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. 1984 Oct;18(1):5–12. doi: 10.1007/BF00205392

Intrapleural administration of OK432 in cancer patients: Augmentation of autologous tumor killing activity of tumor-associated large granular lymphocytes

Atsushi Uchida 1,✉, Michael Micksche 1, Takashi Hoshino 3
PMCID: PMC11039175  PMID: 6333269

Abstract

Ten patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) injections of the streptococcal preparation OK432 on day 0 and the effects of i.pl. OK432 on the lysis of fresh or cryopreserved autologous tumor cells isolated from the pleural effusions were observed on day 7. In eight patients tumor cells in the effusions had decreased or disappeared by day 7. The other two patients, however, had no clinical evidence of therapeutic benefit from i.pl. OK432. Effusion tumor cells were relatively resistant to lysis by autologous lymphocytes when tested in a 4-h 51Cr-release assay. Positive reactions were recorded for blood and effusion lymphocytes in two of ten untreated patients. Injection of OK432 i.pl. resulted in an induction or augmentation of cytotoxicity against autologous tumor cells and K562 in the effusions of seven of ten subjects by day 7. In contrast, autologous tumor killing activity of blood lymphocytes was not always modified by i.pl. OK432. Purification of large granular lymphocytes (LGL) by discontinuous Percoll gradient centrifugation enriched autologous tumor killing activity, with no reactivity in LGL-depleted, small T lymphocytes. Significant lysis of autologous tumor cells was observed with effusion LGL from seven of ten untreated patients. Seven days after i.pl. OK432 injection, effusion LGL expressed enhanced cytotoxicity against autologous effusion tumor cells, whereas T cells were still not cytotoxic to autologous tumor cells on day 7. The frequency of LGL among effusion lymphocytes was not altered by i. pl. OK432. Adherent effusion cells were not involved in lysis of autologous effusion tumor cells in either untreated or OK432-treated patients. In vitro treatment of blood and effusion lymphocytes with OK432 induced an enhancement of autologous tumor-killing activity in patients who subsequently responded to i.pl. OK432 treatment. OK432 augmented in vitro autologous tumor killing activity of LGL, whereas T cells failed to lyse autologous tumor cells even after in vitro activation with OK432. These results indicate that i.pl. administration of OK432 to cancer patients will result in an augmentation of autologous tumor killing activity of LGL in the pleural effusions, and that this could be responsible for the antitumor activity of i.pl. OK432 therapy.

Keywords: Pleural Effusion, Autologous Tumor, Autologous Tumor Cell, Large Granular Lymphocyte, Percoll Gradient Centrifugation

References

  • 1.Allavena P, Introna M, Sessa C, Mangioni C, Mantovani A. Interferon effect of cytotoxicity of peripheral blood and tumor-associated lymphocytes against human ovarian carcinoma cells. J Natl Cancer Inst. 1982;68:555. [PubMed] [Google Scholar]
  • 2.Becker S, Siessling R, Lee N, Klein G. Modulation of sensitivity to natural killer cell lysis after in vitro explanation of a mouse lymphoma. J Natl Cancer Inst. 1978;61:1495. [PubMed] [Google Scholar]
  • 3.Collota F, Rambaldi A, Colombo N, Tabacchi L, Introna M, Mantovani A. Effect of a streptococcal preparation (OK432) on natural killer activity of tumor-associated lymphoid cells in human overian carcinoma and on lysis of fresh ovarian tumor cells. Br J Cancer. 1983;48:515. doi: 10.1038/bjc.1983.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.De Vries JE, Meyering M, Van Dongren A, Rümke P. The influence of different isolation procedures and the use of target cells from melanoma cell lines and short-term cultures on the nonspecific cytotoxic effects of lymphocytes from healthy donors. Int J Cancer. 1975;15:391. doi: 10.1002/ijc.2910150305. [DOI] [PubMed] [Google Scholar]
  • 5.Fossati G, Balsari A, Taramelli D, Sensi ML, Pellegris G, Nava M, Parmiani G. Lysis of autologous human melanoma cells by in vitro allosensitized peripheral blood lymphocytes. Cancer Immunol Immunother. 1982;14:99. doi: 10.1007/BF00200176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Grimm EA, Rosenberg SA. The human lymphokine-activated killer cell phenomenon. In: Pick E, Landy M, editors. Lymphokines, vol 9. New York: Academic Press; 1984. [Google Scholar]
  • 7.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]
  • 8.Ichimura I, Suzuki S, Sugawara Y, Osawa T. Characterization of mouse natural killer cell activating factor (NKAF) induced by streptococcus preparation OK432. In: Hoshino T, Koren HS, Uchida A, editors. Natural killer activity and its regulation. Amsterdam: Exerpta Medica; 1984. p. 208. [Google Scholar]
  • 9.Klein E, Vanky F. A review. Natural and activated cytotoxic lymphocytes. Which act on autologous and allogeneic tumor cells. Cancer Immunol Immunother. 1981;11:183. [Google Scholar]
  • 10.Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood. 1975;45:334. [PubMed] [Google Scholar]
  • 11.Mantovani A, Sessa C, Peri G, Allavena P, Introna M, Polentarutti N, Mangioni C. Intraperitoneal administration of Corynebacterium parvum in patients with ascitic ovarian tumors resistant to chemotherapy. Effects on cytotoxicity of tumor-associated macrophages and NK cells. Int J Cancer. 1981;27:437. doi: 10.1002/ijc.2910270404. [DOI] [PubMed] [Google Scholar]
  • 12.Matsubara S, Suzuki F, Ishida N. Induction of immune interferon in mice treated with a bacterial immunopotentiator, OK432. Cancer Immunol Immunother. 1979;6:41. [Google Scholar]
  • 13.Mazumder A, Grimm EA, Zhang HZ, Rosenberg SA. Lysis of fresh human solid tumors by autologous lymphocytes activated in vitro with lectins. Cancer Res. 1982;42:913. [PubMed] [Google Scholar]
  • 14.Murayma T, Natsuume-Sakai S, Ryoyama K, Koshimura S. Studies of the properties of a streptococcal preparation, OK432 (NSV-B116209), as an immunopotentiator. II. Mechanisms of macrophage activation by OK432. Cancer Immunol Immunother. 1982;12:141. [Google Scholar]
  • 15.Nagao K, Takizawa H, Sugita T, Watanabe S. Treatment of malignant pleural effusion with OK432, with reference to intercostal tube drainage method. Cancer Chemother. 1979;6:1161. [Google Scholar]
  • 16.Oshimi K, Kano S, Takaku F, Okumura K. Augmentation of mouse natural killer cell activity by a streptococcal preparation, OK432. J Natl Cancer Inst. 1980;65:1265. [PubMed] [Google Scholar]
  • 17.Saito M, Nanjo M, Aonuma E, Noda T, Nakadate I, Ebina T, Ishida N. Activated macrophages are responsible for the tumor inhibitory effect in mice receiving intravenous injection of OK432. Int J Cancer. 1984;33:271. doi: 10.1002/ijc.2910330217. [DOI] [PubMed] [Google Scholar]
  • 18.Strausse JL, Mazumder A, Grimm EA, Lotze MT, Rosenberg SA. Lysis of human solid tumors by autologous cells sensitized in vitro to alloantigens. J Immunol. 1981;127:266. [PubMed] [Google Scholar]
  • 19.Timonen T, Ortaldo JR, Herberman RB. Analysis by a single cell cytotoxicity assay of natural killer (NK) cell frequencies among human large granular lymphocytes and of the effects of interferon on their activity. J Immunol. 1982;128:2514. [PubMed] [Google Scholar]
  • 20.Uchida A. Lysis of fresh human tumor cells by autologous blood and tumor-associated natural killer cells. In: Hoshino T, Koren HS, Uchida A, editors. Natural killer activity and its regulation. Amsterdam: Excerpta Medica; 1984. p. 341. [Google Scholar]
  • 21.Uchida A, Hoshino T. Clinical studies on cell-mediated immunity in patients with malignant disease. I. Effect of immunotherapy with OK432 on lymphocyte subpopulation and phytomitogen responsiveness in vitro. Cancer. 1980;45:476. doi: 10.1002/1097-0142(19800201)45:3<476::aid-cncr2820450311>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  • 22.Uchida A, Hoshino T. Reduction of suppressor cells in cancer patients treated with OK432 immunotherapy. Int J Cancer. 1980;26:401. doi: 10.1002/ijc.2910260403. [DOI] [PubMed] [Google Scholar]
  • 23.Uchida A, Micksche M. In vitro augmentation of natural killer activity by OK432. Int J Immunopharmacol. 1981;3:365. doi: 10.1016/0192-0561(81)90032-1. [DOI] [PubMed] [Google Scholar]
  • 24.Uchida A, Micksche M. Natural killer cells in carcinomatous pleural effusions. Cancer Immunol Immunother. 1981;11:131. [Google Scholar]
  • 25.Uchida A, Micksche M. Suppressor cells for natural killer activity in carcinomatous pleural effusions of cancer patients. Cancer Immunol Immunother. 1981;11:255. [Google Scholar]
  • 26.Uchida A, Micksche M. Augmentation of NK cell activity in cancer patients by OK432. Activation of NK cells and reduction of suppressor cells. In: Herberman RB, editor. NK cells and other natural effector cells. New York: Academic Press; 1982. p. 1303. [Google Scholar]
  • 27.Uchida A, Micksche M. Intrapleural administration of OK432 in cancer patients: activation of NK cells and reduction of suppressor cells. Int J Cancer. 1983;31:1. doi: 10.1002/ijc.2910310102. [DOI] [PubMed] [Google Scholar]
  • 28.Uchida A, Micksche M. Lysis of fresh human tumor cells by autologous large granular lymphocytes from peripheral blood and pleural effusions. Int J Cancer. 1983;32:37. doi: 10.1002/ijc.2910320107. [DOI] [PubMed] [Google Scholar]
  • 29.Uchida A, Micksche M. Lysis of fresh human tumor cells by autologous peripheral blood lymphocytes and pleural effusion lymphocytes activated by OK432. J Natl Cancer Inst. 1983;71:673. [PubMed] [Google Scholar]
  • 30.Uchida A, Yanagawa E (1984) Autologous tumor killing and natural killing in cancer patients: Involvement of overlapping effector cells determined in two-target conjugate cytotoxicity assay. J Natl Cancer Inst (in press) [PubMed]
  • 31.Uchida A, Yagita M, Hoshino T. Augmentation of natural and autotumor killing activity by OK432. In: Hoshino T, Koren HS, Uchida A, editors. Natural killer activity and its regulation. Amsterdam: Excerpta Medica; 1984. p. 220. [Google Scholar]
  • 32.Uchida A, Yanagawa E, Micksche M. In vivo and in vitro augmentation of natural killing and autotumor killing activity by OK432. In: Hoshino T, Uchida A, editors. Clinical and experimental studies with immunomodulators. Amsterdam: Excerpta Medica; 1984. [Google Scholar]
  • 33.Vanky F, Klein E. Specificity of auto-tumor cytotoxicity exerted by fresh, activated and propagated human T lymphocytes. Int J Cancer. 1982;29:547. doi: 10.1002/ijc.2910290510. [DOI] [PubMed] [Google Scholar]
  • 34.Vanky F, Argov SA, Einhorn SA, Klein E. Role of alloantigens in natural killing. Allogeneic but not autologous tumor biopsy cells are sensitive for interferon-induced cytotoxicity of human blood lymphocytes. J Exp Med. 1980;151:1151. doi: 10.1084/jem.151.5.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Vanky F, Masucci MG, Bejarano MT, Klein E. Lysis of tumor biopsy cells by blood lymphocyte subsets of various densities. Autologous and allogeneic studies. Int J Cancer. 1984;33:185. doi: 10.1002/ijc.2910330206. [DOI] [PubMed] [Google Scholar]
  • 36.Vose BM. Cytotoxicity of adherent cells associated with some human tumors and lung tissues. Cancer Immunol Immunother. 1979;5:173. [Google Scholar]
  • 37.Vose BM, Bonnard GD. Limiting dilution analysis of the frequency of human T cells and large granular lymphocytes proliferating in response to interleukin 2. I. The effect of lectin on the proliferative frequency and cytotoxic activity of cultured lymphoid cells. J Immunol. 1983;130:687. [PubMed] [Google Scholar]
  • 38.Vose BM, Vanky F, Klein E. Lymphocyte cytotoxicity against autologous tumor biopsy cells in humans. Int J Cancer. 1977;20:512. doi: 10.1002/ijc.2910200407. [DOI] [PubMed] [Google Scholar]
  • 39.Yanagawa E, Uchida A, Kokoschka EM, Micksche M. Natural cytotoxicity of lymphocytes and monocytes and its augmentation by OK432 in melanoma patients. Cancer Immunol Immunother. 1984;16:131. doi: 10.1007/BF00205418. [DOI] [PMC free article] [PubMed] [Google Scholar]

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