Abstract
A combination treatment with thymosin α1 (200 µg/kg) for 4 days, followed by a single injection of murine interferon α/β (3 × 104 international units/mouse), starting 2 days after cyclophosphamide treatment (200 mg/kg, single injection) demonstrated a dramatic and rapid disappearance of tumor burden in mice bearing Lewis lung carcinoma (3LL) tumor. The effectiveness of this new chemoimmunotherapy protocol was evident even on the long-term survival in a high percentage of animals, and was statistically significant when compared to treatment with the single agents in conjunction with chemotherapy or to chemotherapy itself. The same combination immunotherapy treatment strongly stimulated natural killer activity and cytotoxicity against autologus 3LL tumor cells in 3LL-tumor-bearing mice treated with cyclophosphamide, whereas treatments with each agent singly did not alter or only slightly modified the cytotoxic activity towards Yac-1 or 3LL target cells. Selective depletion with antibodies showed that killer cells stimulated by combination chemoimmunotherapy treatment bear phenotypic characteristics of asialo-GM1-positive cells. A histological study has shown a high number of infiltrating lymphoid cells in the tumors obtained from mice treated with combination chemoimmunotherapy.
Keywords: Interferon, Cyclophosphamide, Combination Treatment, Single Injection, Lewis Lung Carcinoma
References
- 1.Bilik R, Mor C, Hazaz B, Moroz C. Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer. Cancer Immunol Immunother. 1989;28:143. doi: 10.1007/BF00199115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bistoni F, Baccarini M, Blasi E, Pucetti P, Marconi P, Garaci E. Correlation between in vivo and in vitro studies of the modulation of resistance to experimentalCandida albicans infection by cyclophosphamide in mice. Infect Immun. 1983;40:46. doi: 10.1128/iai.40.1.46-55.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cheever MA, Greenberg PD. Immunity to cancer. Orlando: Academic Press; 1985. Adoptive cellular immunotherapy; p. 453. [Google Scholar]
- 4.Cohen MH, Chretien PB, Ihde DC, Fossieck BE, Makuch R, Bunn PA, Johnston AV, Shackney SE, Matthews MJ, Lipson SD, Kenady DE, Minna JD. Thymosin fraction 5 and intensive combination chemotherapy prolonging the survival of patients with small-cell lung cancer. J Am Med Assoc. 1979;241:1813. doi: 10.1001/jama.241.17.1813. [DOI] [PubMed] [Google Scholar]
- 5.Favalli C, Jezzi T, Mastino A, Rinaldi-Garaci C, Riccardi C, Garaci E. Modulation of natural killer activity by thymosin alpha 1 and interferon. Cancer Immunol Immunother. 1985;20:189. doi: 10.1007/BF00205574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Favalli C, Mastino M, Jezzi T, Grelli S, Goldstein AL. Synergistic effect of thymosin alpha 1 and alpha-beta interferon on NK activity in tumor-bearing mice. Int J Immunopharmacol. 1989;5:443. doi: 10.1016/0192-0561(89)90172-0. [DOI] [PubMed] [Google Scholar]
- 7.Forni G, Giovarelli M, Santoni A, Modesti A, Forni M. Tumor inhibition by interleukin-2 at the tumor/host interface. Biochim Biophys Acta. 1986;865:307. doi: 10.1016/0304-419x(86)90020-x. [DOI] [PubMed] [Google Scholar]
- 8.Frasca D, Adorini L, Mancini C, Doria G. Reconstitution of T-cell functions in aging mice by thymosin alpha 1. Immunopharmacology. 1986;11:155. doi: 10.1016/0162-3109(86)90017-2. [DOI] [PubMed] [Google Scholar]
- 9.Garaci E, Mastino A, Favalli C. Enhanced immune response and antitumor immunity with combinations of biological response modifiers. Bull NY Acad Med. 1989;65:111. [PMC free article] [PubMed] [Google Scholar]
- 10.Goldstein AL, Low TLK, Adoo M, McClure J, Thurman GB, Rossio G, Lay CY, Chang D, Wang SS, Harwey C, Ramel AH, Meienhofer J. Thymosin alpha 1: isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci USA. 1977;74:725. doi: 10.1073/pnas.74.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Goldstein AL, Schulof RS. Immunity to cancer. Orlando: Academic Press; 1985. Thymosins in the treatment of cancer; p. 469. [Google Scholar]
- 12.Griffith KD, Read J, Carrasquillo JA, Carter CS, Yang JC, Fisher B, Aebersold P, Packard BS, Yu MY, Rosemberg SA. In vivo distribution of adoptively transferred indium-111-labeled tumor infiltrating lymphocytes and peripheral blood lymphocytes in patients with metastatic melanoma. J Natl Cancer Inst. 1989;81:1709. doi: 10.1093/jnci/81.22.1709. [DOI] [PubMed] [Google Scholar]
- 13.Hanna N. Immunobiology of natural killer cells. Boca Raton, Flq.: CRC Press; 1986. In vivo activities of NK cells against primary and metastatic tumors in experimental animals; p. 1. [Google Scholar]
- 14.Herberman RB. Immunity to cancer. Orlando: Academic Press; 1985. Natural killer (NK) cells: characteristics and possible role in resistance against tumor growth; p. 217. [Google Scholar]
- 15.Herberman RB, Nunn ME, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity. Int J Cancer. 1975;16:216. doi: 10.1002/ijc.2910160204. [DOI] [PubMed] [Google Scholar]
- 16.Hosokawa M, Sawamura Y, Morikage T, Okada F, Xu Z, Morikawa K, Itoh K, Kobayashi H. Improved therapeutic effects of interleukin 2 after the accumulation of lymphokine-activated killer cells in tumor tissue of mice previously treated with cyclophosphamide. Cancer Immunol Immunother. 1988;26:250. doi: 10.1007/BF00199937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Klein AS, Lang R, Eshel I, Sharabi Y, Shoham J. Modulation of immune response and tumor development in tumor-bearing mice treated by the thymic factor thymostimulin. Cancer Res. 1987;47:3351. [PubMed] [Google Scholar]
- 18.Lala PK, Santer V, Libenson H, Parhar RS. Changes in the host natural killer cell population in mice during tumor development. I. Kinetics and in vivo significance. Cell Immunol. 1985;93:250. doi: 10.1016/0008-8749(85)90132-7. [DOI] [PubMed] [Google Scholar]
- 19.Mihich E. Rationale of biological response modifiers in cancer treatment. Tokyo: Excerpta Medica; 1985. Relationships between chemotherapy and immunotherapy: a brief overview; p. 105. [Google Scholar]
- 20.North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of established tumor depends on elimination of tumor induced suppressor cells. J Exp Med. 1982;155:1063. doi: 10.1084/jem.155.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Papa MZ, Yang JC, Vetto JT, Shiloni E, Eisenthal A, Rosemberg SA. Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors. Cancer Res. 1988;48:122. [PubMed] [Google Scholar]
- 22.Punturieri A, Santoni A, Ming WJ, Nobili N, Mantovani A, Bottazzi B. In vitro migration of rat large granular lymphocytes. Cell Immunol. 1989;123:257. doi: 10.1016/0008-8749(89)90286-4. [DOI] [PubMed] [Google Scholar]
- 23.Serrate SA, Schulof RS, Leondaridis L, Goldstein AL, Sztein MB. Modulation of human natural killer cell cytotoxic activity, lymphokine production, and interleukin 2 receptor expression by thymic hormones. J Immunol. 1987;139:2338. [PubMed] [Google Scholar]
- 24.Sztein MB, Serrate SA, Goldstein AL. Modulation of interleukin 2 receptor expression on normal human lymphocytes by thymic hormones. Proc Natl Acad Sci USA. 1986;83:6107. doi: 10.1073/pnas.83.16.6107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Trinchieri G, Perussia B. Biology of disease. Human natural killer cells: biologic and pathologic aspects. Lab Invest. 1984;50:489. [PubMed] [Google Scholar]
- 26.Uchida A. The cytolytic and regulatory role of natural killer cells in human neoplasia. Biochim Biophys Acta. 1986;865:329. doi: 10.1016/0304-419x(86)90021-1. [DOI] [PubMed] [Google Scholar]
- 27.Umeda Y, Sakamoto A, Nakamura J, Ishitsuka H, Yagui Y. thymosin alpha 1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays. Cancer Immunol Immunother. 1983;15:78. doi: 10.1007/BF00199694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Wise JA, Mokyr MB, Dray S. Effect of low-dose cyclophosphamide therapy on specific and nonspecific T cell-dependent immune response of spleen cells from mice bearing large MOPC-315 plasmacytomas. Cancer Immunol Immunother. 1988;27:191. doi: 10.1007/BF00205439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Zatz MM, Oliver J, Samuels C, Skotnicki AB, Sztein MB, Goldstein AL. Thymosin increases production of T cell growth factor by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA. 1985;81:2882. doi: 10.1073/pnas.81.9.2882. [DOI] [PMC free article] [PubMed] [Google Scholar]