Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study.

DAB486IL-2 is a recombinant toxin with the cell surface-binding domain of diphtheria toxin (DT) replaced by interleukin-2 (IL-2). To correlate clinical response with expression of components of the IL-2 receptor (IL-2R), 14 patients with cutaneous T-cell lymphoma (CTCL) received five daily 90-minute infusions every 21 days. There were no complete responses, 1 partial response (PR), 2 major biologic effects (major cutaneous improvement without change in circulating neoplastic cells), 3 stable disease (SD), and 8 progressive disease (PD). Responders had easily detected expression of CD25 (Tac; alpha-chain of IL-2R) in skin, and in two responders expression of the beta chain of the IL-2 receptor (beta-IL-2R) was detectable by reverse transcriptase-polymerase chain reaction. CD25 was also detected in 8 of 11 SD or PD patients, with beta-IL-2R in 3 of 8 SD or PD patients. Two of the three responders had anti-DT antibodies before treatment. Reversible increased hepatic transaminases occurred in 13 of 14 patients during the first course, with decreased frequency in repeated courses. The maximal serum concentration after the first infusion of DAB486IL-2 varied (1,369 +/- 1,155 ng/mL [mean +/- SD]; n = 14; range, 55 to 3,999 ng/mL) with a short half-life (T1/2 beta = 0.21 +/- 0.12 h [mean +/- SD]; range, 0.099 to 0.57 h). The area under the concentration curve varied inversely with anti-DT antibody titer. We conclude that DA-B486IL-2 has valuable activity in certain patients with CTCL. Expression of the IL-2R may be necessary but is not sufficient to predict response.

[1]  T. Greiner,et al.  Flow cytometric detection of neoplastic T cells in patients with mycosis fungoides based on levels of T-cell receptor expression. , 1994, American journal of clinical pathology.

[2]  T. Woodworth,et al.  Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  F. Craig,et al.  Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers. , 1993, Cancer research.

[4]  M. Bernengo,et al.  Thymopentin in Sézary syndrome. , 1992, Journal of the National Cancer Institute.

[5]  J. Reuben,et al.  Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor. , 1992, Blood.

[6]  G. Yamada,et al.  Impact of interleukin‐2‐receptor‐targeted cytotoxins on a unique model of murine interleukin‐2‐receptor‐expressing malignancy , 1991, International journal of cancer.

[7]  R. Wittes Manual of oncologic therapeutics , 1991 .

[8]  P. Bunn,et al.  Photochemotherapy alone or combined with interferon alpha-2a in the treatment of cutaneous T-cell lymphoma. , 1990, The Journal of investigative dermatology.

[9]  F. Mandelli,et al.  Interferon alpha‐2a in cutaneous T‐cell lymphoma , 1990, European journal of haematology. Supplementum.

[10]  T. Strom,et al.  Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. , 1990, The Journal of biological chemistry.

[11]  Kendall A. Smith,et al.  Interleukin 2 receptor‐targeted cytotoxicity. Receptor binding requirements for entry of a diphtheria toxin‐related interleukin 2 fusion protein into cells , 1990, European journal of immunology.

[12]  E. Kohn,et al.  Phase II trial of intermittent high-dose recombinant interferon alfa-2a in mycosis fungoides and the Sézary syndrome. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  S. Steinberg,et al.  A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. , 1989, The New England journal of medicine.

[14]  A. W. Tam,et al.  Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. , 1989, BioTechniques.

[15]  T. Taniguchi,et al.  Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. , 1989, Science.

[16]  R. Vollmer,et al.  Interferon alfa-2a in the treatment of cutaneous T cell lymphoma. , 1989, Journal of the American Academy of Dermatology.

[17]  E. V. Van Scott,et al.  Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. , 1989, Journal of the American Academy of Dermatology.

[18]  G. Marti,et al.  Expression of interleukin-2 receptor beta subunit in hematopoietic malignancies. , 1989, Blood.

[19]  G. Wood,et al.  Benign and malignant forms of erythroderma: cutaneous immunophenotypic characteristics. , 1988, Journal of the American Academy of Dermatology.

[20]  E. Sausville,et al.  Histopathologic staging at initial diagnosis of mycosis fungoides and the Sézary syndrome. Definition of three distinctive prognostic groups. , 1988, Annals of internal medicine.

[21]  G. Wilson,et al.  The interleukin-2 receptor and its expression in the acute leukaemias and lymphoproliferative disorders. , 1988, Disease Markers.

[22]  T. Strom,et al.  Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor- mediated action of a diphtheria toxin-related interleukin 2 fusion protein , 1988, The Journal of experimental medicine.

[23]  J. Strauchen,et al.  IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases. , 1987, The American journal of pathology.

[24]  K Wolff,et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. , 1987, The New England journal of medicine.

[25]  W. Bishai,et al.  Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. , 1987, Protein engineering.

[26]  S. Kaplanski,et al.  An OKT4+ T‐Cell Population in Séezary Syndrome: Attempts to Elucidate Its Lack of Proliferative Capacity and Its Suppressive Effect , 1986, Scandinavian journal of immunology.

[27]  E. Sausville,et al.  Histologic assessment of lymph nodes in mycosis fungoides/Sézary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system. , 1985, Human pathology.

[28]  D. Nelson,et al.  Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. , 1985, Journal of immunology.

[29]  J. Yodoi,et al.  Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. , 1985, The Journal of clinical investigation.

[30]  J. Olerud,et al.  Immunopathology of cutaneous T-cell lymphomas. , 1985, The American journal of pathology.

[31]  T. Honjo,et al.  Molecular cloning of cDNA encoding human interleukin-2 receptor , 1984, Nature.

[32]  W. Blattner,et al.  Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. , 1984, The Journal of clinical investigation.

[33]  Z. Fuks,et al.  Electron-beam therapy for mycosis fungoides: the Stanford University experience. , 1979, Cancer treatment reports.

[34]  B. Safai,et al.  Electron-beam therapy for mycosis fungoides. , 1978, The Journal of dermatologic surgery and oncology.

[35]  T. Waldmann,et al.  The Sézary syndrome: a malignant proliferation of helper T cells. , 1976, The Journal of clinical investigation.

[36]  T. Waldmann,et al.  A MALIGNANT PROLIFERATION OF HELPER T CELLS , 1976 .

[37]  A. Ahmed,et al.  Cutaneous T-cell lymphomas: the Sézary syndrome, mycosis fungoides, and related disorders. , 1975, Annals of internal medicine.

[38]  L. Thomas,et al.  Mycosis fungoides: The pathology of extracutaneous involvement , 1974, Cancer.

[39]  A. Eisen,et al.  Mycosis fungoides: Natural history and aspects of its relationship to other malignant lymphomas , 1963 .