Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1994 May;39(3):193–197. doi: 10.1007/BF01533386

Loco-regional immunotherapy with recombinant interleukin-2 and adherent lymphokine-activated killer cells (A-LAK) in recurrent glioblastoma patients

Amerigo Boiardi 1,✉, Antonio Silvani 1, Pier Adelchi Ruffini 2, Licia Rivoltini 2, Giorgio Parmiani 2, Giovanni Broggi 1, Andrea Salmaggi 1
PMCID: PMC11038507  PMID: 7923250

Abstract

Nine patients with recurrent glioblastoma were given autologous adherent lymphokine-activated killer (A-LAK) cells and interleukin-2 (IL-2) administered directly into the tumor cavity through an Ommaya tube placed during surgery/biopsy. The immunotherapy was well tolerated and the response rate was 33% (one complete response, two partial responses, four with stable disease and two with progressive disease). However, survival 18 months from initial diagnosis did not differ from that reported in the literature for patients treated conventionally. Serial determinations of IL-2 in the tumor cavity during the course of treatment revealed that IL-2 concentrations were sufficient to maintain lymphocyte activation. Since steroid medication was discontinued during treatment and A-LAK cells have greater antitumor activity than standard LAK cells, other factors are discussed that might explain the limited results.

Key words: Glioblastoma, A-LAK, Loco-regional immunotherapy

References

  • 1.Burger PC, Boyko OB. The pathology of the central nervous system radiation injury. In: Gutin PH, Leibel SA, Sheline GE, editors. Radiation injury to the nervous system. New York: Raven Press; 1991. p. 236. [Google Scholar]
  • 2.Chocair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MSB, Wilson CB. Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg. 1986;65:654. doi: 10.3171/jns.1986.65.5.0654. [DOI] [PubMed] [Google Scholar]
  • 3.Denicoff KD, Rubinov DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE, Rosestein D, Rosenberg SA. The neuropsychiatric effects of the treatment with interleukin-2 and lymphokine-activated killer cells. Ann Int Med. 1987;107:293. doi: 10.7326/0003-4819-107-2-293. [DOI] [PubMed] [Google Scholar]
  • 4.Gillis S, Ferm MM, Ou W, Smith KA. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978;120:2027. [PubMed] [Google Scholar]
  • 5.Gutin PH, Leibel SA, Wara WM, Chouchair A, Levin VA, Philips TL, Silver P, Da Silva V, Edwards MSB, Davis RL, Weaver KA, Lamb S. Recurrent malignant gliomas: Survival following interstitial brachitherapy with high-activity iodine-124 sources. J Neurosurg. 1987;67:864. doi: 10.3171/jns.1987.67.6.0864. [DOI] [PubMed] [Google Scholar]
  • 6.Inge TH, Hoover SK, Susskind BM, Barret SK, Bear HD. Inhibition of tumor-specific cytotoxic T-lymphocyte responses by transforming growth factor-b1. Cancer Res. 1992;52:1386. [PubMed] [Google Scholar]
  • 7.Jaaskelainen J, Kalliomaki P, Paetau A, Timoen T. Effect of LAK cells against three-dimensional tumor tissue. In vitro study using multicellular human glioma spheroids as targets. J Immunol. 1989;142:1036. [PubMed] [Google Scholar]
  • 8.Jaaskelainen J, Maenpaa A, Patarroyo M, Gambher CG, Somersalo K, Tarkannen J, Kallio M, Timonen T. Migration of recombinant IL-2 activated T and natural killer cells in the intracellular space of human H-2 glioma spheroid in vitro. A study on adhesion molecules involved. J. Immunol. 1992;149:260. [PubMed] [Google Scholar]
  • 9.Jacobs SK, Wilson DJ, Kornblith PL, Grimm EA. Interleukin-2 or autologous lymphokine activated killer cell treatment of malignant glioma: phase I trial. Cancer Res. 1986;46:2101. [PubMed] [Google Scholar]
  • 10.Jaeckle KA, Mittelman A, Hill FH. Phase II trial ofSerratia marcescens extract in recurrent malignant astrocytoma. J Clin Oncol. 1990;8:1408. doi: 10.1200/JCO.1990.8.8.1408. [DOI] [PubMed] [Google Scholar]
  • 11.Kelly KA, Kirkwood JM, Kapps DS. Glioblastoma multiforme: pathology, natural history and treatment. Cancer Treat Rev. 1984;11:1. doi: 10.1016/0305-7372(84)90014-8. [DOI] [PubMed] [Google Scholar]
  • 12.Krueger JM, Walter C, Dinnarello CA, Wolff SM, Chedid L. Sleep promoting effects of endogenous pyrogen (interleukin-1) Am J Physiol. 1984;245:R 994. doi: 10.1152/ajpregu.1984.246.6.R994. [DOI] [PubMed] [Google Scholar]
  • 13.Kuppner MC, Hamou MF, Sawamura Y, Bodmer S, De Tribolet N. Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor-β2. J Neurosurg. 1989;71:211. doi: 10.3171/jns.1989.71.2.0211. [DOI] [PubMed] [Google Scholar]
  • 14.Kuppner MC, Sawamura Y, Hamou MF, De Tribolet N. Influence of PGE2 and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2 activated lymphocytes. J Neurosurg. 1990;72:619. doi: 10.3171/jns.1990.72.4.0619. [DOI] [PubMed] [Google Scholar]
  • 15.Mahaley MS. Neuro-oncology index and review (adult primary brain tumors. J Neurooncol. 1991;11:85. doi: 10.1007/BF02390173. [DOI] [PubMed] [Google Scholar]
  • 16.Mahaley MS, Brooks WH, Roszman TL, Bigner DD, Dudka L, Richardson S. Immunobiology of primary intracranial tumors. Part I. Studies of the cellular and humoral general immune competence of brain tumor patients. J Neurosurg. 1977;46:467. doi: 10.3171/jns.1977.46.4.0467. [DOI] [PubMed] [Google Scholar]
  • 17.Melder RJ, Whiteside TL, Vujanovic NL, Hiserodt JC, Herberman RB. A new approach to generating antitumor effectors for adoptive immunotherapy using adherent lymphokine-activated killer cells. Cancer Res. 1988;48:3461. [PubMed] [Google Scholar]
  • 18.Merchant RE, Ellison MD, Young HF. Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes. A review of preclinical and clinical investigation. J Neuroncol. 1990;8:173. doi: 10.1007/BF00177842. [DOI] [PubMed] [Google Scholar]
  • 19.Merchant RE, Mc Vicar DW, Merchant LH, Young HF. Treatment of recurrent malignant glioma by repeated intracerebral injection of human recombinant interleukin-2 alone or in combination with systemic interferon-α. Results of a phase I clinical trial. J Neurooncol. 1992;12:75. doi: 10.1007/BF00172459. [DOI] [PubMed] [Google Scholar]
  • 20.Mulé JJ, Schwarz SL, Roberts AB, Sporn MB, Rosenberg SA. Transforming growth factor-b inhibits the in vitro generation of lymphokine-activated killer cells and cytotoxic T cells. Cancer Immunol Immunother. 1988;26:95. doi: 10.1007/BF00205600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Nitta T, Sato K, Yagito H, Okumura K, Ishii S. Preliminary trial of specific targeting therapy against malignant glioma. Lancet. 1990;335:368. doi: 10.1016/0140-6736(90)90205-j. [DOI] [PubMed] [Google Scholar]
  • 22.Palma L, Di Lorenzo N, Guidetti B. Lymphocyte infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate and relevance to prognosis in 228 operated cases. J Neurosurg. 1978;49:854. doi: 10.3171/jns.1978.49.6.0854. [DOI] [PubMed] [Google Scholar]
  • 23.Ruffini PA, Rivoltini L, Silvani A, Boiardi A, Parmiani G. Factors, including transforming growth factor b, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells. Cancer Immunol Immunother. 1993;36:409. doi: 10.1007/BF01742258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Schwharz RE, Vujanovic NL, Hiserodt JC. Enhanced antimetastatic activity of lymphokine activated killer cells purified and expanded by their adherence to plastic. Cancer Res. 1989;49:1441. [PubMed] [Google Scholar]
  • 25.Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC. Regulation of lymphokine activated killer activity and poreforming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor β. J Immunol. 1991;146:3289. [PubMed] [Google Scholar]
  • 26.Yoshida S, Tanaka R, Takai N, Ono K. Local administration of autologous lymphokine-activated killer cells and recombinant interleukin 2 to patients with malignant brain tumors. Cancer Res. 1988;48:5011. [PubMed] [Google Scholar]
  • 27.Whiteside TL, Wang YL, Selker RG, Herberman RB. In vitro generation and antitumor activity of adherent lymphokine-activated killer cells from the blood of patients with brain tumors. Cancer Res. 1988;48:6069. [PubMed] [Google Scholar]
  • 28.Tzeng JJ, Barth RF, Orosz CG, James SM. Phenotype and functional activity of tumor-infiltrating lymphocytes isolated from immunogenic and non immunogenic rat brain tumors. Cancer Res. 1991;51:2373. [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES