Thymosin Alpha-1 Research & Studies

This study aims to assess the safety and efficacy of Thymosin Alpha 1 (Tα1) through a comprehensive narrative review of clinical studies involving over 11 000 human subjects in more than 30 trials. The focus was on Tα1's application in COVID-19, autoimmune conditions, and cancer treatment, with implications for future considerations.

This systematic review was conducted to assess the curative effect of Thymosin alpha 1 in the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients. Six electronic databases including EMBASE, PubMed, Cochrane Library, China National Knowledge Infrastructure Database, Chinese Biomedical Database, and Wanfang Database were searched for eligible papers focusing on the thymosin alpha 1 treatment in AECOPD patients. The effectiveness outcomes included T cell subset, pulmonary function, arterial blood gases, and the length of hospital stay. Stata and Review Manager Software were used for data analysis. Thirty-nine randomised controlled trials with a total of 3,329 patients were included. Compared with the control treatment, Thymosin alpha 1 therapy significantly improved forced expiratory volume in 1 second [MD = 0.29, 95% (0.26, 0.32), p <0.001] and the ratio of forced expiratory volume in the first second to forced vital capacity [MD = 6.24, 95% (3.83, 8.65), p <0.001], increased the arterial partial pressure of oxygen [MD = 7.24, 95% (3.42, 11.07), p = 0.0002], lowered the arterial partial pressure of carbon dioxide [MD = -5.85, 95% (-9.38, -2.33), p = 0.001], shortened the length of hospital stay [MD = -5.39, 95% (-7.82, -2.97), p <0.001], raised the level of CD4+ T lymphocytes count [MD = 7.54, 95%(6.66, 8.41), p <0.001] and the ratio of CD4+/CD8+ [MD = 0.40, 95% (0.34, 0.46), p <0.001], and decreased level of CD8+ T lymphocytes count [MD = -2.74, 95% (-3.86, -1.63), p <0.001]. Thymosin alpha 1 could significantly boost the immune function, and improve pulmonary function and arterial blood gas of AECOPD patients than routine treatment only. More high-quality randomised controlled trials are needed to further confirm Thymosin alpha 1 efficacy. Key Words: Thymosin alpha 1, Efficacy, Acute exacerbation of chronic obstructive pulmonary disease, Meta-analysis.

Effort to search for the optimal COVID-19 treatment has continuously been attempted. Thymosin alpha-1 have immunomodulatory properties which may be beneficial in case of viral infection. This study's goal is to determine whether thymosin alpha-1 is effective in treating people with moderate-to-severe COVID-19.

Thymosin α-1 (Tα-1) is an immunomodulating polypeptide of 28 amino acids, which was the first peptide isolated from thymic tissue and has been widely used for the treatment of viral infections, immunodeficiencies, and especially malignancies. Tα-1 stimulates both innate and adaptive immune responses, and its regulation of innate immune cells and adaptive immune cells varies under different disease conditions. Pleiotropic regulation of immune cells by Tα-1 depends on activation of Toll-like receptors and its downstream signaling pathways in various immune microenvironments. For treatment of malignancies, the combination of Tα-1 and chemotherapy has a strong synergistic effect by enhancing the anti-tumor immune response. On the basis of the pleiotropic effect of Tα-1 on immune cells and the promising results of preclinical studies, Tα-1 may be a favorable immunomodulator to enhance the curative effect and decrease immune-related adverse events of immune checkpoint inhibitors to develop novel cancer therapies.

The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5'-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer.

Thymosin alpha 1 is a peptide naturally occurring in the thymus that has long been recognized for modifying, enhancing, and restoring immune function. Thymosin alpha 1 has been utilized in the treatment of immunocompromised states and malignancies, as an enhancer of vaccine response, and as a means of curbing morbidity and mortality in sepsis and numerous infections. Studies have postulated that thymosin alpha 1 could help improve the outcome in severely ill corona virus disease 2019 patients by repairing damage caused by overactivation of lymphocytic immunity and how thymosin alpha 1 could prevent the excessive activation of T cells. In this review, we discuss key literature on the background knowledge and current clinical uses of thymosin alpha 1. Considering the known biochemical properties including antibacterial and antiviral properties, time-honored applications, and the new promising findings regarding the use of thymosin, we believe that thymosin alpha 1 deserves further investigation into its antiviral properties and possible repurposing as a treatment against severe acute respiratory syndrome coronavirus-2.

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR.

Sepsis is a life-threatening organ dysfunction caused by host immune response to infection. In this regard, modifying host immune response may help to eliminate systemic infection and restore organ function. Thymosin alpha 1 (Tα1), acting as an immune modulator, exerts great biological influence in activating and restoring the dysregulated immune response for patients with sepsis.

Thymosin alpha 1 (Ta1) is a natural occurring peptide hormone that is crucial for the maintenance of the organism homeostasis. It has been chemically synthesized and used in diseases where the immune system is hindered or malfunctioning.

In spite of the consistent benefits for HIV-1 infected patients undergoing antiretroviral therapy, a complete immune reconstitution is usually not achieved. Actually, antiretroviral therapy may be frequently accompanied by immunological unresponsiveness, persistent inflammatory conditions and inefficient cytotoxic T-cell response. Thymosin alpha 1 is a thymic peptide that demonstrates a peculiar ability to restore immune system homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. This review reports the present knowledge on the in vitro and in vivo studies concerning the use of thymosin alpha 1 in HIV-1 infection. Recent findings and future perspectives of therapeutic intervention are discussed.

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Stimulating a successful host immune response may be a promising helpful therapy to achieve elimination of hepatitis B virus (HBV) infection in chronic hepatitis B (CHB). Thymosin α-1 (Tα-1), as an immunomodulatory agent, can enhance T-cell response in CHB patients and has been widely studied either alone or in combination with nucleos(t)ide analogs. This editorial reviews these articles to present the efficacy of Tα-1 in CHB.

Thymosin α 1 (Tα1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered.

The development of thymosin beta(4) from a thymic hormone to an actin-sequestering peptide and back to a cytokine supporting wound healing will be outlined. Thymosin fraction 5 consists of a mixture of polypeptides and improves immune response. Starting with fraction 5, several main peptides (thymosin alpha(1), polypeptide beta(1), and thymosin beta(4)) were isolated and tested for biological activity. However, none of the isolated peptides were really thymic hormones. They are all biological important peptides with diverse functions. Polypeptide beta(1) is identical to ubiquitin truncated by two C-terminal glycine residues. Several peptides related to thymosin beta(4) were isolated and sequenced from various species. Large amounts of thymosin beta(4) were found in many cells. It was postulated that the beta-thymosins might have a general function. The identification of a biological function of thymosin beta(4) was tedious. In 1990, Dan Safer and his colleagues recognized that thymosin beta(4) sequesters G-actin. The dissociation constant of the complex in the micromolar range allows for fast binding and release of G-actin. beta-Thymosins are the main intracellular G-actin-sequestering peptides in most vertebrate cells. Thymosin beta(4) is unstructured but folds into a stable conformation on binding to G-actin. It is present in the nucleus as well as the cytoplasm and might be responsible for sequestering nuclear actin. Several biological effects are attributed to thymosin beta(4), oxidized thymosin beta(4), or to ac-SDKP possibly generated from thymosin beta(4). However, very little is known about molecular mechanisms mediating the effects attributed to extracellular beta-thymosins.

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. In this context, our group has extensively explored a protocol of combined therapy consisting of the use of chemotherapeutic agents associated with thymosin alpha 1 (Talpha 1) and different cytokines, whose efficacy has been demonstrated in experimental models as well as in human cancers. In this manuscript, the main data supporting a pivotal role of Talpha 1 in such combination protocols are reviewed. In particular, a special mention of the molecular mechanisms underlying the effects of Talpha 1 on immune effector cells as well as on target tumour cells is provided. These data contribute to explain the mechanism of action of Talpha 1, when used in combination therapy, for the treatment of cancer and provide new insights in predicting further possible applications of this peptide in other pathological conditions.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of thymosin alpha-1 (TA1) are reviewed. TA1 is a synthetic polypeptide. The drug is in Phase III trials for the treatment of hepatitis C and in Phase II trials for hepatitis B. Additional possible indications are malignant melanoma, hepatocellular carcinoma, drug-resistant tuberculosis, and DiGeorge's syndrome. TA1 is thought to modulate the immune system by augmenting T-cell function. TA1 may affect thymocytes by stimulating their differentiation or by converting them to active T cells. TA1 is rapidly absorbed, achieving peak serum concentrations within two hours. Blood levels return to baseline within 24 hours, and the serum half-life is approximately 2 hours. TA1's efficacy in hepatitis B has been evaluated in 195 patients in four clinical trials. One study found hepatitis B virus (HBV) DNA clearance at six months in 9 of 17 patients receiving TA1, compared with 10 of 16 patients treated with interferon alfa-2b (IFN-alpha 2b) and 4 of 15 historical controls. An open-label trial found HBV DNA clearance in 53% of patients at six months. A randomized, controlled trial found HBV DNA clearance in 40.6% and 25.6% of patients treated with TA1 for 6 and 12 months, respectively, compared with 9.4% of untreated controls. Efficacy for hepatitis C has been evaluated in 162 patients in three clinical trials. In one trial, the number of patients who achieved normal serum alanine aminotransferase (ALT) levels did not differ significantly between TA1 and placebo. In the other two trials, combination TA1 and IFN-alpha 2b was compared with IFN-alpha 2b alone. One trial found a normal serum ALT level at six months in 71% of patients receiving combination therapy, versus 35% of patients receiving IFN-alpha 2b alone. Hepatitis C virus RNA clearance occurred in 65% of patients treated with combination therapy and 29% of patients treated with IFN-alpha 2b alone. The third trial, comparing combination TA1 and IFN-alpha 2b with IFN-alpha 2b alone and with placebo, found normalization of ALT levels at six months in 37.1% of patients receiving combination therapy, 16.2% of patients receiving IFN-alpha 2b alone, and 2.7% of patients receiving placebo. TA1 is well tolerated. Most studies observed only local irritation at the injection site. For hepatitis B and C, TA1 1.6 mg (900 micrograms/m2) should be administered subcutaneously twice a week. Clinical trials of TA1 for chronic hepatitis B or C have had mixed results. TA1 may be useful as monotherapy for hepatitis B or in combination with IFN-alpha 2b for hepatitis C, but its effects on morbidity and mortality remain to be seen.

T-cell adjuvancy involves the use of agents to stimulate preferentially delayed type hypersensitivity (DTH). Traditional adjuvants like Alum, Freunds, muramyl peptides, and endotoxins are not selective. Natural infection (e.g. vaccinia) may yield selective DTH. Low dose cyclophosphamide (CY) with mycobacteria was the first experimental T-cell adjuvant. New adjuvant formulations (ISCOMS, MAPS, etc.) with synthetic T-cell epitopes offer improved formulations. Upregulation of TH-1 helper cells and their actions with interleukins like IL-2, IL-12, and gamma IFN or antibodies to IL-4 and IL-10 may augment potently pathogen and tumor resistance. Similarly, transfection of tumor target cells with genes for IL-2, IL-12, gamma IFN, etc., offers novel vaccine treatment approaches. Finally, "thymomimetic" peptides like thymosin alpha 1 or drugs like levamisole or isoprinosine alone or in conjunction with interleukins may augment TH-1 and DTH responses. These approaches are seeing increasing emphasis in new treatment strategies for cancer and infections like HIV.