Skip to main content
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1987 Feb;24(1):76–85. doi: 10.1007/BF00199837

Tumor-derived interleukin-2-dependent lymphocytes in adoptive immunotherapy of lung cancer

Richard L Kradin 1,, Lenora A Boyle 1, Frederic I Preffer 1, Ronald J Callahan 1, Martha Barlai-Kovach 1, H William Strauss 1, Steven Dubinett 1, James T Kurnick 1
PMCID: PMC11038966  PMID: 3493073

Abstract

A trial of adoptive immunotherapy was performed in which long-term cultured, interleukin-2 (IL2)-dependent T-lymphocytes were administered to patients with metastatic adenocarcinoma of the lung. Lymphocytes were isolated from explants of cancer tissues that were cultured in medium with recombinant IL-2. These T-cells expressed surface markers of activation, and killed a broad panel of tumor targets. Intravenously injected 111indium-labeled T-cell blasts distributed primarily to lungs, liver, and spleen. Despite a paucity of infused lymphocytes detected by external imaging at sites of tumor, five of seven patients showed reduction of their cancers. However, in no case was greater than 50% reduction of total tumor burden achieved. Evidence of increased delayed cutaneous hypersensitivity to protein antigens was observed in three patients following therapy. We conclude that long-term cultured tumor-derived T-cells can be transferred safely into humans and that these cells may be capable of enhancing immune responses and mediating tumor reduction in vivo.

Keywords: Immune Response, Lung Cancer, Adenocarcinoma, Cancer Research, Cancer Tissue

References

  • 1.Allavena P, Ortaldo JR. Specificity and phenotype of IL-2 expanded clones and human large granular lymphocytes. Diagn Immunol. 1983;1:162. [PubMed] [Google Scholar]
  • 2.Biddison WE, Rao PE, Tale MA, Goldstein G, Shaw S. Possible involvement of the OKT4 molecule in T-cell recognition of class II HLA antigens: evidence from studies of cytotoxic T-lymphocytes specific for SB antigens. J Exp Med. 1982;156:1065. doi: 10.1084/jem.156.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Cerrotinni JC, Brunner KT. Cell mediated cytotoxicity, allograft rejection and tumor immunity. Adv Immunol. 1974;18:67. doi: 10.1016/s0065-2776(08)60308-9. [DOI] [PubMed] [Google Scholar]
  • 4.Cheever MA, Kempf RA, Fefer A. Tumor neutralization, immunotherapy, and chemoimmunotherapy of a Friend leukemia with cells secondarily immunized in vitro. J Immunol. 1977;119:714. [PubMed] [Google Scholar]
  • 5.Cheever MA, Greenberg PD, Fefer A. Specificity of adoptive chemoimmunotherapy of established syngeneic tumors. Cancer Res. 1980;41:2658. [PubMed] [Google Scholar]
  • 6.Cheever MA, Greenberg PD, Fefer A, Gillis S. The potential role for T-cells in cancer therapy. New York: Raven Press; 1982. Specific adoptive therapy of murine leukemia with cells secondarily sensitized in vitro and expanded by culture in Interleukin-2; p. 127. [Google Scholar]
  • 7.Cheever MA, Thompson DB, Klarnet JP, Greenberg PD. Antigen-driven long-term cultured T-cells proliferate in vivo, distribute widely, mediate specific tumor therapy, and persist long-term as functional memory T cells. J Exp Med. 1986;163:1100. doi: 10.1084/jem.163.5.1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Dailey MO, Gallatin WM, Weissman IL. The in vivo behavior of T-cell clones: altered migration due to loss of lymphocyte homing receptor. J Mol Immunol. 1985;2:23. [PubMed] [Google Scholar]
  • 9.Eberlein TJ, Rosenstein M, Rosenberg SA. Regression of a disseminated solid tumor by systemic transfer of lymphoid cells expanded in IL-2. J Exp Med. 1982;156:385. doi: 10.1084/jem.156.2.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Engleman EG, Warnke R, Fox RI, Levy R. Studies of a human T lymphocyte antigen recognized by a monoclonal antibody. Proc Natl Acad Sci USA. 1981;78:1791. doi: 10.1073/pnas.78.3.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Fernandez-Cruz E, Woda BA, Feldman JD. Elimination of syngeneic sarcomas in rats by a subset of T-lymphocytes. J Exp Med. 1980;152:823. doi: 10.1084/jem.152.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Fidler IJ, Kripke ML. Tumor cell antigenicity, host immunity, and cancer metastasis. Cancer Immunol Immunother. 1980;7:201. [Google Scholar]
  • 13.Gallatin WM, Weissman IL, Butcher EC. A cell surface molecule involved in organ-specific hoing of lymphocytes. Nature. 1983;303:30. doi: 10.1038/304030a0. [DOI] [PubMed] [Google Scholar]
  • 14.Greenberg PD, Cheever MA, Fefer A. The potential role of T-cells in cancer therapy. New York: Raven Press; 1982. Prerequisites for successful adoptive immunotherapy: Nature of effector cells and role of H-2 restriction; p. 31. [Google Scholar]
  • 15.Greene WC, Leonard WJ. The human Interleukin-2 receptor. Annu Rev Immunol. 1986;4:69. doi: 10.1146/annurev.iy.04.040186.000441. [DOI] [PubMed] [Google Scholar]
  • 16.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. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Grimm EA, Ramsey KM, Mazumder A, Wilson DJ, Djieu JY, Rosenberg SA. Lymphokine-activated killer cell phenomenon II. The precursor phenotype is serologically distinct from peripheral T-lymphocytes, memory CTL and NK cells. J Exp Med. 1983;157:884. doi: 10.1084/jem.157.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Hellstrom I, Hellstrom K. Specific sensitization of lymphocytes to tumor antigens by co-cultivation with peritoneal cells exposed to such antigens. Int J Cancer. 1976;17:748. doi: 10.1002/ijc.2910170610. [DOI] [PubMed] [Google Scholar]
  • 19.Jalkanen S, Reichert RA, Gallatin WM, Bargatze RF, Weissman IL, Butcher EC. Homing receptors and the control of lymphocyte migration. Immunol Rev. 1986;91:39. doi: 10.1111/j.1600-065x.1986.tb01483.x. [DOI] [PubMed] [Google Scholar]
  • 20.Kelly K, Cochran B, Stiles CD, Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983;35:603. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  • 21.Kiessling R, Klein E, Wigzell H. Natural killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975;5:112. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  • 22.Klein G. Tumor antigens. Annu Rev Microbiol. 1960;20:223. doi: 10.1146/annurev.mi.20.100166.001255. [DOI] [PubMed] [Google Scholar]
  • 23.Klein G, Klein E. Rejectability of virus-induced tumors and non-rejectability of spontaneous tumors: A lesson in contrasts. Transplant Proc. 1977;9:1095. [PubMed] [Google Scholar]
  • 24.Kurnick JT, Kradin RL, Blumberg R, Schneeberger EE, Boyle La. Functional characterization of T lymphocytes propagated from human lung carcinomas. Clin Immunol Immunopathol. 1986;38:367. doi: 10.1016/0090-1229(86)90247-3. [DOI] [PubMed] [Google Scholar]
  • 25.Lanier LL, Phillips JH. Evidence for three types of human cytotoxic lymphocytes. Immunol Today. 1986;7:5. doi: 10.1016/0167-5699(86)90076-9. [DOI] [PubMed] [Google Scholar]
  • 26.Lanier LL, Le AM, Phillips JH, Warner NL, Babcock GF. Subpopulations of natural killer cells defined by expression of Leu-7 (HNK-1) and Leu-11 (HNK-15) antigens. J Immunol. 1983;131:1789. [PubMed] [Google Scholar]
  • 27.Levy PC, Yhaw GM, LoBuglio A. Human monocyte, lymphocyte, and granulocyte antibody dependent cell-mediated cytotoxicity toward tumor cells. J Immunol. 1979;123:594. [PubMed] [Google Scholar]
  • 28.Lotze MT, Line BR, Mathisen DJ, Rosenberg SA. The in vivo distribution of autologous human and murine lymphoid cells grown in T-cell growth factor (TCGF): Implications for the adoptive immunotheerapy of tumors. J Immunol. 1980;125:1487. [PubMed] [Google Scholar]
  • 29.Lotze MT, Robb RJ, Sharrow SO, Frana LW, Rosenberg SA. Systemic administration of interleukin-2 in humans. J Biol Response Mod. 1984;3:475. [PubMed] [Google Scholar]
  • 30.Mayer TG, Fuller TC, Lazarovits AI, Boyle LA, Kurnick JT. Characterization of in vivo-activated allograft T lymphocytes propagated from human renal allograft biopsies undergoing rejection. J Immunol. 1985;134:258. [PubMed] [Google Scholar]
  • 31.Mazumder A, Grimm EA, Rosenberg SA. Lysis of fresh human solid tumor cells by autologous lymphocytes activated in vitro by allosensitization. Cancer Immunol Immunother. 1983;15:1. doi: 10.1007/BF00199454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Mazumder A, Eberlein TJ, Grimm EA, Wilson DJ, Keenan AM, Aamodt R, Rosenberg SA. Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells. Cancer. 1984;53:896. doi: 10.1002/1097-0142(19840215)53:4<896::aid-cncr2820530414>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  • 33.McAfee JG, Thakur ML. Survey of radioactive agents for the in vitro labeling of phagocytic leukocytes. I. Soluble agents. J Nucl Med. 1976;17:480. [PubMed] [Google Scholar]
  • 34.Moller E. Contact-induced cytotoxicity by lymphoid cells containing foreign isoantigens. Science. 1965;147:873. doi: 10.1126/science.147.3660.873. [DOI] [PubMed] [Google Scholar]
  • 35.Ortaldo JR, Bonnard GD, Kind PD, Herberman RB. Cytotoxicity by cultured human lymphocytes: Characteristics of effectors and specificity of cytotoxicity. J Immunol. 1979;122:1489. [PubMed] [Google Scholar]
  • 36.Reinherz EL, Meuer SC, Schlossman SF. The delineation of antigen receptors on human T-lymphocytes. Immunol Today. 1983;4:5. doi: 10.1016/0167-5699(83)90094-4. [DOI] [PubMed] [Google Scholar]
  • 37.Rosenberg SA. Important advances in oncology. Philadelphia: JB Lippincott Co; 1986. Adoptive immunotherapy of cancer using lymphokine activated killer cells and recombinant Interleukin-2; p. 55. [PubMed] [Google Scholar]
  • 38.Rosenberg SA, Terry WD. Passive immunity of cancer in animals and man. Adv Cancer Res. 1977;25:323. doi: 10.1016/s0065-230x(08)60637-5. [DOI] [PubMed] [Google Scholar]
  • 39.Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, et al. 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]
  • 40.Rosenstein M, Rosenberg SA. Generation of lytic and proliferative lymphoid clones to syngeneic tumors: in vitro and in vivo studies. J Natl Cancer Inst. 1984;72:1161. [PubMed] [Google Scholar]
  • 41.Shu S, Chou T, Rosenberg SA. In vitro sensitization and expansion with viable tumor cells and Interleukin-2 in the generation of specific therapeutic effector cells. J Immunol. 1986;136:3891. [PubMed] [Google Scholar]
  • 42.Thakur ML, Lavender JP, Arnot RN, Silvester DJ, Segal W. 111Indium-labeled autologous leukocytes in man. J Nucl Med. 1977;18:1014. [PubMed] [Google Scholar]
  • 43.Trowbridge IA, Omary MB. Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci. 1981;78:3039. doi: 10.1073/pnas.78.5.3039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Vanky F, Peterffy A, Book K, Willems J, Klein E, Klein G. Correlation between lymphocyte-mediated auto-tumor reactivities and the clinical course. II. Evaluation of 69 patients with lung carcinoma. Cancer Immunol Immunother. 1983;16:17. doi: 10.1007/BF00199900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Vose BM, Vanky F, Klein E. Human tumour-lymphocyte interaction in vitro. V. Comparison of the reactivity of tumor infiltrating, blood and lymph node lymphocytes with autologous tumor cells. Int J Cancer. 1977;20:1977. doi: 10.1002/ijc.2910200612. [DOI] [PubMed] [Google Scholar]
  • 46.Wright SC, Bonavida B. Studies on the mechanism of natural killer toxicity. III. Activation of NK cells by interferon augments the lytic activity of released natural killer cytotoxic factors (NKCF) J Immunol. 1983;130:2960. [PubMed] [Google Scholar]

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

RESOURCES