Background: The importance of immunotherapy in cancer treatment has been increased owing to its non-toxicity and application to personalized medicine. However, precise estimation indices of immunotherapy have yet to be established. To determine effective evaluation indices of immunotherapy for cancer treatment, we analyzed the CD4/CD8 ratio under various conditions in clinical patients with advanced cancer. Patients and Methods: Thirty-four patients who underwent one course of adoptive activated immunotherapy with or without additional conventional chemotherapy were enrolled. Before and after one course of immunotherapy, changes in the CD4/CD8 ratio were estimated by flow cytometry. Results: All patients showed a tendency toward a decrease in the CD4/CD8 ratio during a 3-month period after one course of adoptive activated T lymphocyte immunotherapy. Patients who had undergone prior surgery showed a remarkable increase in CD8 T cell number. Thus, adoptive activated T lymphocyte immunotherapy improves immunological ability against cancer invasion. The Eastern Cooperative Oncology Group’s performance status during one course of immunotherapy was significantly improved in the antecedent surgery group, with no evidence of improved PS in the non-antecedent surgery group. Patients with an increased CD4/CD8 ratio (n = 6) may have a worse outcome during adoptive activated T lymphocyte immunotherapy even with an additional course of immunotherapy. Improved actuarial survival rate of patients in the antecedent surgery group showed significant long-term benefit compared to those in the non-antecedent surgery group (p = 0.0298), as previously reported. Conclusion: The CD4/CD8 ratio is a significant indicator of outcome of adoptive activated T lymphocyte immunotherapy.
KeywordsImmunotherapyAdoptive Activated T Lymphocyte therapyFlow CytometryPerformance StatusAdvanced Cancer
S. A. Rosenberg, M. T. Lotse, L. M. Mull, S. Leitman, A. E. Chang, J. T. Votto, C. A. Seipp and C. Simpson, “A New Approach to the Therapy of Cancer Based on the Systemic Administration of Autologous Lymphokine-Activated Killer Cells and Recombinant Interleukine-2,” Surgery, Vol. 100, No. 2, 1986, pp. 262-272.
K. Egawa, “Immuno-Cell Therapy in Japan,” Anticancer Research, Vol. 24, 2004, pp. 3321-3326.
H. Kimura and Y. Yamaguchi, “A Phase Ⅲ Randomized Study of Interleukin-2 Lymphokine-Activated Killer Cell Immunotherapy Combined with Chemotherapy or Radiotherapy after Curative or Non-Curative Resection of Primary Lung Carcinoma,” Cancer, Vol. 80, No. 1, 1997, pp. 42-49.
T. Takayama, T. Sekine, M. Makuuchi, S. Yamasaki, T. Kosuge, J. Yamamoto, K. Shimada, M. Sakamoto, S. Hirohashi, Y. Ohashi and T. Kakizoe, “Adoptive Immunotherapy to Lower Postsurgical Recurrence Rates of Hepatocellular Carcinoma: A Randomized Trial,” Lancet, Vol. 356, No. 9232, 2000, pp. 802-807. http://dx.doi.org/10.1016/S0140-6736(00)02654-4
S. Goto, T. Kaneko, Y. Miyamoto, M. Eriguchi, A. Kato, T. Akiyama, K. Fujimoto, H. Tomonaga and K. Egawa, “Combined Immuno-Cell Therapy Using Activated Lymphocytes and Monocytes-Derived Dendritic Cells for Malignant Melanoma,” Anticancer Research, Vol. 25, 2005, pp. 3741-3746.
T. Kaneko, S. Goto, A. Kato, A. M. Akeyama, K. Tomonaga, Y. Fujimoto, Y. Miyamoto, M. Eriguchi and K. Egawa, “Efficacy of Immuno-Cell Therapy in Patients with Advanced Pancreatic Cancer,” Anticancer Research, Vol. 25, 2005, pp. 3709-3714.
K. Iwai, K. Soejima, S. Kudoh, Y. Umezato, T. Kanako, K. Yoshimori, H. Tokuda, T. Yamaguchi, A. Mizoo, Y. Setoguchi, T. Kamigaki, Y. Fujimoto and S. Goto, “Extended Survival Observed in Adoptive Activated T Lymphocyte Immunotherapy for Advanced Lung Cancer: Results of a Multicenter Historical Cohort Study,” Cancer ImmunolImmunother, Vol. 61, No. 10, 2012, pp. 1781-1790.
G. Parmiani and A. Anichini, “T Cell Infiltration and Prognosis in HCC Patients,” Journal of Hepatology, Vol. 45, No. 2, 2006, pp. 178-181. http://dx.doi.org/10.1016/j.jhep.2006.06.005
A. F. Carpentier and Y. Meng, “Recent Advances in Immunotherapy for Human Glioma,” Current Opinion in Oncology, Vol. 18, No. 6, 2006, pp. 631-636.
G. Shindo, T. Endo, M. Onda, Y. Miyamoto, T. Kaneko and S. Goto, “Immuno-Cell Therapy with Antecedent Surgery Has Superior Actuarial Survival to Immuno-Cell Therapy without Antecedent Surgery for Advanced Cancers,” Cancer Immunology, Immunotherapy, Vol. 60, No. 10, 2011, pp. 1397-1403. http://dx.doi.org/10.1007/s00262-011-1044-0
K. Egawa, “On the Safety Assurance of All Processing Carried Out on Medical Institutions for Autologous Immune-Cell Therapy,” Human Cell, Vol. 17, No. 1, pp. 1-6. http://dx.doi.org/10.1111/ j.1749-0774.2004.tb00014.x
S. Goto, A. Noguchi, H. Jinguji and M. Takahara, “The Therapeutic Potential of Immuno-Cell Therapy of Cancer in Combination with Aminobiophosphonates” Anticancer Research, Vol. 26, pp. 3989-3995.
M. J. Fulwyler, “Electronic Separation of Biological Cells by Volume,” Science, Vol. 150, No. 12, 1965, pp. 910-911.
L. A. Herzenberg, M. H. Julius and T. Masada, “Demonstration That Antigen-Binding Cells Are Precursors of Antibody-Producing Cells after Purification with Fluorescence Activated Cell Sorter,” PNAS, Vol. 69, No. 7, 1972, pp. 1934-1938. http://dx.doi.org/10.1073/pnas.69.7.1934
A. Agarwal, S. Verma, U. Burra, N. S. Murthy, N. K. Mohanty and S. Saxena, “Flow Cytometric Analysis of Th1 and Th2 Cytokines in PBMCs as a Parameter of Immunological Dysfunction of Superficial Transitional Cell Carcinoma of Bladder,” Cancer Immunology, Immunotherapy, Vol. 55, No. 6, 2006, pp. 734-743. http://dx.doi.org/10.1007/s00262-005-0045-2
Y. Wada, O. Nakashima, R. Kutami, O. Yamamoto and M. Kojiro, “Clinicopathological Study on Hepatocellular Carcinoma with Lymphocytic Infiltration,” Hepatology, Vol. 27, No. 2, 1998, pp. 404-414. http://dx.doi.org/10.1002/hep.510270214
D. J. Powell Jr., M. E. Dudley, K. A. Hogan, J. R. Wunderlich and S. A. Rosenberg, “Adopted Transfer of Vaccine-Induced Peripheral Blood Mononuclear Cells to Patients with Metastatic Melanomas Following Lymphodepletion,” The Journal of Immunology, Vol. 177, No. 9, 2006, pp. 6527-6539.
F. Recchia, G. Sica, G. Candeloro, S. Necozione, R. Bisegna, M. Bratta and S. Rea, “Maintenance Immunotherapy in Metastatic Breast Cancer,” Oncology Reports, Vol. 20, 2008, pp. 1173-1179.
M. Sakamoto, J. Nakajima, T. Murakawa, T. Fukami, Y. Yoshida, T. Murayama, S. Takamoto, H. Matsushita and K. Kakimi, “Adoptive Immunotherapy for Advanced Non-Small Lung Cancer Using Zoledronate-Expanded γδΤ Cells: A Phase 1 Clinical Study,” The Journal of Immunology, Vol. 34, No. 2, 2011, pp. 202-211.
E. Ishikawa, K. Tsuboi, K. Saijo, H. Harada, S. Takano, T. Nose and T. Ohno, “Autologous Natural Killer Cell Therapy for Human Recurrent Malignant Glioma,” Anticancer Research, Vol. 24, 2004, pp. 1861-1872.
A. Kuemmel, K. Single, F. Bittinger, A. Faldum, L. H. Schmidt, M. Sebastia, P. Micke, C. Taube, R. Buhl and R. Wiewrodt, “TA-MUC1 Epitope in Non-Small Cell Lung Cancer,” Lung Cancer, Vol. 63, No. 1, 2009, pp. 98-105. http://dx.doi.org/10.1016/j.lungcan.2008.04.005
V. Mazzaforro, J. Coppa, M. G. Garrabba, L. Rivoltini, M. Schiavo, E. Regalia, L. Mariani, T. Camerini, A. Marchiano, S. Andreola, R. Camerini, M. Corsi, J. J. Lewis, P. K. Srivastava and G. Parmiani, “Vaccination with Autologous Tumor-Derived Heat-Shock Protein Gp 96 after Liver Resection for Metastatic Colorectal Cancer,” Clinical Cancer Research, Vol. 9, No. 9, 2003, pp. 3235-3245.
H. Norell, I. Poschke, J. Charo, W. Z. Wei, L. Erskine, M. P. Piechocki, K. L. Knutson, J. Bergh, E. Lidbrink and R. Kiessling, “Vaccination with a Plasmid DNA Encoding HER-2/neu Together with Low Dose of GM-CSF and IL-2 in Patients with Metastatic Breast Carcinoma: A Pilot Clinical Trial,” Journal of Translational Medicine, Vol. 8, No. 6, 2010, pp. 53-64. http://dx.doi.org/10.1186/1479-5876-8-53
L. A. Emens, “Re-Purposing Cancer Therapeutics for Breast Cancer Immunology,” Cancer Immunology, Immunotherapy, Vol. 61, No. 8, 2012, pp. 1299-1305. http://dx.doi.org/10.1007/ s00262-012-1247-z
H. Nishikawa and S. Sakaguchi, “Regulatory T Cells in Tumor Immunity,” International Journal of Cancer, Vol. 127, No. 4, 2010, pp. 759-767.
K. Shirabe, T. Motomura, J. Muto, T. Toshima, R. Matono, Y. Mano, K. Takeishi, H. Ijichi, N. Harada, H. Uchiyama, T. Yoshizumi, A. Takatomi and Y. Maehara, “Tumor Infiltrating Lymphocytes and Hepatocellular Carcinoma: Pathology and Clinical Management,” International Journal of Clinical Oncology, Vol. 15, No. 6, 2010, pp. 552-558. http://dx.doi.org/10.1007/s10147-010-0131-0
B. Fong, R. Jin, X. Wang, M. Safaee, D. N. Lisiero, I. Yang, G. Li, L. M. Liau and R. M. Prins, “Monitoring of Regulatory T Cell Frequencies and Expression of CTLA-4 on T Cells, Before and after DC Vaccination, Can Predict Survival in GBM Patients,” PLoS ONE, Vol. 7, No. 4, 2012, pp. 1-9.
P. Salama, C. Stewart, C. Forrest, C. Platell and B. Iacopetta, “FoxP3+ Cell Density in Lymphoid Follicles from Histlogically Normal Mucosa Is a Strong Prognostic Factor in Early Stage Colon Cancer,” Cancer Immunology, Immunotherapy, Vol. 61, No. 8, 2012, pp. 1183-1190. http://dx.doi.org/ 10.1007/s00262-011-1191-3