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A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS)

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Abstract

A Phase I study of recombinant interferon-gamma (rIFN-γ) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-γ. rIFN-γ was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2–4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7–12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1–1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-γ is given at doses at or near this MTD.

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References

  1. Gutterman JU, Rosenblum MG, Rios A, Fritsche HA, Quesada JR: Pharmacokinetic study of partially pure γ-interferon in cancer patients. Cancer Res 44:4164–4171, 1984

    Google Scholar 

  2. Foon KA, Sherwin SA, Abrams PG, Stevenson HC, Holmes P, Maluish AE, Oldham RK, Herberman RB: A phase I trial of recombinant gamma interferon in patients with cancer. Cancer Immunol Immunother 20:193–197, 1985

    Google Scholar 

  3. Kurzrock R, Rosenblum MG, Sherwin SA, Rios A, Talpaz M, Quesada JR, Gutterman JU: Pharmacokinetics, single-dose tolerance, and biological activity of recombinant γ-interferon in cancer patients. Cancer Res 45:2866–2872, 1985

    Google Scholar 

  4. Fauci AS, Masur H, Gelmann EP, Markham PD, Hahn BH, Lane HC: The acquired immunodeficiency syndrome: An update. Ann Intern Med 102:800–813, 1985

    Google Scholar 

  5. Jacobs JL, Murray HW: Immunologic developments in AIDS-1985. Year Immunol 2:323–328, 1986

    Google Scholar 

  6. Krown SE, Real FX, Cunningham-Rundles S, Myskowski PL, Koziner B, Fein S, Mittelman A, Oettgen HF, Safai B: Preliminary observations on the effect of recombinant leukocyte α interferon in homosexual men with KS. N Engl J Med 308:1071–1076, 1983

    Google Scholar 

  7. Merigan TC: Human interferon as a therapeutic agent: A decade passes. N Engl J Med 318:1458–1460, 1988

    Google Scholar 

  8. Groopman JE, Gottlieb MS, Goodman J, Mitsuya RT, Conant MA, Prince H, Fahey JL, Derezin M, Weinstein WM, Casavante C, Rothman J, Rudnick SA, Volberding PA: Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med 100:671–676, 1984

    Google Scholar 

  9. Gelmann EP, Preble OT, Steis R, Lane HC, Rock AH, Wesley M, Jacob J, Fauci A, Masur H, Longo D: Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome: Clinical response and prognostic parameters. Am J Med 78:737–741, 1985

    Google Scholar 

  10. Lane HC, Feinberg J, Davey V, Deyton L, Baselar M, Manischewitz J, Masur H, Kovacs JA, Herpin B, Walker R, Metcalf JA, Salzman N, Quinnan G, Fauci AS: Anti-retroviral effects of interferon-α in AIDS-associated Kaposi's sarcoma. Lancet 2:1218–1222, 1988

    Google Scholar 

  11. de Wit R, Schattenkerk JK, Boucher CA, Bakker PJ, Veenhof KH, Danner SA: Clinical and virological effects of high-dose recombinant interferon-alpha in disseminated AIDS-related Kaposi's sarcoma. Lancet 2:1214–1217, 1988

    Google Scholar 

  12. Deyton, L, Kovacs JA, Masur H, Metcalf JA, Lee D, Salzman N, Baselar M, Bigley J, Lane HC, Fauci AS: Phase I–II trial of zidovudine combined with lymphoblastoid interferon alpha in patients with AIDS and Kaposi's sarcoma. Clin Res 36:438A, 1988 (abstr)

    Google Scholar 

  13. Murray HW: Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med 108:595–608, 1988

    Google Scholar 

  14. Murray HW, Rubin BY, Masur H, Roberts RB: Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med 310:883–889, 1984

    Google Scholar 

  15. Murray HW, Gellene RA, Libby DM, Rothermel CD, Rubin BY: Activation of tissue macrophages from AIDS patients:In vitro response of AIDS alveolar macrophages to lymphokines and interferon-γ. J Immunol 135:2374–2377, 1985

    Google Scholar 

  16. Murray HW, Hillman JK, Rubin BY, Kelly CD, Jacobs JL, Tyler LW, Donelly DM, Carriero SM, Godbold JH, Roberts RB: Patients at risk for AIDS-related opportunistic infections: Clinical manifestations and impaired gamma interferon production. N Engl J Med 313:1504–1510, 1985

    Google Scholar 

  17. Lane HC, Depper JM, Greene WC, Whalen G, Waldmann TA, Fauci AS: Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. N Engl J Med 313:79–84, 1985

    Google Scholar 

  18. Murray HW, Scavuzzo D, Jacobs JL, Kaplan MH, Libby DM, Schindler J, Roberts RB:In vitro andin vivo activation of human mononuclear phagocytes by interferon-γ: Studies with normal and AIDS monocytes. J Immunol 138:2457–2462, 1987

    Google Scholar 

  19. Jacobsen H: Interferons and antiviral activity. Arzneimittel-forschung 36:512–516, 1986

    Google Scholar 

  20. Rubin BY, Gupta SL: Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc Natl Acad Sci 77:5928–5932, 1980

    Google Scholar 

  21. Dolei A, Fattorossi A, D'amelio R, Aiuti F, Dianzani F: Direct and cell-mediated effects of interferon-α and -γ on cells chronically infected with HTLV-III. J Interferon Res 6:543–549, 1986

    Google Scholar 

  22. Vadhan-Raj S, Nathan CF, Sherwin SA, Oettgen HF, Krown SE: Phase I trial of recombinant interferon gamma by 1-hour infusion. Cancer Treat Rep 70:609–614, 1986

    Google Scholar 

  23. Kurzrock R, Quesada JR, Talpaz M, Hersh EM, Reuben JM, Sherwin SA, Gutterman JU: Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J Clin Oncol 4:1101–1109, 1986

    Google Scholar 

  24. Vadhan-Raj S, Al-Katib A, Bhalla R, Pelus L, Nathan CF, Sherwin SA, Oettgen HF, Krown SE: Phase I trial of recombinant interferon gamma in cancer patients. J Clin Oncol 4:137–146, 1986

    Google Scholar 

  25. Parkin JM, Eales LJ, Galazka AR, Pinching AJ: Atopic manifestations in the acquired immune deficiency syndrome: Response to recombinant interferon gamma. Br Med J 294:1185–1186, 1987

    Google Scholar 

  26. Rinderknecht E, O'Connor BH, Rodriguez H: Natural human interferon-gamma: Complete amino acid sequence and determination of sites of glycosylation. J Biol Chem 259:6790–6797, 1984

    Google Scholar 

  27. Rubinstein S, Familletti PC, Pestka S: Convenient assay for interferons. J Virol 37:755–758, 1981

    Google Scholar 

  28. CDC. Revision of the case definition of acquired immunodeficiency syndrome for national reporting—United States. MMWR 34:373–375, 1985

    Google Scholar 

  29. Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207–214, 1981

    Google Scholar 

  30. Lane HC, Masur H, Gelmann EP, Longo DL, Steis RG, Chused T, Whalen G, Edgar LC, Fauci AS: Correlation between immunologic function and clinical subpopulations of patients with the acquired immune deficiency syndrome. Am J Med 78:417–422, 1985

    Google Scholar 

  31. Rook AH, Masur H, Lane HC, Frederick W, Kasahara T, Macher AM, Djeu JY, Manischewitz JF, Jackson L, Fauci AS, Quinnan GV: Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest 72:398–403, 1983

    Google Scholar 

  32. Smith PD, Elson CO, Keister DB, Nash TE. Human host response toGiardia lamblia: Spontaneous killing by mononuclear leukocytesin vitro. J Immunol 128:1372–1376, 1982

    Google Scholar 

  33. Quinnan GV, Masur H, Rook AH, Armstrong G, Frederick WR, Epstein J, Manischewitz JF, Macher AM, Jackson L, Ames J, Smith HA, Parker M, Pearson GR, Parrillo J, Mitchell C, Straus SE: Herpesvirus infections in the acquired immune deficiency syndrome. JAMA 252:72–77, 1984

    Google Scholar 

  34. Lane HC, Fauci AS: Immunologic reconstitution in the acquired immunodeficiency syndrome. Ann Intern Med 103:714–718, 1985

    Google Scholar 

  35. Fauci AS, Lane HC: Antiretroviral therapy and immunologic reconstitution in AIDS. Ann Inst Pasteur/Immunol 138:261–268, 1987

    Google Scholar 

  36. Pennington JE, Groopman JE, Small GJ, Laubenstein L, Finberg R: Effect of intravenous recombinant γ-interferon on the respiratory burst of blood monocytes from patients with AIDS. J Infect Dis 153:609–612, 1986

    Google Scholar 

  37. Ganser A, Brucher W, Brodt HR, Busch W, Brandhorst I, Helm EB, Hoelzer D: Treatment of AIDS-related Kaposi's sarcoma with recombinant γ-interferon. Onkologie 9:163–166, 1986

    Google Scholar 

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Authors and Affiliations

  1. Laboratory of Immunoregulation, NIAID, National Institutes of Health, Building 10, Room 11B09, 20892, Bethesda, Maryland

    H. Clifford Lane, Richard T. Davey Jr., Margaret E. Easter & Anthony S. Fauci

  2. Genentech, Inc., 460 Point San Bruno Boulevard, 94080, South San Francisco, California

    Stephen A. Sherwin

  3. Critical Care Medicine Department, National Institutes of Health, Building 10 Room 10D48, 20892, Bethesda, Maryland

    Henry Masur

  4. Department of Dermatology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 2 Gates, 19104, Philadelphia, Pennsylvania

    Alain H. Rook

  5. Center for Biologics Evaluation & Research, FDA, Building 29, Room 129, 20892, Bethesda, Maryland

    Jody F. Manischewitz & Gerald V. Quinnan

  6. National Institutes of Health, Building 30, Room 322, 20892, Bethesda, Maryland

    Phillip D. Smith

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  1. H. Clifford Lane
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  2. Richard T. Davey Jr.
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  4. Henry Masur
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  7. Gerald V. Quinnan
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  9. Margaret E. Easter
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  10. Anthony S. Fauci
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Lane, H.C., Davey, R.T., Sherwin, S.A. et al. A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). J Clin Immunol 9, 351–361 (1989). https://doi.org/10.1007/BF00918667

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  • DOI: https://doi.org/10.1007/BF00918667

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