Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1982 Sep;13(3):164–173. doi: 10.1007/BF00205382

Immunological studies in a double blind randomized trial comparing intrapleural BCG against placebo in patients with resected stage I non-small cell lung cancer

Robert K Oldham 1,✉, Mitchell H Gail 1, Michael A Baker 1, James T Forbes 1, William Heineman 1, Evan Hersh 1, E Carmack Holmes 1, Roy E Ritts 1, Peter W Wright 1; the Lung Cancer Study Group
PMCID: PMC11039098  PMID: 6762247

Abstract

Immunological data were obtained during the course of a randomized trial comparing intrapleural BCG plus oral isoniazid (INH) with intrapleural saline plus oral placebo after resection of stage I non-small cell lung cancer. Immunological testing with a variety of assays was carried out with good standardization among six collaborating laboratories and with good reproducibility within each laboratory. Those patients with larger tumors tended to have higher initial white cell counts. The percentage of lymphocytes in the differential was greatest in those with non-squamous cancer histology. Otherwise, no associations were found between initial immunologic parameters and baseline variables. The main effect of BCG/INH therapy was to cause statistically significant increases in purified protein derivative (PPD) skin test induration and PPD in vitro blastogenesis compared with controls. Other skin tests and in vitro assays increased more in the saline/placebo control group, but these treatment differences were usually not statistically significant. Initial white count and neutrophil count elevations were found to be associated with increased risk of recurrence. Even after adjustment for treatment and tumor stage, initial neutrophil count elevation was associated with increased risk of recurrence. Surprisingly, a low 29° C T cell rosette index was associated with a decreased risk of recurrence, though the differences were minimal. Serial immunological tests were carried out to evaluate their potential for monitoring disease recurrence. White count elevations continued to be significantly associated with increased risk of recurrence, but more follow-up data are needed before other associations can be assessed.

Keywords: Isoniazid, Skin Test, White Cell Count, Purify Protein Derivative, Resected Stage

Footnotes

Members of the Lung Cancer Study Group include: E. C. Holmes** (Group Chairman), W. F. Coulson, K. P. Ramming, and T. H. Weisenburger from the University of California, Los Angeles; Z. Petrovich from Wadsworth Veterans Hospital, Los Angeles; R. T. Eagan**, R. E. Lee, W. S. Payne, R. E. Ritts, and L. Weiland from the Mayo Clinic, Rochester; C. F. Mountain**, H. T. Barkley, O. H. Frazier, K. Hermes, E. Hersh, and M. Valdivieso from the University of Texas System Cancer Center, MD Anderson Hospital, Houston; L. D. Hill**, M. D. Hafermann, and E. Morgan from the Mason Clinic, Seattle; P. W. Wright**, and K. E. Hellstrom from the Hutchinson Cancer Center, Seattle; C. Bagley, L. P. Johnson, H. Kellogg, and R. D. Pinkman from the Swedish Medical Center, Seattle; T. D. Ivey from University Hospital, Seattle; S. Hammar from Virginia Mason Hospital, Seattle; W. Nelems from St Paul's Hospital, Vancouver; R. Feld**, D. Bergsagel, T. C. Brown, J. Curtis, C. Keen, J. F. Pringle, I. Quirt, and L. Yeod from the Princess Margaret Hospital, Toronto; M. Blackstein and M. Goldberg from Mount Sinai Hospital, Toronto; F. G. Pearson**, D. W. Chamberlain, J. Cooper, W. Evans, and T. Todd from Toronto General Hospital, Toronto; M. Baker and R. Ginsberg from Toronto Western Hospital, Toronto; R. I. Mitchell from Wellesley Hospital, Toronto; R. K. Oldham**, J. T. Forbes, F. A. Greco, D. L. Page, R. Prager, R. L. Richardson, and S. L. Stroup from Vanderbilt University, Nashville; J. M. Lukeman** and S. M. Sajjad from the Pathology Reference Center of UT MD Anderson Hospital, Houston; P. Grifone, A. Lebeck, A. Sharpe, and T. Voss from the Operations Office, Silver Spring, Maryland; M. Gail and L. Rubinstein, Group Statisticians, W. McGuire, J. Allegra, G. Witman, Project Officers, from the National Cancer Institute, Bethesda, Maryland; and W. Heineman, J. Beach, L. Close, and B. Sharkey from Information Services, Bethesda, Maryland. Asterisks designate principal investigators

References

  • 1.Cox DR. Regression models and life tables. Journal of the Royal Statistical Society [B] 1972;34:187. [Google Scholar]
  • 2.Dean JH, Connors R, Herberman RB, Silva J, Oldham RK, McCoy JL. The relative proliferation index as a more sensitive parameter for evaluating lymphoproliferative response of cancer patients to mitogens and alloantigens. Int J Cancer. 1977;20:359. doi: 10.1002/ijc.2910200307. [DOI] [PubMed] [Google Scholar]
  • 3.Dean JH, Cannon GV, Jerrels TR, McCoy JL, Herberman RB. Sensitive measurement of immunocompetence and anti-tumor reactivity in lung cancer patients and possible mechanisms of immunosuppression. In: Crispin R, editor. Neoplasm immunity: Experimental and clinical. Amsterdam: Elsevier/North Holland; 1980. p. 357. [Google Scholar]
  • 4.Djeu J, Payne S, Alford C, Heim W, Pomeroy T, Cohen M, Oldham RK, Herberman RB. Detection of decreased proportion of lymphocytes forming rosettes with sheep erythrocytes at 29°C in the blood of cancer patients: Analysis of factors affecting the assay. Clin Immunol Immunopathol. 1977;8:405. doi: 10.1016/0090-1229(77)90005-8. [DOI] [PubMed] [Google Scholar]
  • 5.Gail MH. Evaluation serial cancer marker studies in patients at risk of recurrent disease. Biometrics. 1981;37:67. [PubMed] [Google Scholar]
  • 6.Gail MH, Oldham RK, Carmack Holmes E, Wright PW, McGuire WP, Mountain CF, Lukeman JM, Feld R, Hill LD, Eagan RT, Pearson FG, the Lung Cancer Study Group Early side-effects of intrathoracic BCG therapy in patients with stage I squamous cell carcinoma, adenocarcinoma or large cell lung cancer. Cancer Immunol Immunother. 1981;10:129. [Google Scholar]
  • 7.Gutterman JU, Rossen RD, Butler WT, McCredie KB, Bodey GP, Freireich EJ, Hersh EM. Immunoglobulin tumor cells in tumor-induced lymphocyte blastogenesis in human acute leukemia. N Engl J Med. 1973;288:169. doi: 10.1056/NEJM197301252880401. [DOI] [PubMed] [Google Scholar]
  • 8.Herberman RB, Oldham RK. Problems associated with study of cell-mediated immunity to human tumors by microcytotoxicity assays. J Natl Cancer Inst. 1975;55:749. doi: 10.1093/jnci/55.4.749. [DOI] [PubMed] [Google Scholar]
  • 9.Hersh EM, Gutterman JU, Mavligit GM. Serial studies of immunocompetence in patients undergoing chemotherapy for acute leukemia. J Clin Invest. 1974;54:401. doi: 10.1172/JCI107775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Hersh EM, Gutterman JU, Mavligit GM. Immunotherapy of human cancer. Adv Intern Med. 1976;22:145. [PubMed] [Google Scholar]
  • 11.Hersh EM, Gutterman JU, Mavligit GM, Mountain CW, McBride CM, Burgess MA, Lurie PM, Zewlen M, Takita H, Vincent RG. Immunocompetency and immunodeficiency in prognosis in cancers. Ann NY Acad Sci. 1976;276:386. doi: 10.1111/j.1749-6632.1976.tb41664.x. [DOI] [PubMed] [Google Scholar]
  • 12.Holden HT, Oldham RK, Ortaldo JR, Herberman RB. Standardization of the 51Cr release cell-mediated cytotoxicity assay: Cryopreservation of mouse effector and target cells. J Natl Cancer Inst. 1977;58:611. doi: 10.1093/jnci/58.3.611. [DOI] [PubMed] [Google Scholar]
  • 13.Holmes EC. Immunology of lung cancer. Ann Thorac Surg. 1976;21:250. doi: 10.1016/s0003-4975(10)64304-4. [DOI] [PubMed] [Google Scholar]
  • 14.Holmes EC, Golub SH. Effect of Levamisole on cell-mediated immunity in patients with lung cancer. In: Chirigos MA, editor. Immune modulation and control of neoplasia by adjuvant therapy. New York: Raven Press; 1978. p. 107. [Google Scholar]
  • 15.Holmes EC, Ramming KP, Mink J, Coulson WF, Morton DL. New method of immunotherapy for lung cancer. Lancet. 1977;I:586. doi: 10.1016/s0140-6736(77)91431-3. [DOI] [PubMed] [Google Scholar]
  • 16.McGuire WP, et al. Proceedings of the Second International Conference on the Adjuvant Therapy of Cancer. New York: Grune & Stratton; 1979. Clinical trials of the Lung Cancer Study Group; p. 561. [Google Scholar]
  • 17.McKneally MF, Maver C, Kausel HW. Regional immunotherapy of lung cancer with intrapleural BCG. Lancet. 1976;I:377. doi: 10.1016/S0140-6736(76)90212-9. [DOI] [PubMed] [Google Scholar]
  • 18.Mountain CF, Gail MH. Surgical adjuvant intrapleural BCG treatment for stage-I non-small cell lung cancer. Preliminary report of the National Cancer Institute Lung Cancer Study Group. J Thorac Cardiovasc Surg. 1981;82:649. [PubMed] [Google Scholar]
  • 19.Oldham RK, Herberman RB. Delayed hypersensitivity skin tests. In: Herberman RB, McIntire R, editors. Immunodiagnosis of cancer. New York: Marcel Dekker; 1980. p. 940. [Google Scholar]
  • 20.Oldham RK, Simmler MC. The use of cryopreserved lymphocytes and lymphoblasts in 51Cr lymphocyte cytotoxicity. In: Weiner RS, Oldham RK, Schwarzenberg L, editors. The cryopreservation of normal and neoplastic cells. Paris: INSERM (Institut National de la Santé et de la Recherche Médicale); 1973. p. 161. [Google Scholar]
  • 21.Oldham RK, Djeu JY, Cannon GB, Siwarski D, Herberman RB. Cellular microcytotoxicity in human tumor systems: Analysis of results. J Natl Cancer Inst. 1975;55:1305. doi: 10.1093/jnci/55.6.1305. [DOI] [PubMed] [Google Scholar]
  • 22.Oldham RK, Weiner RS, Mathé G, Breard J, Simmler MC, Carde P, Herberman RB. Cell-mediated immune responsiveness of patients with acute lymphocytic leukemia in remission. Int J Cancer. 1976;17:326. doi: 10.1002/ijc.2910170308. [DOI] [PubMed] [Google Scholar]
  • 23.Oldham RK, Dean J, Cannon GB, Graw R, Dunston G, Applebaum F, McCoy J, Herberman RB. Cryopreservation of lymphocyte activity as measured by in vitro assays. Int J Cancer. 1976;18:145. doi: 10.1002/ijc.2910180203. [DOI] [PubMed] [Google Scholar]
  • 24.Oldham RK, Weese JL, Herberman RB, Perlin E, Mills M, Heim W, Blom J, Green D, Reid J, Berllinger S, Law I, McCoy JL, Dean JH, Cannon GB, Djeu J. Immunological monitoring and immunotherapy in carcinoma of the lung. Int J Cancer. 1976;18:739. doi: 10.1002/ijc.2910180604. [DOI] [PubMed] [Google Scholar]
  • 25.Oldham RK, Ortaldo JR, Holden HT, Herberman RB. Cytotoxicity inhibition assay: Cryopreservation and standardization. J Natl Cancer Inst. 1977;59:1321. doi: 10.1093/jnci/59.4.1321. [DOI] [PubMed] [Google Scholar]
  • 26.Ortaldo JR, Oldham RK, Holden HT, Herberman RB. Immune response to Gross virus-induced lymphoma: Cryopreservation of functional activity of rat lymphocytes and tumor cells. Cell Immunol. 1976;25:60. doi: 10.1016/0008-8749(76)90097-6. [DOI] [PubMed] [Google Scholar]
  • 27.Richardson RL, Oldham RK, Pomeroy TC, Weese JL, McCoy JL, Cannon GO, Dean JH, Herberman RB. Immunological monitoring in Ewin's sarcoma. Cancer Immunol Immunother. 1978;4:87. [Google Scholar]
  • 28.Ritts RE., Jr . Immunological factors and immunotherapy in lung cancer. In: Shields TW, editor. Bronchial carcinoma. Springfield: Thomas; 1974. p. 32. [Google Scholar]
  • 29.Ritts RE Jr, Carr DT (1974) Cellular immunocompetency in stage III bronchogenetic carcinoma. Proceedings of the XI International Cancer Congress, vol 2: Clinical monitoring of immune competence, p 110
  • 30.Ritts RE, Jr, Jacobsen DA, Caron J, Weyl KG, Eagan RT, Offord JR, Weiland LH, carr DT. Is the lung cancer patient immunologically competent? An assessment of cell immunity by extent of tumor burden and histological cell type. In: Williams TE, Wilson HE, Young DS, editors. Perspectives in lung cancer. Basel: Karger; 1977. p. 47. [Google Scholar]
  • 31.Ruckdeschel JC, Codish SD, Stranahan A, McKneally MF. N Engl J Med. 1972;287:1013. doi: 10.1056/NEJM197211162872004. [DOI] [PubMed] [Google Scholar]
  • 32.Stanley K. March 1981 report on Ludwig Lung Cancer Study 1. Boston: Sidney Farber Cancer Institute; 1981. [Google Scholar]
  • 33.Weese JL, Oldham RK, Tormey DC, Barlock AL, Morales A, Cohen MH, Alford TC, Shorb PE, Tsangaris NT, West WH, Cannon GB, Dean JH, Djeu J, McCoy JL. Immunologic monitoring in carcinoma of the breast. Surg Gynecol Obstet. 1977;145:209. doi: 10.1016/0002-9610(81)90273-7. [DOI] [PubMed] [Google Scholar]
  • 34.Weese JL, Herberman RB, Hollinshead AC, Cannon GB, Keels M, Kibrite A, Morales A, Char DH, Oldham RK. Specificity of delayed hypersensitivity reactions to extracts of human tumor cells. J Natl Cancer Inst. 1978;60:255. doi: 10.1093/jnci/60.2.255. [DOI] [PubMed] [Google Scholar]
  • 35.Wells SA, Jr, Burdick JF, Joseph WL, Christiansen CL, Wolfe WG, Adkins PC, Durham NC. Delayed cutaneous hypersensitivity reaction to tumor cell antigens and to non-specific antigens. J Thorac Cardiovasc Surg. 1973;66:557. [PubMed] [Google Scholar]
  • 36.West WH, Sienknecht CW, Townes AS, Herberman RB. Performance of a rosette assay between lymphocytes and sheep erythrocytes at elevated temperatures to study patients with cancer and other diseases. J Clin Immunol Immunopathol. 1976;5:60. doi: 10.1016/0090-1229(76)90149-5. [DOI] [PubMed] [Google Scholar]
  • 37.Wright PW, Hill LD, Anderson RP, Hammar SP, Bernstein ID, Prentice RL. Immunotherapy of resectable non-small cell cancer of the lung: A prospective comparison of intrapleural BCG +levamisole versus intrapleural BCG versus placebo. In: Salmon SE, Jones SE, editors. Adjuvant therapy of cancer. Amsterdam: Biomedical Press Elsevier/North Holland; 1977. p. 217. [Google Scholar]
  • 38.Wright PW, Hellstrom I, Warner G, Prentice R, Jones RF. Serotherapy of malignant melanoma. In: Terry D, Windhorst D, editors. Immunotherapy of cancer: Present status of trials in man. New York: Raven Press; 1978. p. 135. [Google Scholar]
  • 39.Wright PW, Feld R, Mountain C, Cooper J, Eagan R, Ginsberg R, Gail M, Hill L, Holmes EC, Lukeman J, McGuire W, Oldham R, Pearson G. A perspective double blind clinical trial of intrapleural Bacillus Calmette Guérin (BCG) in patients with stage I non-small cell lung cancer (NSCLC) In: Jones SE, Salmon SE, editors. Proceedings of the Third International Conference on Adjuvant Therapy of Cancer. New York: Grune & Stratton; 1981. p. 265. [Google Scholar]

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

RESOURCES