Abstract
High-dose interleukin-(IL-2) has been broadly studied in tumour therapy, yet it may be inhibitory to T-cell-dependent immunity. Therefore immune and tumour responses mediated by low-dose IL-2 were studied systematically with respect to the feedback organisation of immune responses. IL-2 was administered once daily at three dose levels: 0.18, 0.9, 4.5 MIU/m2 according to three different schedules requiring subcutaneous (s.c.) injection once weekly (four doses, stratum I), thrice weekly every other day (nine doses, stratum II), or five times weekly every other week (ten doses, stratum III). A total of 46 patients with advanced cancer were randomly assigned to one of the nine treatment groups. Systemic effects were induced at doses as low as 0.18 MIU/m2 IL-2 s.c. as demonstrated from measurable IL-2 serum levels, induction of circulating IL-6, a transient lymphopenia, and stimulation of delayed-type hypersensitivity (DTH) responses of the skin. Analysis of the different IL-2 schedules demonstrated (a) prolonged effects of once-weekly injections on DTH responses, lymphocyte and eosinophil counts, and (b) maximum increase of eosinophil counts and preferential expansion of activated NK cells with repeated injections every 48 h or 72 h (stratum II), while sequential treatment according to stratum III was found to be more potent in increasing the number of activated T cells. A tumour response was observed in 1/15 patients with renal cell carcinoma who experienced more than 50% tumour regression for 8 months; 12 patients had stable disease for 4 months (median). These data demonstrate prolonged immunological effects of ultra-low doses of s. c. IL-2 despite its short half-life. Furthermore, scheduling of IL-2 was found to affect immune responsiveness specifically as demonstrated by the differential effects on natural killer and T cell populations.
Key words: IL-2, Dosing, Scheduling, Immunity, Cancer patients
Footnotes
Supported by Bundesministerium für Forschung und Technologie, Förderkennzeichen 01GA8901/3 to R. M.
References
- 1.Bocci V. Interleukins. Clinical pharmacokinetics and practical implications. Clin Pharmacokinet. 1991;21:274–284. doi: 10.2165/00003088-199121040-00004. [DOI] [PubMed] [Google Scholar]
- 2.van den Brink MRM, Boggs SS, Herbermann RB, Hiserodt JC. The generation of natural killer (NK) cells from NK precursor cells in rat long-term bone marrow cultures. J Exp Med. 1990;172:303–313. doi: 10.1084/jem.172.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cantrell DA, Smith KA. The transient expression of interleukin 2 receptors. Consequences for T cell growth. J Exp Med. 1983;158:1895–1905. doi: 10.1084/jem.158.6.1895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Klein J. Regulation of the immune response. In: Klein J, editor. Immunology. Boston: Blackwell; 1990. pp. 386–391. [Google Scholar]
- 6.Kolitz JE, Mertelsmann R. The immunotherapy of human cancer with interleukin-2: present status and future directions. Cancer Invest. 1991;9:529–542. doi: 10.3109/07357909109018951. [DOI] [PubMed] [Google Scholar]
- 7.Konrad MW, Hemstreet G, Hersh EM, Mansell PWA, Mertelsmann R, Kolitz JE, Bradley EC. Pharmacokinetic of recombinant interleukin 2 in humans. Cancer Res. 1990;50:2009–2017. [PubMed] [Google Scholar]
- 8.Lenardo MJ. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature. 1991;353:858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
- 9.Lindemann A, Herrmann F, Oster W, Mertelsmann R. Lymphokine activated killer cells. Blut. 1989;59:375–384. doi: 10.1007/BF00321208. [DOI] [PubMed] [Google Scholar]
- 10.Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CAY, Custer MC, Rosenberg SA. In vivo administration of purified human interleukin 2. J Immunol. 1985;135:2865–2875. [PubMed] [Google Scholar]
- 11.McElrath MJ, Kaplan G, Burkhardt RA, Cohn ZA. Cutaneous response to recombinant interleukin 2 in human immunodeficiency virus 1-seropositive individuals. Proc Natl Acad Sci USA. 1990;87:5783–5787. doi: 10.1073/pnas.87.15.5783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mulé JJ, Shu S, Rosenberg SA. The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin 2 in vivo. J Immunol. 1985;135:646–652. [PubMed] [Google Scholar]
- 13.Nagler A, Lanier LL, Cwirla S, Phillips JH. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989;143:3183–3191. [PubMed] [Google Scholar]
- 14.Pahwa R, Chatila T, Pahwa S, Paradise C, Day NK, Geha R, Schwartz SA, Slade H, Oyaizu N, Good RA. Recombinant interleukin 2 therapy in severe combined immuno-deficiency disease. J Immunol. 1989;86:5069–5073. doi: 10.1073/pnas.86.13.5069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Philips JH, Gemlo BT, Myers WW, Rayner AA, Lanier LL. In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy. J Clin Oncol. 1987;5:1933–1941. doi: 10.1200/JCO.1987.5.12.1933. [DOI] [PubMed] [Google Scholar]
- 16.Rand TH, Silberstein DS, Kornfeld H, Weller PF. Human eosinophils express functional interleukin 2 receptors. J Clin Invest. 1991;88:825–832. doi: 10.1172/JCI115383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Soiffer RJ, Murray Ch, Cochran K, Cameron Ch, Wang E, Schow PW, Daley JF, Ritz J. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood. 1992;79:517–526. [PubMed] [Google Scholar]
- 18.Wiebke EA, Rosenberg SA, Lotze MT. Acute immunologic effects of interleukin-2 therapy in cancer patients: decreased delayed type hypersensitivity response and decreased proliferative response to soluble antigens. J Clin Oncol. 1988;6:1440–1449. doi: 10.1200/JCO.1988.6.9.1440. [DOI] [PubMed] [Google Scholar]
- 19.Yamaguchi Y, Suda T, Shiozaki H, Miura Y, Hitoshi Y, Tominaga A, Takatsu K, Kasahara T. Role of IL-5 in IL-2-induced eosinophilia: in vivo and in vitro expression of IL-5 mRNA by IL-2. J Immunol. 1990;145:873–877. [PubMed] [Google Scholar]
- 20.Yamaguchi Y, Suda T, Ohta S, Tominaga K, Miura Y, Kasahara T. Analysis of the survival of mature human eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils. Blood. 1991;78:2542–2547. [PubMed] [Google Scholar]