Skip to main content
SpringerLink
Log in

Combination of Chronic Indomethacin and Intermittent IL-2 Therapy in the Treatment of Disseminated Cancer

  • Chapter
Combination Therapies 2

  • 40 Accesses

Abstract

Numerous effector cells of the immune system are capable of killing tumor cells in vitro as well as in vivo when properly activated. Antigen-specific T lymphocytes when exposed to certain tumor-specific antigens (TSA) in association with self MHC antigen can be triggered to produce tumor-specific cytotoxic cells in the presence of a second signal derived from T helper cells, now recognized as interleukin-2 (IL-2). However, only a small minority of spontaneously-derived tumors express TSA1. Secondly, T lymphocytes infiltrating tumor sites often remain inactive in situ because of host or tumor-related suppressor mechanisms, so that immunotherapy employing IL-2 alone may not be fully effective. However, the findings that tumor-infiltrating lymphocytes (TIL), when adoptively transferred, can selectively migrate to the tumor site, have led to promising therapeutic strategies employing IL-2 therapy in combination with TIL, or therapy with genetically modified TIL designed to deliver tumoricidal molecules at the tumor site2. Other anti-tumor effector cells do not require antigen-specific priming. These are natural killer (NK) lymphocytes and macrophages. When appropriately activated, e.g. with IL-2 or IL-2 in combination with other cytokines, these cells can kill a large spectrum of tumor cells in vitro as well as in vivo, and thus constitute a major effector arm of IL-2 therapy. Both these cell classes, NK cells in particular, represent a major component of the tumor-infiltrating mononuclear cells3,6. However, these cells also remain inactive in situs 5,6 and may resist adequate activation with IL-2 therapy alone. Our aims have been to elucidate the mechanisms underlying this inactivation and exploit this information to achieve maximal in situ activation of all killer cell lineages for eradication of the metastatic disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. H. Hewitt, E. Blake and A. Walder, A critique for the evidence of active host defense against cancer, based on personal studies of 27 murine tumors of spontaneous origin. Brit. J. Cancer. 33: 241–259 (1976).

    Article  PubMed  CAS  Google Scholar 

  2. S. Rosenberg, The immunotherapy and gene therapy of cancer. J. Clin. Oncol. 10: 180–199 (1992).

    PubMed  CAS  Google Scholar 

  3. H.F. Pross and R.S. Kerbel, An assessment of intratumor phagocytic and surface marker-bearing cells in a series of autochthonous and early passaged chemically induced murine sarcomas. J. Nat. Cancer Inst., 57: 1157–1167 (1976).

    PubMed  CAS  Google Scholar 

  4. V. Santer, J.H. Mastromarino and P.K. Lala, Characterization of lymphocyte subsets in spontaneous mouse mammary tumors and host lymphoid organs. Int. J. Cancer, 25: 159–168 (1980).

    Article  PubMed  CAS  Google Scholar 

  5. P.K. Lala, V. Santer, H. Libenson and R.S. Parhar, Changes in the natural killer cell population during tumor development. I. Kinetics and in vivo significance. Cell Immunol., 93: 250–264 (1985).

    Article  PubMed  CAS  Google Scholar 

  6. R.S. Parhar and P.K. Lala, Changes in the host natural killer cell population during tumor development. II. The mechanism of suppression of NK activity. Cell Immunol. 93: 265–279 (1985).

    Article  PubMed  CAS  Google Scholar 

  7. J.S. Goodwin and J. Ceuppens, Regulation of the immune response by prostaglandins. J. Clin. Immunol. 3: 295–315 (1983).

    Article  PubMed  CAS  Google Scholar 

  8. M.R. Young and S. Knies, Prostaglandin E production by Lewis lung carcinoma: mechanism for tumor establishment in vivo. J. Natl. Cancer Inst., 72: 919–922 (1984).

    CAS  Google Scholar 

  9. A.M. Fulton, H.E. Ownby, J. Frederick and M.J. Brennan, Relationship of tumor prostaglandin levels to early recurrence in women with primary breast cancer: clinical update. Invasion Metastasis, 6: 83–94 (1986).

    PubMed  CAS  Google Scholar 

  10. P.K. Lala, PGE2-mediated inactivation of potentially tumoricidal effector cells of the host during tumor development: relevance to metastasis and immunotherapy. In: “Carcinogenesis and Dietary Fat” S. Abraham, ed., Martinus Nijhoff, Publisher, Norwell, MA, pp. 219–232 (1989).

    Chapter  Google Scholar 

  11. R.S. Parhar and P.K. Lala, PGE2-mediated inactivation of various killer lineage cells by tumor bearing host macrophages. J. Leukocyte Biol., 46: 474–484 (1988).

    Google Scholar 

  12. J.A.S. Nelson, R.S. Parhar, J.M. Scodras and P.K. Lala, Down-regulation of macrophage 1-A expression in tumor-bearing mice. J. Leukocyte Biol., 48: 394–402 (1990).

    PubMed  CAS  Google Scholar 

  13. P.K. Lala, T.G. Kennedy and R.S. Parhar, Suppression of lymphocyte alloreactivity by early gestational human decidua. II Characterization of suppressor mechanisms. Cell Immunol., 116: 411–422 (1988).

    Article  PubMed  CAS  Google Scholar 

  14. S. Chouaib, K.K. Weite, R. Mertelsman, et al., Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interluekin-2 production and down-regulation of transferrin receptor expression. J. Immunol., 135: 1172–1179 (1985).

    PubMed  CAS  Google Scholar 

  15. M. Elkashab, R.S. Parhar and P.K. Lala, Chronic indomethacin therapy reverses PGE2-mediated suppression of interferon-gamma and IL-2 receptor development on lymphoyctes of tumor-bearing mice and augments receptor development during therapy with IL-2, interferon-gamma or interferon-gamma plus IL-2. XIX International Leukocyte Culture Conference, Banff,AB, p 79 (Abstract) (1988).

    Google Scholar 

  16. M.R. Young, M.E. Young and H.T. Wepsik, Effect of prostaglandin EZ producing nonmetastataic Lewis lung carcinoma cells on the migration of prostaglandin-E2 responsive metastataic Lewis lung carcinoma cells. Cancer Res., 47: 3679–3683 (1987).

    Google Scholar 

  17. P.K. Lala, R.S. Parhar and P. Singh, Indomethacin-therapy abrogates prostaglandin mediated suppression of natural killer activity in tumor bearing mice and prevents tumor metastasis. Cell Immunol. 99: 108–118 (1986).

    Article  PubMed  CAS  Google Scholar 

  18. R.S. Parhar and P.K. Lala, Amelioration of B16F10 melanoma lung metastasis in mice by combination therapy with indomethacin and interleukin-2. J. Exp. Med., 165: 14–28 (1987).

    Article  PubMed  CAS  Google Scholar 

  19. P.K. Lala and R.S. Parhar, Cure of B16F10 melanoma lung metastasis in mice by chronic indomethacin therapy combined with repeated rounds of IL-2: Characteristics of killer cells generated in situ. Cancer Research, 48: 1072–1079 (1988).

    PubMed  CAS  Google Scholar 

  20. R.S. Parhar, A. Chambers and P.K. Lala, A comparison of the efficacy of indomethacin, IL-2, IFN-r or their various combinations in the treatment of experimental murine lung metastases. Proc. 19th Internat. Leucocyte Culture Conf., Banff, AB, Abstract, 79 (1988).

    Google Scholar 

  21. P.K. Lala and R.S. Parhar, Chronic indomethacin therapy combined with IL-2 cures primary mammary adenocarcinomas and their spontaneous lung metastases. Proc. Amer. Assoc. Cancer Res. 29: 405 (1988).

    Google Scholar 

  22. P.K. Lala and R.S. Parhar, Cure of primary adenocarcinomas and their spontaneous lung metastases with chronic indomethacin therapy combined with IL-2. Proc. Can. Fed. Biol. Soc., Abstract, 29: 130 (1988).

    Google Scholar 

  23. P.K. Lala, M. Elkhashab, R.S. Kerbel and R.S. Parhar, Cure of human melanoma lung metastases in nude mice with chronic indomethacin therapy combined with multiple rounds of IL-2: characteristics of killer cells generated in situ. Internat. Immunol., 2: 1149–1161 (1990).

    Article  CAS  Google Scholar 

  24. R.S. Parhar, R.S. Kerbel and P.K. Lala, Killer cell activation in situ and cure of multi-organ human melanoma metastases in nude mice with chronic indomethacin + IL-2 therapy. Proc. Amer. Assoc. Cancer Res., Abstract, 3: 379 (1989).

    Google Scholar 

  25. R. Lafreniere and S. Rosenberg, Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin-2. Cancer Res., 45: 3735–3740 (1985).

    PubMed  CAS  Google Scholar 

  26. N.K.S. Khoo, F.P.H. Chan, M.N. Saarloos and P.K. Lala, Immunotherapy of mammary adenocarcinoma metastases in C3H/HeN mice with chronic administrtion of cyclo-oxygenase inhibitors alone or in combination with IL-2. Clin. Exp. Metastasis, 10: 239–252 (1992).

    Article  PubMed  CAS  Google Scholar 

  27. N.K.S. Khoo, F.P.H. Chan, M.N. Saarloos and P.K. Lala, Immunotherapy of mammary adenocarcinoma metastases in C3H/HeN mice with chronic administrtion of cyclo-oxygenase inhibitors alone or in combination with IL-2. Clin. Exp. Metastasis, 10: 239–252 (1992).

    Article  PubMed  CAS  Google Scholar 

  28. W.C. Mertens, V.H.C. Bramwell, D. Banerjee, F. Gwardry-Sridhar, N. Al-Mutter, R.S. Parhar and P.K. Lala, Chronic oral indomethacin and ranitidine with intermittent continuous infusion interleukin-2 in advanced renal cell carcinoma. Submitted for publication (1992).

    Google Scholar 

  29. V.H.C. Bramwell, W.C. Mertens and P.K. Lala, Continuous oral indomethacin (Indo) and ranitidine (Rant) and continuous venous infusion of interleukin-2 (IL-2) in advanced renal carcinoma. Proc. Amer. Soc. Clin. Oncol., Abstract, 10: 171 (1991).

    Google Scholar 

  30. W.C. Mertens, V.H.C. Bramwell, F. Gwadry-Sridhar, W. Romano, D. Banerjee and P.K. Lala, Do indomethacin and ranitidine contribute to responses seen in advanced melanoma patients treated with high dose interleukin-2? Lancet, in press (1992).

    Google Scholar 

  31. W.C. Mertens, V.H.C. Bramwell and P.K. Lala, Do indomethacin (Indo) and ranitidine (Rant) contribute significantly to responses in advanced melanoma patients treated with high dose interleukin-2 ? Proc. Amer. Soc. Clin. Oncol. 10: 209 (1991).

    Google Scholar 

  32. S.A. Rosenberg, Clinical immunotherapy studies in the surgery branch of the U.S. National Cancer Institute. Cancer Treat. Rev. 16 (Suppl A): 115–121 (1989).

    Article  PubMed  Google Scholar 

  33. R.I. Fisher, C.A. Coltman, J.A. Doroshow, et al., A phase II clinical trial of interleukin-2 and lymphokine activated killer cells (LAK) in metastatic renal cancer. Ann. Intern. Med. 108: 518–523 (1988).

    PubMed  CAS  Google Scholar 

  34. J.P. Dutcher. S. Creekmore. G.R. Weiss, et al., A phase II study of interleukin2 and lymphokine activated killer (LAK) cells in patients with metastatic malignant melanoma. J. Clin. Oncol. 7: 477–485 (1989).

    PubMed  CAS  Google Scholar 

  35. M.S. McCabe, D. Stablein and M.J. Hawkins, The modified group C experience - phase III randomized trials of IL-2 versus IL-2/LAK in advanced renal cell carcinoma and advanced melanoma. Proc. Am. Soc. Clin. Oncol. Abstract, 10: 213 (1991).

    Google Scholar 

  36. D.R. Parkinson, R.I. Fisher, A.A. Rayner, et al., 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., 8: 1630–1636 (1990).

    PubMed  CAS  Google Scholar 

  37. M. Bar, M. Sznol, M.B. Atkins, et al., Metastatic malignant melanoma treated with combined bolus and continuous infusion interleuken-2 and lymphokine-activated killer cells. J. Clin. Oncol., 8: 1138–1147 (1990).

    PubMed  CAS  Google Scholar 

  38. R.O. Dillman, R.K. Oldham, K.W. Tauer, et al., Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer. A National Biotherapy Study Group trial. J. Clin. Oncol. 9: 1233–1240 (1991).

    PubMed  CAS  Google Scholar 

  39. J.P. Dutcher, E.R. Gaynor, D.H. Boldt, et al., A phase II study of high dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma. J. Clin. Oncol., 9: 641–648 (1991).

    PubMed  CAS  Google Scholar 

  40. J.S. Abrams, A.A. Rayner, P.H. Wiernik, et al., High dose recombinant interleukin-2 alone: a regimen with limited activity in the treatment of advanced renal cell carcinoma. J. Natl. Cancer Inst. 82: 1202–1206 (1990).

    Article  PubMed  CAS  Google Scholar 

  41. D.R. Parkinson, J.S. Abrams, P.H. Wiernik, et al., Interleukin-2 therapy in patients with metastatic malignant melanoma: A phase II study. J. Clin. Oncol. 8: 1650–1656 (1990).

    PubMed  CAS  Google Scholar 

  42. J.G. Cairncross, D.R. MacDonald, J.H.W. Pexman and J. Ives, Steroid-induced CT changes in patients with recurrent malignant glioma. Neurology, 38: 724–726 (1988).

    Article  Google Scholar 

  43. D.E. Griswold, S. Alexxi, A.M. Badger, G. Poste and N. Hanna, Inhibition of T suppressor cell expression by histamine type 2 (H2) receptor antagonists. J. Immunol., 132: 3054–3057 (1984).

    PubMed  CAS  Google Scholar 

  44. J.I. Allen, H.J. Syropoulos, G. Grant, et al., Cimetidine modulates natural killer cell function of patients with chronic lymphocytic leukemia. J. Lab. Clin. Med., 109: 396–401 (1987).

    PubMed  CAS  Google Scholar 

  45. F. Aweeka, P. Lizak, M. Garovoy, et al., Interleukin-2 and immunoglobulin increases with H2-antagonists in humans. Transplant Proc. 21: 1718–1721 (1989).

    PubMed  CAS  Google Scholar 

  46. T. Smith, Histamine type 2-receptor antagonists in cancer immunotherapy. Compr. Ther., 16: 8–13 (1990).

    PubMed  CAS  Google Scholar 

  47. P.K. Lala, W. Mertens, R.S. Parhar and N. Al-Mutter, Effects of ranatidine on LAK cell generation with PBL of normal and cancer-bearing subjects. Proc. Am. Assoc. Cancer Res., Abstract, 31: 277 (1990).

    Google Scholar 

  48. D. Banerjee, W.C. Mertens, V.H.C. Bramwell and P.K. Lala, Sequential changes in lymphocyte subsets in patients on chronic indomethacin + IL-2 therapy for advanced cancer. Proc. Amer. Assoc. Cancer Res., Abstract, 32: 247 (1992).

    Google Scholar 

  49. P.K. Lala, W.C. Mertens, V.H.C. Bramwell, D. Banerjee and N. Al-Mutter, Correlation of in vitro tumoricidal responses to chronic oral indomethacin therapy and intravenous IL-2 in melanoma and renal carcinoma patients. Proc. Amer. Assoc. Cancer Res., Abstract, 32: 248 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Anatomy, The University of Western Ontario, London, Ontario, Canada, N6A 5C1

    Peeyush K. Lala, Nahla Al-Mutter, Ranjit Parhar & Mary Nel Saarloos

  2. Departments of Oncology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1

    Peeyush K. Lala, Vivien Bramwell & William C. Mertens

  3. Departments of Pathology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1

    Diponkar Banerjee

Authors
  1. Peeyush K. Lala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nahla Al-Mutter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ranjit Parhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Nel Saarloos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vivien Bramwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William C. Mertens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diponkar Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Rome “Tor Vergata”, Rome, Italy

    Enrico Garaci

  2. The Institute for Advanced Studies in Immunology and Aging, Washington, D.C., USA

    Allan L. Goldstein

Rights and permissions

Reprints and permissions

Copyright information

© 1993 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lala, P.K. et al. (1993). Combination of Chronic Indomethacin and Intermittent IL-2 Therapy in the Treatment of Disseminated Cancer. In: Garaci, E., Goldstein, A.L. (eds) Combination Therapies 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2964-4_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2964-4_18

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6289-0

  • Online ISBN: 978-1-4615-2964-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation