 262: 1874–1877, 1993
Noguchi M, Nakamura Y, Russell SM, Zielger SF, Tsang M, Cao X, Leonard WJ: Interleukin-2 receptor ? chain: a functional component of interleukin-7 receptor. Science 262: 1877–1880, 1993
Russell SM, Johnston M, Noguchi M, Kawamura M, Bacon CM, Freidmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O: Interaction of IL-2 receptor beta and gamma chain with JAK 1 and JAK 3: implications for XSCID and XCID. Science 266: 1042–1045, 1994
Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D: Utilization of beta and gamma chains of the IL-2 receptor by novel cytokine IL-15. EMBO J 13: 2822–2830, 1994
Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K: Cutting edge: the common gammachain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167: 1–5, 2001
Murata T, Obiri NI, Puri RK: Structure and signal transduction through interleukin-4 and interleukin-13 receptors. Int J Mol Med 1: 551–557, 1998
Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE: The IL-4 receptor: signaling mechanism and biologic functions. Annu Rev Immunol 17: 701–738, 1999
Murata T, Noguchi PD, Puri RK: Receptors for interleukin (IL)-4 do not associate with the common ? chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. J Biol Chem 270: 30829–30836, 1995
Obiri NI, Debinski W, Leonard WJ, Puri RK: Receptor for interleukin 13: interaction with interleukin 4 by a mechanism that does not involve the common γ-chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem 270: 8797–8804, 1995
Husain SR, Behari N, Kreitman RJ, Pastan, I, Puri RK: Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy. Cancer Res 58: 3649–3653, 1998
Obiri NI, Siegel JP, Varricchio F, Puri RK: Expression and function of high affinity interleukin-4 receptors on human melanoma, ovarian and breast carcinoma cells. Clin Exp Immunol 95: 148–155, 1994
Murata T, Taguchi J, Puri RK: Interleukin-13 receptor ?' chain but not ? chain: a functional component of interleukin-4 receptor. Blood 91: 3884–3891, 1998
Caput D, Laurent P, Kaghad M, Lelias JM, Lefort S, Vita N, Ferrara P: Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor ? chain. J Biol Chem 271: 16921–16926, 1996
Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H, Henderson SL, O'Hara RM Jr, Beier DR, Turner KJ, Wood CR, Collins M: The murine IL-13 receptor ą2: molecular cloning, characterization, and comparison with murine IL-13 receptor ą1. J Immunol 161: 2317–2324, 1998
Kawakami K, Taguchi J, Murata T, Puri RK: The interleukin-13 receptor ą2 chain: an essential component for binding and internalization but not for IL-13 induced signal transduction through the STAT6 pathway. Blood 97: 2673–2679, 2001
Kawakami K, Kawakami M, Snoy PJ, Husain SR, Puri RK: In vivo overexpression of IL-13 receptor ą2 chain inhibits tumorigenicity of human breast and pancreatic tumors in immunodeficient mice. J Exp Med 194: 1743–1754, 2001
Rahaman SO, Sharma P, Harbor PC, Aman MJ, Vogelbaum MA, Haque SJ: IL-13Rą2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res 62: 1103–1109, 2002
Bernard J, Treton D, Vermot-Desroches C, Boden C, Horellou P, Angevin E, Galanaud P, Wijdenes J, Richard Y: Expression of interleukin 13 receptor in glioma and renal cell carcinoma: IL-13Ralpha2 as a decoy receptor for IL-13. Lab Invest 81: 1223–1231, 2001
Reiter Y: Recombinant immunotoxins in targeted cancer cell therapy. Adv Cancer Res 81: 93–124, 2001
Frankel AE: Increased sophistication of immunotoxins. Clin Cancer Res 8: 942–944, 2002
Kawakami K, Kawakami M, Puri RK: Overexpressed cell surface interleukin-4 receptor molecules can be successfully targeted for antitumor cytotoxin therapy. Crit Rev Immunol 21: 299–310, 2001
Pennell CA, Erickson HA: Designing immunotoxins for cancer therapy. Immunol Res 2: 177–191, 2002
Debinski W, Puri RK, Kreitman RJ, Pastan I: A wide range of human cancers express interelukin-4 receptors that can be targeted with chimeric toxin composed of IL-4 and Pseudomonas exotoxin. J Biol Chem 268: 14065–14070, 1993
Puri RK, Debinski W, Obiri NI, Kreitman RJ, Pastan I: Human renal cell carcinoma cells are sensitive to the cytotoxic effect of a chimeric protein comprised of human interleukin-4 and Pseudomonas exotoxin. Cell Immunol 154: 369–379, 1994
Pastan I, Chaudhary V, FitzGerald DJ: Recombinant toxins as novel therapeutic agents. Annu Rev Biochem 61: 331–354, 1992
Kreitman RJ, Puri RK, Pastan I: A circularly permuted recombinant interleukin 4 toxin with increased activity. Proc Natl Acad Sci USA 91: 6889–6893, 1994
Puri RK, FitzGerald D, Leland P, Kozak RW, Pastan I: In vitro and in vivo suppression of interleukin-2-activated killer cell activity by chimeric proteins between interleukin-2 and Pseudomonas exotoxin. Cell Immunol 143: 324–334, 1992
Kawakami K, Kawakami M, Leland P, Puri RK. Internalization property of interleukin-4 receptor ą-chain increases cytotoxic effect of interleukin-4 receptor-targeted cytotoxin in cancer cells. Clin Cancer Res 8: 258–266, 2002
Morrison BW, Leder P:Areceptor binding domain of mouse interleukin-4 defined by a solid phase binding assay and in vitro mutagenesis. J Biol Chem 267: 11957–11963, 1992
Kreitman RJ, Puri RK, Pastan I: Increased antitumor activity of a circularly permuted interleukin 4-toxin in mice with interleukin 4 receptor-bearing human carcinoma. Cancer Res 55: 3357–3363, 1995
Rand RW, Kreitman RJ, Patronas N, Varrichio F, Pastan I, Puri RK: Advances in brief: intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res 6: 2157–2165, 2000
Laske DW, Youle RJ, Oldfield EH: Tumor regression with regional distribution of the targeted toxin TF-CRM 107 in patients with malignant brain tumors. Nat Med 3: 1362–1368, 1997
Asher AL, Weber F, Bucholz R, Berger M, Prados M, Bruce J, Hall W, Rainov NG, Westphal M, Warnick R, Willaims RL, Hingorani VN, Puri RK: Tumor response, safety and tolerability of IL4-toxin (NBI-3001) in patients with recurrent malignant gliomas. 51st Annual Meeting of Congress of Neurological Surgeons. San Diego Convention Center, San Diego, California. September 29–October 4, 2001, Abstract No. 763, p 140
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Kawakami, M., Kawakami, K. & Puri, R.K. Interleukin-4-Pseudomonas Exotoxin Chimeric Fusion Protein for Malignant Glioma Therapy. J Neurooncol 65, 15–25 (2003). https://doi.org/10.1023/A:1026294416718
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DOI: https://doi.org/10.1023/A:1026294416718