Immunopharmacology of Thymosin 1 and Cytokine Synergy (original) (raw)
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Immunopharmacology of thymosin α 1 and cytokine synergy
Annals of the New York Academy of Sciences, 2007
Thymosin ␣1 (T␣1) is a 28 amino acid biologically active protein cleaved from positions 2-29 of a precursor protein, prothymosin ␣. Since its discovery, T␣1 has been administered to animals and humans in a wide variety of settings and its pharmacologic effects are to enhance cellular immunity. T␣1 administration is highly effective in settings where irradiation, chemotherapy, tumor burden, or immune senescence have caused a reduction of T cell number and/or function. Recent in vitro studies, including the one reported here, suggest that T␣1 may act via pathways commonly used by various cytokines. This raises the possibility that T␣1 and cytokines may have synergistic activity through potentiation of cytokine activity by T␣1. Improved control of tumor growth when tumor-bearing mice were treated with T␣1 and high doses of IL-2 has been previously reported. We extended those studies with the Lewis lung carcinoma mouse model using IRX-2, a natural welldefined biologic containing multiple cytokines, in combination with T␣1 (IRX-3). Although IRX-2 was effective alone (using doses that contain significantly less IL-2 than in most typical studies), adding T␣1 led to significant improvement in survival of the tumor-bearing mice. Based on these observations, the immunopharmacology of T␣1 predicts an important clinical role for T␣1 in the restoration of cellular immune activity when used in combination with cytokines. Patients who experience immune suppression due to the presence of tumor, irradiation, and/or chemotherapy or aging of the host would most benefit from this treatment combination.
Preclinical studies with IRX-2 and thymosin α1 in combination therapy
Annals of the New York Academy of Sciences, 2010
Thymosin α1 (Tα1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin α1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Tα1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.
Annals of the New York Academy of Sciences, 2010
Thymosin α1 (Tα1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin α1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Tα1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.
International Journal of Cancer, 1992
In this study we have investigated the effects of thymosin a, (Ta,) and interleukin-2 (IL-2). singly or in combination with cyclophosphamide (CY), on tumor growth, survival and cytotoxicity in C57B1/6NCrlBR mice with Lewis lung carcinoma (3LL). Combined administration of Ta, plus IL-2. after CY treatment, was much more effective than use of each biological response modifier (BRM) alone, and induced complete tumor regression in all of the mice studied. Combination immunotherapy alone without CY only slightly reduced the rate of tumor growth, and these results are in accordance with previous studied which showed that the 3LL carcinoma is resistant to cytokines.
Thymosin α1 in combination with cytokines and chemotherapy for the treatment of cancer
International Immunopharmacology, 2003
Multiple therapeutic approaches have been tested in different experimental tumour models and in human cancers. Most part of them are based on the hypothesis that the inhibition of tumour growth requires a strong immune response in which a main role is played by CTLs. It is known, however, that an efficient CTL response requires expression of tumour antigens, MHC class I surface molecules presentation, expression of different co-stimulatory molecules and a sustained generation and proliferation of specific cytotoxic CD8+ cells with an efficient CD4+ cooperation.
Thymosin α 1 potentiates interleukin 2-induced cytotoxic activity in mice
Cellular Immunology, 1991
We have investigated the effects of interleukin 2 (IL-2) on cytotoxic activity of spleen lymphocytes, from normal and cyclophosphamide (200 mg/kg) or B-16 melanoma suppressed mice, after in vitro or in vivo pretreatment with thymosin (Y 1 (TA 1). The results of this study indicate that pretreatment in vitro (100 rig/ml for I hr) or in vivo (200 pg/kg/day for 4 days) with thymosin LY I (TAI), significantly increased the IL-2 (from 100 to 500 U/ml) in vitro induced cytotoxic activity of spleen lymphocytes, collected from both normal and cyclophosphamide and tumorsuppressed animals, against both YAC-I (NK sensitive) and MBL-2 (NK resistant) cell lines. The potential use in combination ofthese two different biological response modifiers, useful in enhancing the immunological responses to IL-2 of lymphocytes, may provide a novel model of immunotherapeutic intervention in cancer.
Thymosin alpha 1 in the treatment of cancer: from basic research to clinical application
International Journal of Immunopharmacology, 2000
Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T a 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue. : S 0 1 9 2 -0 5 6 1 ( 0 0 ) 0 0 0 7 5 -8 E. Garaci et al.
Thymosin Alpha 1: From Bench to Bedside
Annals of the New York Academy of Sciences, 2007
After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (T␣1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with T␣1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using T␣1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with T␣1 and IFN-␣ low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of T␣1 and IFN-␣ was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of T␣1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose-response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information
IRX-2 and Thymosin 1 (Zadaxin) Increase T Lymphocytes in T Lymphocytopenic Mice and Humans
Annals of the New York Academy of Sciences, 2007
Mouse studies showed a synergy of thymosin ␣1 (T␣1) and a natural cytokine mixture (IRX-2) in increasing T lymphocyte number and responses. Clinical studies with IRX-2 showed increases of T lymphocytes in lymphocytopenic cancer patients but relatively little effect on irradiated, lymphocytopenic patients. The present phase 1 and 2 study shows that T␣1 enhances the effect of IRX-2 in these lymphocytopenic patients. Patients (seven) were treated with subcutaneously injected IRX-2 (200 units IL-2 equivalence), T␣1 (1.6 mg/day) (four patients), or the combination of IRX-2 and T␣1 (seven patients) daily for 10 days. Peripheral blood lymphocytes (T, B, NK) and subsets (CD4, CD8) were measured at the start of treatment and on day 11. IRX-2 and T␣1 had little or no significant effect. The combination markedly increased various lymphocyte populations (>350 cells/L). Four patients followed for 6 weeks displayed sustained increases involving both naïve and memory T cells. Responses to persistent infections were observed in three of the four patients and no significant toxicity was observed. T␣1 and IRX-2 synergize to increase safely T cells in lymphocytopenic patients.