Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells

doi:10.1084/jem.155.4.1063

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Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells

RJ North

On the basis of preceding studies showing that tumor-induced, T cell- mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor- sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells.
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Siddiqui, S. A., Frigola, X., Bonne-Annee, S., Mercader, M., Kuntz, S. M., Krambeck, A. E., Sengupta, S., Dong, H., Cheville, J. C., Lohse, C. M., Krco, C. J., Webster, W. S., Leibovich, B. C., Blute, M. L., Knutson, K. L., Kwon, E. D. (2007). Tumor-Infiltrating Foxp3-CD4+CD25+ T Cells Predict Poor Survival in Renal Cell Carcinoma. Clin. Cancer Res. 13: 2075-2081 [Abstract] [Full Text]
Chen, A., Liu, S., Park, D., Kang, Y., Zheng, G. (2007). Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer. Cancer Res. 67: 1291-1298 [Abstract] [Full Text]
Nava-Parada, P., Forni, G., Knutson, K. L., Pease, L. R., Celis, E. (2007). Peptide Vaccine Given with a Toll-Like Receptor Agonist Is Effective for the Treatment and Prevention of Spontaneous Breast Tumors. Cancer Res. 67: 1326-1334 [Abstract] [Full Text]
Markel, G., Seidman, R., Stern, N., Cohen-Sinai, T., Izhaki, O., Katz, G., Besser, M., Treves, A. J., Blumberg, R. S., Loewenthal, R., Mandelboim, O., Orenstein, A., Schachter, J. (2006). Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions. J. Immunol. 177: 6062-6071 [Abstract] [Full Text]
Wang, R.-F. (2006). Regulatory T cells and toll-like receptors in cancer therapy.. Cancer Res. 66: 4987-4990 [Abstract] [Full Text]
Lizee, G., Radvanyi, L. G., Overwijk, W. W., Hwu, P. (2006). Immunosuppression in melanoma immunotherapy: potential opportunities for intervention.. Clin. Cancer Res. 12: 2359s-2365s [Abstract] [Full Text]
Taieb, J., Chaput, N., Schartz, N., Roux, S., Novault, S., Menard, C., Ghiringhelli, F., Terme, M., Carpentier, A. F., Darrasse-Jese, G., Lemonnier, F., Zitvogel, L. (2006). Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines.. J. Immunol. 176: 2722-2729 [Abstract] [Full Text]
Harano, M., Eto, M., Iwai, T., Tatsugami, K., Kiyoshima, K., Kamiryo, Y., Tsuneyoshi, M., Yoshikai, Y., Naito, S. (2005). Renal Cancer Treatment with Low Levels of Mixed Chimerism Induced by Nonmyeloablative Regimen Using Cyclophosphamide in Mice. Cancer Res. 65: 10032-10040 [Abstract] [Full Text]
Wang, L.-X., Shu, S., Plautz, G. E. (2005). Host Lymphodepletion Augments T Cell Adoptive Immunotherapy through Enhanced Intratumoral Proliferation of Effector Cells. Cancer Res. 65: 9547-9554 [Abstract] [Full Text]
Gattinoni, L., Finkelstein, S. E., Klebanoff, C. A., Antony, P. A., Palmer, D. C., Spiess, P. J., Hwang, L. N., Yu, Z., Wrzesinski, C., Heimann, D. M., Surh, C. D., Rosenberg, S. A., Restifo, N. P. (2005). Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202: 907-912 [Abstract] [Full Text]
Ercolini, A. M., Ladle, B. H., Manning, E. A., Pfannenstiel, L. W., Armstrong, T. D., Machiels, J.-P. H., Bieler, J. G., Emens, L. A., Reilly, R. T., Jaffee, E. M. (2005). Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response. J. Exp. Med. 201: 1591-1602 [Abstract] [Full Text]
Dudley, M. E., Wunderlich, J. R., Yang, J. C., Sherry, R. M., Topalian, S. L., Restifo, N. P., Royal, R. E., Kammula, U., White, D. E., Mavroukakis, S. A., Rogers, L. J., Gracia, G. J., Jones, S. A., Mangiameli, D. P., Pelletier, M. M., Gea-Banacloche, J., Robinson, M. R., Berman, D. M., Filie, A. C., Abati, A., Rosenberg, S. A. (2005). Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma. JCO 23: 2346-2357 [Abstract] [Full Text]
Wang, H. Y., Peng, G., Guo, Z., Shevach, E. M., Wang, R.-F. (2005). Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells. J. Immunol. 174: 2661-2670 [Abstract] [Full Text]
Turk, M. J., Guevara-Patino, J. A., Rizzuto, G. A., Engelhorn, M. E., Houghton, A. N. (2004). Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells. J. Exp. Med. 200: 771-782 [Abstract] [Full Text]
Chin, C. S., Miller, C. H.T., Graham, L., Parviz, M., Zacur, S., Patel, B., Duong, A., Bear, H. D. (2004). Bryostatin 1/ionomycin (B/I) ex vivo stimulation preferentially activates L-selectinlow tumor-sensitized lymphocytes. Int Immunol 16: 1283-1294 [Abstract] [Full Text]
Mihalyo, M. A., Doody, A. D. H., McAleer, J. P., Nowak, E. C., Long, M., Yang, Y., Adler, A. J. (2004). In Vivo Cyclophosphamide and IL-2 Treatment Impedes Self-Antigen-Induced Effector CD4 Cell Tolerization: Implications for Adoptive Immunotherapy. J. Immunol. 172: 5338-5345 [Abstract] [Full Text]
Danna, E. A., Sinha, P., Gilbert, M., Clements, V. K., Pulaski, B. A., Ostrand-Rosenberg, S. (2004). Surgical Removal of Primary Tumor Reverses Tumor-Induced Immunosuppression Despite the Presence of Metastatic Disease. Cancer Res. 64: 2205-2211 [Abstract] [Full Text]
Azuma, T., Takahashi, T., Kunisato, A., Kitamura, T., Hirai, H. (2003). Human CD4+ CD25+ Regulatory T Cells Suppress NKT Cell Functions. Cancer Res. 63: 4516-4520 [Abstract] [Full Text]
Dudley, M. E., Wunderlich, J. R., Robbins, P. F., Yang, J. C., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., Sherry, R., Restifo, N. P., Hubicki, A. M., Robinson, M. R., Raffeld, M., Duray, P., Seipp, C. A., Rogers-Freezer, L., Morton, K. E., Mavroukakis, S. A., White, D. E., Rosenberg, S. A. (2002). Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes. Science 298: 850-854 [Abstract] [Full Text]
Ibe, S., Qin, Z., Schuler, T., Preiss, S., Blankenstein, T. (2001). Tumor Rejection by Disturbing Tumor Stroma Cell Interactions. J. Exp. Med. 194: 1549-1560 [Abstract] [Full Text]
Pelaez, B., Campillo, J. A., Lopez-Asenjo, J. A., Subiza, J. L. (2001). Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism. J. Immunol. 166: 6608-6615 [Abstract] [Full Text]
Machiels, J.-P. H., Reilly, R. T., Emens, L. A., Ercolini, A. M., Lei, R. Y., Weintraub, D., Okoye, F. I., Jaffee, E. M. (2001). Cyclophosphamide, Doxorubicin, and Paclitaxel Enhance the Antitumor Immune Response of Granulocyte/Macrophage-Colony Stimulating Factor-secreting Whole-Cell Vaccines in HER-2/neu Tolerized Mice. Cancer Res. 61: 3689-3697 [Abstract] [Full Text]
Kawano, T., Nakayama, T., Kamada, N., Kaneko, Y., Harada, M., Ogura, N., Akutsu, Y., Motohashi, S., Iizasa, T., Endo, H., Fujisawa, T., Shinkai, H., Taniguchi, M. (1999). Antitumor Cytotoxicity Mediated by Ligand-activated Human V{{alpha}}24 NKT Cells. Cancer Res. 59: 5102-5105 [Abstract] [Full Text]
Saxton, M. L., Longo, D. L., Wetzel, H. E., Tribble, H., Alvord, W. G., Kwak, L. W., Leonard, A. S., Ullmann, C. D., Curti, B. D., Ochoa, A. C. (1997). Adoptive Transfer of Anti-CD3-Activated CD4+ T Cells Plus Cyclophosphamide and Liposome-Encapsulated Interleukin-2 Cure Murine MC-38 and 3LL Tumors and Establish Tumor-Specific Immunity. Blood 89: 2529-2536 [Abstract] [Full Text]
Mule, J., Shu, S, Schwarz, S., Rosenberg, S. (1984). Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 225: 1487-1489 [Abstract]
Granstein, R., Parrish, J., McAuliffe, D., Waltenbaugh, C, Greene, M. (1984). Immunologic inhibition of ultraviolet radiation-induced tumor suppressor cell activity. Science 224: 615-617 [Abstract]