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 IJMPCERO  Vol.5 No.1 , February 2016
The Hematopoietic and Immunomodulatory Effect of rhIL-12 for Liver Cancer
Abstract: Purpose: To explore the effect of rhIL-12 on the number of the blood cells and CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells in liver cancer patients following radiation therapy. Methods: We selected forty liver cancer patients who carried out by cyber knife (the patients were given 5 Gy every time for 5 times continuously) to observe the size of the tumor. After thirty hours, rhIL-12 was injected into the liver cancer patients via subcutaneous at the concentration of 50 ng/kg, 100 ng/kg, 200 ng/kg and 300 ng/kg in different patients, respectively. And there were ten patients in the four groups, respectively. The twenty patients who were selected from the hospital without rhIL-12 treatment were used as controls. All the blood cells were collected from different groups on day 0, hour 12, day 7, day 14, day 21 and day 28 after rhIL-12 treatment, respectively. The full number of blood cells in every group was analyzed by ELISA. The number of CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells were detected by Flow Cytometry. After one month with rhIL-12 treatment, ECOG and WHO were used to evaluate the prognosis of liver cancer. Results: In present study, we found that the number of blood cells was significantly decreased on day 0 - day 3, while recovered from day 7 - day 14 and down-regulated on day 21 after rhIL-12 treatment. The number of CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells was elevated with any concentration of rhIL-12. Furthermore, results showed that number of white blood cells was obviously higher than in patients without rhIL-12 treatment (P < 0.05). However, there was no significant difference of erythrocyte and platelet, between groups treated with rhIL-12 and control groups. In addition, the immune cells including CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells were reduced on day 0 - day 3, recovered from day 7, and then decreased from day 21 in rhIL-12 treatment groups related to control groups (P < 0.05). Furthermore, studies showed that five patients developed symptoms of fever, bilirubin increased and liver dysfunction with the dose of 300 ng/kg. So we found that the safe and well-tolerated human dose of 200 ng/kg is within this efficacious range based on exposure parameters through the research. Higher ECOG and WHO scores were observed in rhIL-12 treatment groups compared to control groups (P = 0.025, P = 0.044, respectively). Conclusion: Our results suggested that rhIL-12 could recover the liver cancer induced aberrant blood cell number and CD4/8+ T, CD45+ leukocytes, and CD56+ NK cells , which may be an effective method to alleviate the progress of liver cancer and played an important role in treating liver cancer.
Cite this paper: Gong, X. , Guo, N. , Wan, L. , Jia, X. and Wang, Y. (2016) The Hematopoietic and Immunomodulatory Effect of rhIL-12 for Liver Cancer. International Journal of Medical Physics, Clinical Engineering and Radiation Oncology, 5, 33-41. doi: 10.4236/ijmpcero.2016.51004.
References

[1]   Pircher, A., Medinger, M. and Drevs, J. (2011) Live Cancer: Targeted Future Options. World Journal of Hepatology, 27, 38-44.
http://dx.doi.org/10.4254/wjh.v3.i2.38

[2]   Ferlay, J., Autier, P., Boniol, M., Heanue, M., Colombet, M. and Boyle, P. (2007) Estimates of the Cancer Incidence and Mortality in Europe in 2006. Annals of Oncology, 18, 581-592.
http://dx.doi.org/10.1093/annonc/mdl498

[3]   Little, R.F., Pluda, J.M., Wyvill, K.M., Rodriguez-Chavez, I.R., Tosato, G., Catanzaro, A.T., Steinberg, S.M. and Yarchoan, R. (2006) Activity of Subcutaneous Interleukin-12 in AIDS-Related Kaposi Sarcoma. Blood, 107, 4650-4657.
http://dx.doi.org/10.1182/blood-2005-11-4455

[4]   Hamza, T., Barnett, J.B. and Li, B. (2010) Interleukin 12 a Key Immunoregulatory Cytokine in Infection Applications. International Journal of Molecular Sciences, 11, 789-806.
http://dx.doi.org/10.3390/ijms11030789

[5]   Pertl, U., Luster, A.D., Varki, N.M., Homann, D., Gaedicke, G. and Reisfeld, R.A. (2001) Lode HN:IFN-Gamma-Inducible Protein-10 Is Essential for the Generation of a Protective Tumor-Specific CD8 T Cell Response Induced by Single-Chain IL-12 Gene Therapy. The Journal of Immunology, 166, 6944-6951.
http://dx.doi.org/10.4049/jimmunol.166.11.6944

[6]   Yao, Q.Y., Zhang, Q.H., Ni, Q.X., et al. (2000) The Expression of Serum IL-6,IL-10,IL-12 Level in Gastrointestinal Neoplasm and Its Significance. Chinese Journal of Gastrointestinal Surgery, 3, 3435.

[7]   Basile, L.A., Gallaher, T.K., Shinbata, D., et al. (2008) Mutilineage Hematopoietic Recovery with Concomitant Antitumor Effects Using Low Dose Interleukin-12 in Myelosuppressed Tumor-Bearing Mice. Journal of Translational Medicine, 6, 26.
http://dx.doi.org/10.1186/1479-5876-6-26

[8]   Chen, T., Burke, K.A., Zhan, Y., Wang, X., Shibata, D. and Zhao, Y. (2007) IL-12 Facilitates Both the Recovery of Endogenous Hematopoiesis and the Engraftment of Stem Cells after Ionizing Radiation. Experimental Hematology, 35, 203-213.
http://dx.doi.org/10.1016/j.exphem.2006.10.002

[9]   Zhou, Z.F., Jiang, J.H., Li, J.Y., Chen, Q. and Ye, Y.B. (2013) IL-12 Plays Anti-Tumor Effect by Inducing NK Cell Activation in Hepatic Carcinoma Microenvironment. Chinese Journal of Cancer Biotherapy, 20, 93-98.

[10]   Kerkar, S.P. and Restifo, N.P. (2012) The Power and Pitfalls of IL-12. Blood, 119, 4096-4097.
http://dx.doi.org/10.1182/blood-2012-03-415018

[11]   Hirayama, F., Katayama, N., Neben, S., Donaldson, D., Nickbarg, E.B., Clark, S.C. and Ogawa, M. (1994) Synergistic Interaction between Interleukin-12 and Steel Factor in Support of Proliferation of Murine Lymphohematopoietic Progenitors in Culture. Blood, 83, 92-98.

[12]   Jacobsen, S.E., Veiby, O.P. and Smeland, E.B. (1993) Cytotoxic Lymphocyte Maturation Factor (Interleukin 12) Is a Synergistic Growth Factor for Hematopoietic Stem Cells. The Journal of Experimental Medicine, 178, 413-418.
http://dx.doi.org/10.1084/jem.178.2.413

[13]   Basile, L.A., Ellefson, D., Gluzman-Poltorak, Z., Junes-Gill, K., Mar, V., Mendonca, S., Miller, J.D., Tom, J., Trinh, A. and Gallaher, T.K. (2012) HemaMax, a Recombinant Human Interleukin-12. Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates. PLoS ONE, 7, 330-434.
http://dx.doi.org/10.1371/journal.pone.0030434

[14]   CDER (2009) Guidance for Industry: Animal Models—Essential Elements to Address Efficacy under the Animal Rule. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research (CBER).

[15]   Dybedal, I., Larsen, S. and Jacobsen, S.E. (1995) IL-12 Directly Enhances in Vitro Murine Erythropoiesis in Combination with IL-4 and Stem Cell Factor. The Journal of Immunology, 154, 4950-4955.

[16]   Gately, M.K., Warrier, R.R., Honasoge, S., Carvajal, D.M., Faherty, D.A., Connaughton, S.E., Anderson, T.D., Sarmiento, U., Hubbard, B.R. and Murphy, M. (1994) Administration of Recombinant IL-12 to Normal Mice Enhances Cytolytic Lymphocyte Activity and Induces Production of IFN-Gamma in Vivo. International Immunology, 6, 157-167.
http://dx.doi.org/10.1093/intimm/6.1.157

[17]   Trudeau, C., Cotreau, M.M., Stonis, L., Dykstra, K.H., Oestreicher, J.L., Strahs, A., Dorner, A.J., Van Cleave, V.H., Trepicchio, W.L. and Schwertschlag, U.S. (2005) A Single Administration of Recombinant Human Interleukin-12 Is Associated with Increased Expression Levels of Interferon-Gamma and Signal Transducer and Activator of Transcription in Healthy Subjects. The Journal of Clinical Pharmacology, 45, 649-658.
http://dx.doi.org/10.1177/0091270005276116

[18]   Ohno, R., Yamaguchi, Y., Toge, T., Kinouchi, T., Kotake, T., Shibata, M., Kiyohara, Y., Ikeda, S., Fukui, I., Gohchi, A., Sugiyama, Y., Saji, S., Hazama, S., Oka, M., Ohhashi, Y., Tsukagoshi, S. and Taguchi, T. (2000) A Dose-Escalation and Pharmacokinetic Study of Subcutaneously Administered Recombinant Human Interleukin 12 and Its Biological Effects in Japanese Patients with Advanced Malignancies. Clinical Cancer Research, 6, 2661-2669.

[19]   Robertson, M.J., Pelloso, D., Abonour, R., Hromas, R.A., Nelson Jr., R.P., Wood, L. and Cornetta, K. (2002) Interleukin 12 Immunotherapy after Autologous Stem Cell Transplantation for Hematological Malignancies. Clinical Cancer Research, 8, 3383-3393.

[20]   Gollob, J.A., Mier, J.W., Veenstra, K., McDermott, D.F., Clancy, D., Clancy, M. and Atkins, M.B. (2000) Phase I Trial of Twice-Weekly Intravenous Interleukin 12 in Patients with Metastatic Renal Cell Cancer or Malignant Melanoma: Ability to Maintain IFN-Gamma Induction Is Associated with Clinical Response. Clinical Cancer Research, 6, 1678-1692.

[21]   Gollob, J.A., Veenstra, K.G., Parker, R.A., Mier, J.W., McDermott, D.F., Clancy, D., Tutin, L., Koon, H. and Atkins, M.B. (2003) Phase I Trial of Concurrent Twice-Weekly Recombinant Human Interleukin-12 plus Low-Dose IL-2 in Patients with Melanoma or Renal Cell Carcinoma. Journal of Clinical Oncology, 21, 2564-2573.
http://dx.doi.org/10.1200/JCO.2003.12.119

 
 
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