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In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma

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Despite considerable advancement in anticancer therapy, minimal residual disease (MRD) is still a major problem in the clinical management of cancer, including lymphoma. In this report, we have studied the antitumor effects of interleukin-12 (IL-12) against an aggressive liver metastatic murine RAW117-H10 lymphoma. Our results using three different doses of IL-12 (0.175, 0.35 and 0.7 µg/mouse) showed that a 0.35 µg dose is the most efficacious against lymphoma grown in intact mice. Furthermore, we have evaluated the therapeutic effects of IL-12 against residual lymphoma in a transplantation setting. BALB/c mice were treated with high-dose therapy (HDT) and transplanted with syngeneic bone marrow cells added with a known number of RAW117-H10 lymphoma cells to mimic the clinical situation of MRD. The mice were then treated with IL-12 (0.25 µg/mouse/day) alone or IL-12 plus activated cytotoxic effector cells. Our results showed that IL-12 had a significant (P<0.05) antitumor therapeutic effect against liver metastatic lymphoma grown in intact mice as well as in lymphoma-bearing mice treated with HDT followed by stem cell transplantation as determined by survival period. The therapeutic effect of IL-12 was also demonstrated by a very significant decrease (P<0.05) in the tumor burden in livers from the IL-12-treated mice. Mice that were treated with IL-12 following HDT and hematopoietic stem cell transplantation had a significant decrease in circulating white blood cells (P<0.05), a significant increase in spleen weight and cellularity (P<0.05), and hematopoietic progenitor cells (P<0.05), a significant increase in the number of splenocytes expressing IL-2 α-chain receptor (P<0.05), and an increase in the frequency of natural killer cells in their spleens. These studies suggest that cytokines such as IL-12 may have the potential to mediate antitumor effects against residual lymphoma without compromising lymphohematopoietic recovery.

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References

  1. Petersen FF, Appelbaum R and Hill, 1990, Autologous marrow transplantation for malignant lymphoma; a report of 101 cases from Seattle. J Clin Oncol, 8, 638–47.

    Google Scholar 

  2. Appelbaum F, 1988, Intensive chemotherapy or chemoradiotherapy with autologous marrow support as treatment for patients with solid tumors. Hematol/Oncol Clin North Am, 2, 345–51.

    Google Scholar 

  3. Arceci JR, 1993, Clinical significance of p-glycoprotein in multidrug resistant malignancies. Blood, 81, 2215–22.

    Google Scholar 

  4. Stern AS, Podlaski FJ, Hulmes JD, et al. 1990, Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblast cells. Proc Natl Acad Sci, USA, 87, 6808–12.

    Google Scholar 

  5. Kobayashi M, Fitz L, Ryan M, et al. 1989, Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biological effects on human lymphocytes. J Exp Med, 170, 827–45.

    Google Scholar 

  6. Gately MK, Wolitzky AG, Quinn PM and Chizzonite R, 1992, Regulation of human cytolytic lymphocyte response by interleukin-12. Cell Immunol, 143, 127–42.

    Google Scholar 

  7. Naume B, Gately M and Espevik T, 1992, A comparative study of IL-12(cytotoxic lymphocyte maturation factor), IL-2, and IL-7-induced effects on immunomagnetically purified CD56+ NK cells. J Immunol, 148, 2429–36.

    Google Scholar 

  8. Gately MK, Warrier RR, Honasoge S, et al. 1994, Administration of recombinant IL-12 to normal mice enhances cytolytic activity and induces production of IFN-γ in vivo. Int Immunol, 6, 157–67.

    Google Scholar 

  9. Afonso LCC, Scharton TM, Vieira LQ, Trinchieri G and Scott P, 1994, IL-12 functions as an effective adjuvant in a vaccine against Leishmania major by directing the development of leishmania specific CD4+ Th 1 cells. Science, 263, 235–7.

    Google Scholar 

  10. Sieling PA, Wang HX, Gately MK, et al. 1994, IL-12 regulates T helper type 1 cytokine response in human infectious disease. J Immunol, 153, 3639–47.

    Google Scholar 

  11. Jackson JD, Yan Y, Brunda MJ, Kelsey LS and Talmadge JE, 1995, IL-12 enhances peripheral hematopoiesis in vivo. Blood, 85, 2371–6.

    Google Scholar 

  12. Ploemacher RE, van Soest PL, Voorwinden H and Boudewijn A, 1993, Interleukin-12 synergizes with interleukin-3 and steel factor to enhance recovery of murine hemopoietic stem cells in liquid culture. Leukemia, 7, 1381–8.

    Google Scholar 

  13. Gately MK, Gubler U, Brunda MJ, et al. 1994, Interleukin-12: a cytokine with therapeutic potential in oncology and infectious disease. Ther Immunol, 1, 187–93.

    Google Scholar 

  14. Brunson KW and Nicolson GL, 1979, Selection and biological properties of malignant variants of a murine lymphosarcoma. J Natl Cancer Inst, 61, 1499–503.

    Google Scholar 

  15. Joshi S, Tilden P, Jackson J, Sharp J and Brunson K, 1987, Cell surface properties associated with malignancy of metastatic large cell lymphoma cells. Cancer Res, 47, 3351–7.

    Google Scholar 

  16. Verbik DJ, Jackson JD, Pirruccello SJ, Patil KD, Kessinger A and Joshi SS, 1995, Functional and phenotypic characterization of human peripheral blood stem cell harvests: A comparative analysis of cells from consecutive collections. Blood, 85, 1964–70.

    Google Scholar 

  17. Pross F, Bains M, Rubin P, Shargge P and Patterson M, 1981, Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol, 1, 51–63.

    Google Scholar 

  18. Verbik DJ and Joshi SS, 1995, Immune cells and cytokines: Their role in cancer immunotherapy. Int J Oncology, 7, 205–24.

    Google Scholar 

  19. Mazumder A and Rosenberg SA, 1984, Successful immunotherapy of NK-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin-2. J Exp Med, 159, 495–507.

    Google Scholar 

  20. LaFreniere R and Rosenberg SA, 1985, Successful immunotherapy of murine experimental hepatic metastases with lymphokine activated killer cells and recombinant interleukin-2. Cancer Res, 45, 3735–41.

    Google Scholar 

  21. Rosenberg SA, Lotze MT, Muul LM, et al. 1987, A progressive report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med, 316, 889–97.

    Google Scholar 

  22. Lister J, Rybka WB, Donnenberg AD, et al. 1995, Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate post-transplant period. Clin Cancer Res, 1, 607–11.

    Google Scholar 

  23. Neta R, Stiefel SM, Finkelman F, Herrmann S and Ali N, 1994, IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation. J Immunol, 153, 4230–7.

    Google Scholar 

  24. Nastala CL, Edington HD, McKinney TC, et al. 1994, Recombinant IL-12 administration induces tumor regression in association with IFN-γ production. J Immunol, 153, 1697–706.

    Google Scholar 

  25. Gazzinelli RT, Wysocka M, Hayashi S, et al. 1994, Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol, 153, 2533–43.

    Google Scholar 

  26. Skorski T, Kawalec M, Hoser G, Ratajczak M, Gnatowski B and Kawiak J, 1988, The kinetics of immunologic and hematologic recovery in mice after lethal total body irradiation and reconstitution with syngeneic bone marrow cells treated or untreated with mafosfamide (ASTA Z 7654). Bone Marrow Transplant, 3, 543–51.

    Google Scholar 

  27. Yanagida T, Kato T, Igarashi O, Inoue T and Nariuchi H, 1994, Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. J Immunol, 152, 4919–28.

    Google Scholar 

  28. Trinchieri G, 1995, Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. In: Paul W, Fathman CG and Metzger H, eds. Annual Review of Immunol. Palo Alto, CA, Annual Review Inc, pp. 251–76.

    Google Scholar 

  29. Jacobsen SE, Veiby OP and Smeland EB, 1993, Cytotoxic lymphocyte maturation factor (interleukin-12) is a synergistic growth factor for hematopoietic stem cells. J Exp Med, 178, 413–18.

    Google Scholar 

  30. Siefer AK, Longo DL, Harrison CL, Reynolds CW and Murphy WJ, 1993, Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice. Blood, 82, 2577–84.

    Google Scholar 

  31. Brunda MJ, Luistro L, Warrier RR, et al. 1993, Antitumor and antimetastatic activity of interleukin-12 against murine tumors. J Exp Med, 178, 1223–30.

    Google Scholar 

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Authors and Affiliations

  1. Departments of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    David J. Verbik, Warren W. Stinson & Shantaram S. Joshi

  2. Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Anne Kessingert

  3. Department of OncologyDepartment of OncologyDepartment of Oncology, Hoffmann-La Roche Inc., NJ, USA

    Michael J. Brunda

Authors
  1. David J. Verbik
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  2. Warren W. Stinson
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  3. Michael J. Brunda
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  4. Anne Kessingert
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  5. Shantaram S. Joshi
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Verbik, D.J., Stinson, W.W., Brunda, M.J. et al. In vivo therapeutic effects of interleukin-12 against highly metastatic residual lymphoma. Clin Exp Metast 14, 219–229 (1996). https://doi.org/10.1007/BF00053895

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  • DOI: https://doi.org/10.1007/BF00053895

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