Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 May;36(3):141–148. doi: 10.1007/BF01741084

Interleukin-2 in cancer treatment: Disappointing or (still) promising? A review

Riks A Maas 1, Hub F J Dullens 1,✉, Willem Den Otter 1
PMCID: PMC11038683  PMID: 8439974

Abstract

The central question to discuss in this review is whether the results of interleukin-2 (IL-2) treatment are still disappointing or again promising. Although in the (recent) past application of high doses of systemically applied rIL-2 has led to some success, the overall results are not as one had hoped. Considering these poor results it seems clear that the application of high systemic doses rIL-2 was not a good choice. IL-2 has been used more or less as a chemotherapeutic compound in the highest tolerable dose. This has led to a great number of unwanted toxic side-effects. In addition, these doses mainly stimulated nonspecific lymphokine-activated killer activity through low-affinity IL-2 receptors, which does not lead to systemic immunity. On the other hand, several groups have shown that application of intratumoral low doses of IL-2 can be highly effective against cancer and without toxic side-effects. Significant tumor loads constituting up to 6% of the total body weight of a mouse were eradicated after treatment with low-dose rIL-2 given locally. Furthermore local treatment can lead to eradication of a tumor at a distant site. This type of therapy is effective in many systems namely against different tumor types in mice, hepatocellular carcinoma in guinea-pigs and vulval papilloma and carcinoma and ocular carcinoma in cattle. Low-dose IL-2 is very effective in experimental animals if it is given relatively late after inoculation of the tumor cells. In other words, it seems necessary that some sort of immune reaction has started or is developing before low doses of rIL-2 effectively stimulate it. In fact there is strong evidence that T lymphocytes, both CD4+ and CD8+ cells, are directly involved in the process leading to induction of specific immunity. In our opinion rIL-2 therapy should therefore aim at the stimulation of such (originally weak) specific immune reaction. Under these conditions also systemic immunity can be induced. In conclusion, application of rIL-2 as a modality for cancer treatment is still promising. High priority should be given to a further delineation of the mechanisms involved after local application. The method of giving IL-2 systemically in the highest tolerable dose should be abandoned. Specific stimulation of the immune system by low-dose rIL-2 is a much more promising option.

Key words: Immunotherapy, Recombinant interleukin-2, Local application

References

  • 1.Allison MAK, Jones SE, McGuffey P. Phase II trial of outpatient interleukin-2 in malignant lymphoma, chronic lymphocytic leukemia, and selected solid tumors. J Clin Oncol. 1989;7:75. doi: 10.1200/JCO.1989.7.1.75. [DOI] [PubMed] [Google Scholar]
  • 2.Anderson PM, Katsanis E, Leonard AS, Schow D, Loeffler CM, Goldstein MB, Ochoa AC. Increased local antitumor effects of interleukin-2 liposomes in mice with MCA 106 sarcoma pulmonary metastases. Cancer Res. 1990;50:1853. [PubMed] [Google Scholar]
  • 3.Ballas ZK, Rasmussen W, Van Otegham JK. Lymphokine-activated killer (LAK) cells: II. Delineation of distinct murine LAK-precursor sub-populations. J Immunol. 1987;138:1647. [PubMed] [Google Scholar]
  • 4.Blankenstein T, Qin Z, Überla K, Müller W, Rosen H, Volk H-D, Diamantstein T. Tumor suppression after tumor cell-targeted tumor necrosis factor α gene transfer. J Exp Med. 1991;173:1047. doi: 10.1084/jem.173.5.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Blay J-Y, Favrot MC, Negrier S, Combaret V, Chouaib S, Mercatello A, Kaemmerlen P, Franks CR, Philip T. Correlation between clinical response to interleukin 2 therapy and sustained production of tumor necrosis factor. Cancer Res. 1990;50:2371. [PubMed] [Google Scholar]
  • 6.Boccoli G, Masciulli R, Ruggeri EM, Carlini P, Giannella G, Montesoro E, Mastroberardino G, Isacchi G, Testa U, Calabresi F, Peschle C. Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose interleukin 2 bolus treatment. Cancer Res. 1990;50:5795. [PubMed] [Google Scholar]
  • 7.Bubenik J, Indrova M. The antitumor efficacy of human recombinant interleukin 2: correlation between sensitivity of tumors to the cytolytic effect of LAK cells in vitro and their susceptibility to interleukin 2 immunotherapy in vivo. Cancer Immunol Immunother. 1987;24:269. doi: 10.1007/BF00205642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Bubenik J, Perlmann P, Indrova M, Simova J, Jandlova T, Neuwirt J. Growth inhibition of an MC-induced mouse sarcoma by TCGF (IL-2)-containing preparations. Preliminary report. Cancer Immunol Immunother. 1983;14:205. doi: 10.1007/BF00205362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Clark JW, Smith JW, II, Steis RG, Urba WJ, Crum E, Miller R, McKnight J, Beman J, Stevenson HC, Creekmore S, Stewart M, Conlon K, Sznol M, Kremers P, Cohen P, Longo DL. Interleukin 2 and lymphokine-activated killer cell therapy: analysis of a bolus interleukin 2 and a continuous infusion interleukin 2 regimen. Cancer Res. 1990;50:7343. [PubMed] [Google Scholar]
  • 10.Colombo MP, Ferrari G, Stoppacciaro A, Parenza M, Rodolfo M, Mavilio F, Parmiani G. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J Exp Med. 1991;173:889. doi: 10.1084/jem.173.4.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Cortesina G, De Stefani A, Giovarelli M, Barioglio MG, Cavallo GP, Jemma C, Forni G. Treatment of recurrent squamous cell carcinoma of the head and neck with low doses of interleukin-2 injected perilymphatically. Cancer. 1988;62:2482. doi: 10.1002/1097-0142(19881215)62:12<2482::aid-cncr2820621205>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  • 12.Crum ED, Kaplan DR. In vivo activity of solid phase interleukin 2. Cancer Res. 1991;51:875. [PubMed] [Google Scholar]
  • 13.Culver K, Cornetta K, Morgan R, Morecki S, Aebersokd P, Kasid A, Lotze M, Rosenberg SA, Anderson WF, Blaese RM. Lymphocytes as cellular vehicles for gene therapy in mouse and man. Proc Natl Acad Sci USA. 1991;88:3155. doi: 10.1073/pnas.88.8.3155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Damle NK, Doyle LV, Bradley EC. Interleukin 2-activated human killer cells are derived from phenotypically heterogeneous precursors. J Immunol. 1986;137:2814. [PubMed] [Google Scholar]
  • 15.Dillman RO, Oldham RK, Tauer KW, Orr DW, Barth NM, Blumenschein G, Arnold J, Birch R, West WH. Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a national biotherapy study group trial. J Clin Oncol. 1991;9:1233. doi: 10.1200/JCO.1991.9.7.1233. [DOI] [PubMed] [Google Scholar]
  • 16.Dullens HFJ, De Wit C. Cancer treatment with interleukin 1, 4 and 6 and combinations of cytokines. A review. In Vivo. 1991;5:567. [PubMed] [Google Scholar]
  • 17.Dutcher JP, Creekmore S, Weiss GR, Margolin K, Markowitz AB, Roper M, Parkinson D, Ciobanu N, Fisher RI, Boldt DH, Doroshow JH, Rayner AA, Hawkins M, Atkins M. A phase II study of interleukin-2 and lymphokine activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol. 1989;7:477. doi: 10.1200/JCO.1989.7.4.477. [DOI] [PubMed] [Google Scholar]
  • 18.Ettinghausen SE, Puri RK, Rosenberg SA. Increased vascular permeability in organs mediated by the systemic administration of lymphokine-activated killer cells and recombinant interleukin-2 in mice. JNCI. 1988;80:177. doi: 10.1093/jnci/80.3.177. [DOI] [PubMed] [Google Scholar]
  • 19.Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, Vogelstein B, Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990;60:397. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
  • 20.Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, O'Garra A. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991;146:3444. [PubMed] [Google Scholar]
  • 21.Fisher B, Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, Yang JC, Yolles P, Larson SM, Rosenberg SA. Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol. 1989;7:250. doi: 10.1200/JCO.1989.7.2.250. [DOI] [PubMed] [Google Scholar]
  • 22.Forni G, Giovarelli M, Santoni A. Lymphokine-activated tumor inhibition in vivo: I. The local administration of interleukin 2 triggers non-reactive lymphocytes from tumor bearing mice to inhibit tumor growth. J Immunol. 1985;134:1305. [PubMed] [Google Scholar]
  • 23.Fujiwara F, Sakagami K, Matsuoka J, Shiozaki S, Uchida S, Fujioka K, Takada Y, Onoda T, Orita K. Application of an interleukin 2 slow delivery system to the immunotherapy of established murine colon 26 adenocarcinoma liver metastases. Cancer Res. 1990;50:7003. [PubMed] [Google Scholar]
  • 24.Gansbacher B, Bannerji R, Daniels B, Zier K, Cronin K, Gilboa E. Retroviral vector-mediated γ-interferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res. 1990;50:7820. [PubMed] [Google Scholar]
  • 25.Ghosh AK, Dazzi H, Thatcher N, Moore M. Lack of correlation between peripheral blood lymphokine-activated (LAK) cell function and clinical response in patients with advanced malignant melanoma receiving recombinant interleukin-2. Int J Cancer. 1989;43:410. doi: 10.1002/ijc.2910430311. [DOI] [PubMed] [Google Scholar]
  • 26.Gillis S, Smith KA. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977;268:154. doi: 10.1038/268154a0. [DOI] [PubMed] [Google Scholar]
  • 27.Glaser M. Augmentation of specific immune response against a syngeneic SV40 induced sarcoma in mice by depletion of suppressor T cells with cyclophosphamide. Cell Immunol. 1979;48:339. doi: 10.1016/0008-8749(79)90128-x. [DOI] [PubMed] [Google Scholar]
  • 28.Heinzel FP, Sadick MD, Mutha SS, Locksley RM. Production of interferon γ, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci USA. 1991;88:7011. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Hermann GG, Geertsen PF, Von der Maase H, Zeuthen J. Interleukin-2 dose, blood monocyte and CD25+ lymphocyte counts as predictors of clinical response to interleukin-2 therapy in patients with renal cell carcinoma. Cancer Immunol Immunother. 1991;34:111. doi: 10.1007/BF01741344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hermann GG, Geertsen PF, Von der Maase H, Steven K, Andersen C, Hald T, Zeuthen J. Recombinant interleukin-2 and lymphokine-activated killer cell treatment of advanced bladder cancer: clinical results and immunological effects. Cancer Res. 1992;52:726. [PubMed] [Google Scholar]
  • 31.Holsti MA, Raulet DH. IL-6 and IL-1 synergize to stimulate IL-2 production and proliferation of peripheral T cells. J Immunol. 1989;143:2514. [PubMed] [Google Scholar]
  • 32.Kalland T, Belfrage H, Bhiladvala P, Hedlund G. Analysis of the murine lymphokine-activated killer (LAK) cell phenomenon: dissection of effectors and progenitors into NK- and T-like cells. J Immunol. 1987;138:3640. [PubMed] [Google Scholar]
  • 33.Karasuyama H, Rolink A, Melchers F. Recombinant interleukin 2 or 5, but not 3 or 4, induces maturation of resting mouse B lymphocytes and propagates proliferation of activated B cell blasts. J Exp Med. 1988;167:1377. doi: 10.1084/jem.167.4.1377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kasahara T, Hooks JJ, Dougherty SF, Oppenheim JJ. Interleukin 2-mediated immune interferon (IFN-γ) production by human T cells and T cell subsets. J Immunol. 1983;130:1784. [PubMed] [Google Scholar]
  • 35.Kasaian MT, Biron CA. The activation of IL-2 transcription in L3T4+ and Lyt-2+ lymphocytes during virus infection in vivo. J Immunol. 1989;142:1287. [PubMed] [Google Scholar]
  • 36.Kasid A, Director EP, Rosenberg SA. Induction of endogenous cytokine-mRNA in circulating peripheral blood mononuclear cells by IL-2 administration to cancer patients. J Immunol. 1989;143:736. [PubMed] [Google Scholar]
  • 37.Kasid A, Director EP, Stovroff MC, Lotze MT, Rosenberg SA. Cytokine regulation of tumor necrosis factor-α and -β (lymphotoxin)-messenger RNA expression in human peripheral blood mononuclear cells. Cancer Res. 1990;50:5072. [PubMed] [Google Scholar]
  • 38.Konrad MW, Hemstreet G, Hersh EM, Mansell PWA, Mertelsmann R, Kolitz JE, Bradley EC. Pharmacokinetics of recombinant interleukin 2 in humans. Cancer Res. 1990;50:2009. [PubMed] [Google Scholar]
  • 39.Kurt-Jones EA, Hamburg S, Ohara J, Paul WE, Abbas AK. Heterogeneity of helper/inducer T lymphocytes. J Exp Med. 1987;166:1774. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Lafrenière R, Rosenberg SA. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res. 1985;45:3735. [PubMed] [Google Scholar]
  • 41.Lee RE, Lotze MT, Skibber JM, Tucker E, Bonow RO, Ognibene FP, Carraquillo JA, Shelhamer JH, Parrillo JE, Rosenberg SA. Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol. 1989;7:7. doi: 10.1200/JCO.1989.7.1.7. [DOI] [PubMed] [Google Scholar]
  • 42.Ley V, Langlade-Demoyen P, Kourilsky P, Larsson-Sciard E-L. Interleukin 2 dependent activation of tumor-specific cytotoxic T lymphocytes in vivo. Eur J Immunol. 1991;21:851. doi: 10.1002/eji.1830210350. [DOI] [PubMed] [Google Scholar]
  • 43.Lotze MT, Matory YL, Rayner AA, Ettinghausen SE, Vetto JT, Seipp CA, Rosenberg SA. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer. 1986;58:2764. doi: 10.1002/1097-0142(19861215)58:12<2764::aid-cncr2820581235>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  • 44.Maas RA, Dullens HFJ, De Jong WH, Den Otter W. Immunotherapy of mice with a large burden of disseminated lymphoma with low-dose interleukin-2. Cancer Res. 1989;49:7037. [PubMed] [Google Scholar]
  • 45.Maas RA, Van Weering DHJ, Dullens HFJ, Den Otter W. Intratumoral low-dose interleukin-2 induces rejection of distant solid tumour. Cancer Immunol Immunother. 1991;33:389. doi: 10.1007/BF01741599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Malkovsky M, Loveland B, North M, Asherson GL, Gao L, Word P, Fiers W. Recombinant interleukin 2 directly augments the cytotoxicity of human monocytes. Nature. 1987;325:262. doi: 10.1038/325262a0. [DOI] [PubMed] [Google Scholar]
  • 47.Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, Weiss GR, Doroshow JH, Jaffe HS, Roper M, Parkinson DR, Wiernik PH, Creekmore SP, Boldt DH. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7:486. doi: 10.1200/JCO.1989.7.4.486. [DOI] [PubMed] [Google Scholar]
  • 48.McIntosh JK, Jablons DM, Mulé JJ, Nordan RP, Rudikoff S, Lotze MT, Rosenberg SA. In vivo induction of IL-6 by administration of exogenous cytokines and detection of de novo serum levels of IL-6 in tumor-bearing mice. J Immunol. 1989;143:162. [PubMed] [Google Scholar]
  • 49.Merchant RE, Merchant LH, Cook SHS, McVicar DW, Young HF. Intralesional infusion of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) for the treatment of patients with malignant brain tumor. Neurosurgery. 1988;23:725. doi: 10.1227/00006123-198812000-00007. [DOI] [PubMed] [Google Scholar]
  • 50.Mills GB, Paetkau V. Generation of cytotoxic lymphocytes to syngeneic tumor by using co-stimulator (interleukin 2) J Immunol. 1980;125:1897. [PubMed] [Google Scholar]
  • 51.Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clones: I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348. [PubMed] [Google Scholar]
  • 52.Mulé JJ, Shu S, Schwarz SL, Rosenberg SA. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984;225:1487. doi: 10.1126/science.6332379. [DOI] [PubMed] [Google Scholar]
  • 53.Mulé JJ, Yang J, Shu S, Rosenberg SA. The antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: direct correlation between reduction of established metastasis and cytolytic activity of lymphokine-activated killer cells. J Immunol. 1986;136:3899. [PubMed] [Google Scholar]
  • 54.Muraguchi A, Kehrl J, Longo DL, Volkman DJ, Smith KA, Fauci AS. Interleukin 2 receptors on human B cells Implications for the role of interleukin 2 in human B cell function. J Exp Med. 1985;161:181. doi: 10.1084/jem.161.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Ottow RT, Eggermont AMM, Steller EP, Sugarbaker PH. The requirements for successful immunotherapy of intraperitoneal cancer using interleukin-2 and lymphokine-activated killer cells. Cancer. 1987;60:1465. doi: 10.1002/1097-0142(19871001)60:7<1465::aid-cncr2820600711>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  • 56.Papa MZ, Mulé JJ, Rosenberg SA. Antitumor efficacy of lymphokine activated killer cells and recombinant interleukin 2 in vivo: successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three distinct histological types. Cancer Res. 1986;46:4972. [PubMed] [Google Scholar]
  • 57.Parkinson DR, Fisher RI, Rayner AA, Paietta E, Margolin KA, Weiss GR, Mier JW, Sznol M, Gaynor ER, Bar MH, Gucalp R, Boldt DH, Mills B, Hawkins MJ. Therapy of renal cell carcinoma with interleukin-2 and lymphokine activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen. J Clin Oncol. 1990;8:1630. doi: 10.1200/JCO.1990.8.10.1630. [DOI] [PubMed] [Google Scholar]
  • 58.Parkinson DR, Abrams JS, Wiernik PH, Rayner AA, Margolin KA, Van Echo DA, Sznol M, Dutcher JP, Aronson FR, Doroshow JH, Atkins MB, Hawkins MJ. Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol. 1990;8:1650. doi: 10.1200/JCO.1990.8.10.1650. [DOI] [PubMed] [Google Scholar]
  • 59.Peace DJ, Cheever MA. Toxicity and therapeutic efficacy of high-dose interleukin-2. In vivo infusion of antibody to NK-11 attenuates toxicity without compromising efficacy against murine leukemia. J Exp Med. 1989;169:161. doi: 10.1084/jem.169.1.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Pizza G, Severini G, Menniti D, De Vinci C, Corrado F. Tumor regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. Int J Cancer. 1984;34:359. doi: 10.1002/ijc.2910340312. [DOI] [PubMed] [Google Scholar]
  • 61.Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM. Observations on the systemic administration of autologous lymphokine activated killer cells and recombinant interleukin 2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485. doi: 10.1056/NEJM198512053132327. [DOI] [PubMed] [Google Scholar]
  • 62.Rosenberg SA, Spiess P, Lafrenière R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233:1318. doi: 10.1126/science.3489291. [DOI] [PubMed] [Google Scholar]
  • 63.Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze M, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma A preliminary report. N Engl J Med. 1988;319:1676. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  • 64.Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210:474. doi: 10.1097/00000658-198910000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Rubin JT, Elwood LJ, Rosenberg SA, Lotze MT. Immunohistochemical correlates of response to recombinant interleukin-2-based immunotherapy in humans. Cancer Res. 1989;49:7086. [PubMed] [Google Scholar]
  • 66.Rutten VPMG, Klein WR, De Jong WAC, Misdorp W, Den Otter W, Steerenberg PA, De Jong WH, Ruitenberg EJ. Local interleukin-2 therapy in bovine ocular squamous cell carcinoma A pilot study. Cancer Immunol Immunother. 1989;30:165. doi: 10.1007/BF01669425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Schoof DD, Gramolini BA, Davidson DL, Massaro AF, Wilson RE, Eberlein TJ. Adoptive immunotherapy of human cancer using low-dose recombinant interleukin 2 and lymphokine-activated killer cells. Cancer Res. 1988;48:5007. [PubMed] [Google Scholar]
  • 68.Sibille S, Chomez P, Wildmann C, Van Pel A, De Plaen E, Maryanski JL, De Bergeyck V, Boon T. Structure of the gene of tum− transplantation antigen P198: a point mutation generates a new antigenic peptide. J Exp Med. 1990;172:35. doi: 10.1084/jem.172.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Siegel JP, Sharon M, Smith PL, Leonard WJ. The IL-2 receptor β chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science. 1987;238:75. doi: 10.1126/science.3116668. [DOI] [PubMed] [Google Scholar]
  • 70.Sondel P, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B. Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res. 1988;48:2561. [PubMed] [Google Scholar]
  • 71.Spiess PJ, Yang JC, Rosenberg SA. In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. JNCI. 1987;79:1067. [PubMed] [Google Scholar]
  • 72.Stein RC, Malkovska V, Morgan S, Galazka A, Aniszewski C, Roy SE, Shearer RJ, Marsden RA, Bevan D, Gordon-Smith EC, Coombes RC. The clinical effects of prolonged treatment of patients with advanced cancer with low-dose subcutaneous interleukin 2. Br J Cancer. 1991;63:275. doi: 10.1038/bjc.1991.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Steis RG, Urba WJ, VanderMolen LA, Bookman MA, Smith JW, II, Clark JW, Miller R, Crum ED, Beckner SK, McKnight JE, Ozols RF, Stevenson HC, Young RC, Longo DL. Intraperitoneal lymphokine-activated killer-cell and interleukin-2 therapy for malignancies limited to the peritoneal cavity. J Clin Oncol. 1990;8:1618. doi: 10.1200/JCO.1990.8.10.1618. [DOI] [PubMed] [Google Scholar]
  • 74.Talmadge JE, Phillips H, Schindler J, Tribble H, Pennington R. Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease. Cancer Res. 1987;47:5725. [PubMed] [Google Scholar]
  • 75.Tepper RI, Pattengale PK, Leder P. Murine interleukin-4 displays potent antitumor activity in vivo. Cell. 1989;57:503. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
  • 76.Thompson JA, Peace DJ, Klarnet JP, Kern DE, Greenberg PD, Cheever MA. Eradication of disseminated murine leukemia by treatment with high dose interleukin 2. J Immunol. 1986;137:3675. [PubMed] [Google Scholar]
  • 77.Vaage J. Local and systemic effects during interleukin-2 therapy of mouse mammary tumors. Cancer Res. 1987;47:4296. [PubMed] [Google Scholar]
  • 78.Van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]
  • 79.Vidovic D, Marusic M, Culo F. Interference of anti-tumor and immunosuppressive effects of cycolphosphamide in tumor bearing rats. Cancer Immunol Immunother. 1982;14:36. doi: 10.1007/BF00199430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.De Waal Malefyt R, Haanen J, Spits H, Roncarolo M-G, Te Velde A, Figdor C, Johnson K, Kastelein R, Yssel H, De Vries JE. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991;174:915. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Wagner H, Hardt C, Heeg K, Röllinghoff M, Pfizenmaier K. T-cell-derived helper factor allows in vivo induction of cytotoxic T cells innu/nu mice. Nature. 1980;284:278. doi: 10.1038/284278a0. [DOI] [PubMed] [Google Scholar]
  • 82.Wahl SM, McCartney-Francis N, Hunt DA, Smith PP, Wahl LM, Katona IM. Monocyte interleukin-2 receptor gene expression and interleukin-2 augmentation of microbicidal activity. J Immunol. 1987;139:1342. [PubMed] [Google Scholar]
  • 83.Weber JS, Jay G, Tanaka K, Rosenberg SA. Immunotherapy of a murine tumor with interleukin 2 Increased sensitivity after MHC class I gene transfer. J Exp Med. 1987;166:1716. doi: 10.1084/jem.166.6.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Weil-Hillman G, Voss SD, Fisch P, Schell K, Hank JA, Sosman JA, Sugamura K, Sondel PM. Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptor and maintain the p55 (Tac) negative phenotype. Cancer Res. 1990;50:2683. [PubMed] [Google Scholar]
  • 85.West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med. 1987;316:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  • 86.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]
  • 87.Yoshino I, Yano T, Murata M, Ishida T, Sugimachi K, Kimura G, Nomoto K. Cytolytic potential of peripheral blood T-lymphocytes following adoptive immunotherapy with lymphokine-activated killer cells and low-dose interleukin 2. Cancer Res. 1991;51:1494. [PubMed] [Google Scholar]
  • 88.Yron I, Wood TA, Jr, Spiess PJ, Rosenberg SA. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol. 1980;125:238. [PubMed] [Google Scholar]
  • 89.Zimmerman RJ, Aukerman SL, Katre NV, Winkelhake JL, Young JD. Schedule dependency of the antitumor activity and toxicity of polyethylene glycol-modified interleukin 2 in murine tumor models. Cancer Res. 1989;49:6521. [PubMed] [Google Scholar]

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

RESOURCES