Skip to main content
SpringerLink
Log in

Immunomodulation following chemotherapy

  • Immunotherapy
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B 16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rosenberg SA: The immunotherapy and gene therapy of cancer. J Clin Oncol 10:180–199, 1992

    PubMed  Google Scholar 

  2. Glazier AD, Tutschka PJ, Farmer ER, Santos GW: Graft-versus-host disease in cyclosporine A-treated rats following syngeneic and autologous bone marrow reconstitution. J Exp Med 158:1–8, 1983

    PubMed  Google Scholar 

  3. Noga SJ, Horwitz L, Kim H, Laulis MK, Hess AD: Interferon-γ potentiates the antitumor effect of cyclosporine-induced autoimmunity. J Hematotherapy 1:75–84, 1992

    Google Scholar 

  4. Gastl G, Marth C, Leiter E, Gattringer C, Mayer I, Daxenbichler G, Flener R, Huber C: Effects of human recombinant α arg-interferon and γ-interferon on human breast cancer cell lines: Dissociation of antiproliferative activity and induction of HLA-DR antigen expression. Cancer Res 45:2957–2961, 1985

    PubMed  Google Scholar 

  5. Linch DC, Brunett AK: Clinical studies of ABMT in acute myeloid leukemia. Clin Hematol 15:167, 1986

    Google Scholar 

  6. Butturini A, Bortin MM, Gale RP: Graft versus leukemia following bone marrow transplantation. Bone Marrow Transplant 2:233–242, 1987

    PubMed  Google Scholar 

  7. Geller RB, Esa AH, Beschorner WE, Frondoza CG, Santos GW, Hess AD: Successful in vitro graftversus-tumor effect against an Ia-bearing tumor using cyclosporine-induced syngeneic graft-versus-host disease in the rat. Blood 74:1165–1171, 1989

    PubMed  Google Scholar 

  8. Charak BS, Brynes RK, Groshen S, Chen SC, Mazumder A: Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice. Blood 76:2187–2190, 1990

    PubMed  Google Scholar 

  9. Ackerstein A, Kedar E, Slavin S: Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematological disorders. Blood 78:1212–1215, 1991

    PubMed  Google Scholar 

  10. Klingemann HG, Grigg AP, Wilkie-Boyd K, Barnett MJ, Eaves AC, Reece DE, Sheperd JD, Philips GL: Treatment with recombinant interferon (α-2b) early after bone marrow transplantation in patients at high risk of relapse. Blood 78:3306–3311, 1991

    PubMed  Google Scholar 

  11. Charak BS, Agah R, Mazumder A: Synergism of interleukin-2 and cyclosporine A in induction of a graft versus tumor effect without graft versus host disease after syngeneic bone marrow transplantation. Blood 80:179–184, 1992

    PubMed  Google Scholar 

  12. Charak BS, Brynes RK, Katsuda S, Groshen S, Chen SC, Mazumder A: Induction of graft versus leukemia effect in bone marrow transplantation: Dosage and time schedule dependency of interleukin 2 therapy. Cancer Res 51:2015–2020, 1991

    PubMed  Google Scholar 

  13. Charak BS, Sadowski RM, Mazumder A: Antitumor effect of interferon plus cyclosporine A for disseminated melanoma. Cancer Res 52:6482–6486, 1992

    PubMed  Google Scholar 

  14. Charak BS, Agah R, Mazumder A: Granulocytemacrophage colony stimulating factor-induced antibody-dependent cellular cytotoxicity in bone marrow transplantation. Blood 81:3474–3479, 1993

    PubMed  Google Scholar 

  15. Verma UN, Charak BS, Rajgopal C, Mazumder A: Interleukin-2 in bone marrow transplantation.In: Buccner D (ed) Technical and Biological Components of Marrow Transplantation. Kluwer, Boston, 1995.

    Google Scholar 

  16. Kennedy MJ, Vogelsang GB, Beveridge RA, Farmer ER, Altomonte V, Huelskamp AM, Davidson NE: Phase I trial of intravenous cyclosporine to induce graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer. J Clin Oncol 11:478–484, 1993

    PubMed  Google Scholar 

  17. Hamon MD, Prentice HG, Gottlieb DJ, Macdonald ID, Cunningham JM, Smith OP, Gilmore M, Gandhi L, Collis C: Preliminary report. Immunotherapy with interleukin 2 after ABMT in AML. Bone Marrow Transplant 11:399–401, 1993

    PubMed  Google Scholar 

  18. Soiffer RJ, Murray C, Cochran K: Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood 79:517–526, 1992

    PubMed  Google Scholar 

  19. Falkson C, Falkson G, Falkson H: Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 9:1403–1408, 1991

    PubMed  Google Scholar 

  20. Ujiie T: Increased sensitivity of tumor cells to immune defense cells following treatment with antineoplastic agents in vitro. Jpn J Exp Med 59:17–26, 1989

    PubMed  Google Scholar 

  21. Kennedy MJ, Jones RJ: Autologous graft-versus-host disease: Immunotherapy of breast cancer after bone marrow transplantation. Breast Can Res Treat 26:s31-s40, 1993

    Google Scholar 

  22. Rosenberg SA, Grimm EA, McGrogan M, et al: Biological activity of recombinant human interleukin-2 produced in Escherichia coli. The Sciences (Wash DC) 223:1412–1417, 1984

    Google Scholar 

  23. Richards JM, Mehta N, Ramming K, Skosey P: Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 10:1338–1343, 1992

    PubMed  Google Scholar 

  24. Rosenberg SA, Lotze MT, Yang JC, et al: Combination therapy with interleukin-2 and alpha interferon for the treatment of patients with advanced cancer. J Clin Oncol 7:1863–1874, 1989

    PubMed  Google Scholar 

  25. Verma UN, Bagg A, Brown E, Mazumder A: Interleukin-2 activation of human bone marrow in long-term cultures: an effective strategy for purging and generation of anti-tumor cytotoxic effectors. Bone Marrow Transplant 13:115–123, 1994

    PubMed  Google Scholar 

  26. Kennedy MJ, Vogelsang GB, Jones RJ, Farmer ER, Hess AD, Altomonte V, Huelskamp AM, Davidson NE: Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer. J Clin Oncol 12:249–257, 1994

    PubMed  Google Scholar 

  27. Verma UN, Areman E, Dickerson SA, Kotula PL, Sacher R, Mazumder A: Interleukin-2 activation of chemotherapy and growth factor mobilized peripheral blood stem cells for generation of cytotoxic effectors [abstract]. Proc Am Soc Hematol, 1994

  28. Hess AD, Horwitz L, Beschorner WE, Santos GW: Development of graft-vs-host disease-like syndrome in cyclosporine treated rats after syngeneic bone marrow transplantation. I. Development of cytotoxic Tlymphocytes with apparent polyclonal anti-Ia specificity, including autoreactivity. J Exp Med 161:718–730, 1985

    PubMed  Google Scholar 

  29. Agah R, Malloy B, Kerner M, Mazumder A: Generation and characterization of IL-2-activated bone marrow cells as a potent graft vs. tumor effector in transplantation. J Immunol 143:3093–3099, 1989

    PubMed  Google Scholar 

  30. Agah R, Malloy B, Kerner M, Girgis E, Bean P, Twomey P, Mazumder A: Potent graft antitumor effect in natural killer-resistant disseminated tumors by transplantation of interleukin-2 activated syngeneic bone marrow in mice. Cancer Res 49:5959, 1989

    PubMed  Google Scholar 

  31. Papa ML, Yang YC, Vetto JT, Shiloni E, Eisenthal A, Rosenberg SA: Combined effects of chemotherapy and interleukin-2 in the therapy of mice with advanced pulmonary tumors. Cancer Res 48:122–129, 1988

    PubMed  Google Scholar 

  32. North RJ: Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor cells. J Exp Med 155:1063–1074, 1982

    PubMed  Google Scholar 

  33. Nagarkatti M, Kaplan AM: The role of suppressor Tcells in BCNU-mediated rejection of a syngeneic tumor. J Immunol 135:1510–1517, 1985

    PubMed  Google Scholar 

  34. Mitchell MS, Kempf RA, Harel W, Shau H, Boswell WD, Lind S, Bradley EC: Effectiveness and tolerability of low dose cyclophosphamide and low dose intravenous interleukin-2 disseminated melanoma. J Clin Oncol 6:409–424, 1988

    PubMed  Google Scholar 

  35. Rosenberg SA: Immunotherapy of cancer using interleukin-2. Current status and future prospects. Immunol Today 9:58–62, 1988

    PubMed  Google Scholar 

  36. Lotze MT, Custer MC, Sharrow LA, et al: In vivo administration of purified human interleukin-2 to patients with cancer: development of interleukin-2 positive cells and circulating soluble interleukin-2 receptors following interleukin-2 administration. Cancer Res 47:2188–2195, 1987

    PubMed  Google Scholar 

  37. Waldmann TA: The multi-subunit interleukin-2 receptor. Ann Rev Biochem 58:875–911, 1989

    PubMed  Google Scholar 

  38. Smith KA. The interleukin-2 receptor.In: Dixon FJ (ed) Advances in Immunology. Academic Press, San Diego, 1988, pp 165–179

    Google Scholar 

  39. Mouawad R, Ichen M, Rixe O, Benhammouda A, Vuillemin E, Weil M, Khayat D, Soubrane C: Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma. Clin Exp Immunol 97:342–346, 1994

    PubMed  Google Scholar 

  40. Khayat D, Borel C, Tourani A, Benhammouda A, Antoine E, Rixe O, Vuillemin E, Bazex PA, Thill L, Franks R, Auclerc G, Soubrane C, Banzet P, Weil M: Sequential chemoimmunotherapy with cisplatin, interleukin-2, and interferon alfa-2a for metastatic melanoma. J Clin Oncol 11:2173–2180, 1993

    PubMed  Google Scholar 

  41. Demchak PA, Mier JW, Robert NJ, et al: Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma. A pilot study. J Clin Oncol 9:1821–1830, 1991

    PubMed  Google Scholar 

  42. Legha S, Plager C, Ring S, et al: A phase II study of biochemotherapy using interleukin 2 + interferon alpha-2a in combination with cisplatin, vinblastine and DTIC in patients with metastatic melanoma. Proc Am Soc Clin Oncol 11:343, 1992

    Google Scholar 

  43. Hamblin TJ, Davies B, Sadullah S, et al: A phase II study of the treatment of metastatic malignant melanoma with a combination of dasarbazine, cisplatin, interleukin 2 and alpha-interferon. Proc Am Soc Clin Oncol 10:294, 1991

    Google Scholar 

  44. Blair S, Flaherty L, Valdivieso M, et al: Comparison of high dose interleukin 2 with combined chemotherapy low-dose IL-2 in metastatic malignant melanoma. Proc Am Soc Clin Oncol 10:294, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Hematolog/Oncology, V.T. Lombardi Cancer Research Center, Georgetown University Hospital, 3800 Reservoir Road, 20007, Washington DC, USA

    M. Obadina, U. Verma, M. Hawkins & A. Mazumder

Authors
  1. M. Obadina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Mazumder
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Obadina, M., Verma, U., Hawkins, M. et al. Immunomodulation following chemotherapy. Breast Cancer Res Tr 38, 41–48 (1996). https://doi.org/10.1007/BF01803782

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01803782

Key words

Search

Navigation