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Meiling Xu,1– 3,* Rongzheng Chen,1– 3,* Yuehong Kong,1– 3,* Junjun Zhang,1– 3 Pengfei Xing,1– 3 Xiangrong Zhao,1– 3 Liyuan Zhang1– 3 1Center of PRaG Therapy, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Center for Cancer Diagnosis and Treatment, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Laboratory for Combined Radiotherapy and Immunotherapy of Cancer, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liyuan Zhang, Email zhangliyuan126@126.comBackground: Radiotherapy combined with immunotherapy shows increasing efficacy in treating metastatic malignancies; however, positive outcomes may be negatively impacted by lymphocytopenia. Previous studies suggest thymosin α 1 (Tα 1) may mitigate radiation-induced lymphocytopenia. This study retrospectively evaluated the effects of a Tα 1 loading dose on peripheral blood lymphocyte counts and assessed the safety and efficacy of radiotherapy combined with of PD-1 inhibitors in patients with advanced or refractory cancers.Methods: A total of 48 patients received a 7-day loading dose of Tα 1 (1.6 or 3.2 mg, once daily) followed by hypofractionated radiotherapy and PD-1 inhibitors. Peripheral blood T cells, B cells, and natural killer cells were quantified by flow cytometry before and after Tα 1 treatment. The primary endpoint was the change from baseline in lymphocyte subset counts. Secondary endpoints included adverse events, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).Results: The median follow-up was 13.7 months. Tα 1 treatment for 7 days significantly increased the median counts of peripheral blood total T cells (422.5/μL to 614.0 /μL, P< 0.001), CD4+ T cells (244.5/μL to 284.5/μL, P< 0.001), and CD8+ T cells (159.0/μL to 222.5/μL, P< 0.001). Among the 36 patients with evaluable data, the ORR was 19.4% and DCR was 69.4%. The median PFS and OS were 5.1 months and 9.6 months, respectively. Two patients (4.2%) experienced grade ≥ 3 treatment-related adverse events.Conclusion: A 7-day loading dose of Tα 1 elevated lymphocyte counts in advanced cancer patients and was accompanied by satisfactory safety and efficacy profiles. It should be noted that the median follow-up of 13.7 months may be insufficient to fully assess long-term survival outcomes and the potential for late-onset toxicities. As this was an exploratory analysis across multiple tumor types, these findings warrant validation in larger, randomized studies with more homogenous cohorts.Keywords: LYMPHOCYTOPENIA, Radiotherapy, PD-1 inhibitor, thymosin α 1, loading dose, advanced cancer

Background Immunological nonresponders (INRs) living with HIV are at increased risk of co-infection and multiple tumors, with no effective strategy currently available to restore their T-cell immune response. This study aimed to explore the safety and efficacy of thymosin α1 in reconstituting the immune response in INRs. Methods INRs with CD4 + T cell counts between 100 and 350 cells/μL were enrolled and received two-staged 1.6 mg thymosin α1 subcutaneous injections for 24 weeks (daily in the first 2 weeks and biweekly in the subsequent 22 weeks) while continuing antiretroviral therapy. T cell counts and subsets, the expression of PD-1 and TIM-3 on T cells, and signal joint T cell receptor excision circles (sjTREC) at week 24 were evaluated as endpoints. Results Twenty three INRs were screened for eligibility, and 20 received treatment. The majority were male (19/20), with a median age of 48.1 years (interquartile range: 40.5–57.0) and had received antiretroviral therapy for 5.0 (3.0, 7.3) years. Multiple comparisons indicated that CD4 + T cell count and sjTREC increased after initiation of treatment, although no significant differences were observed at week 24 compared to baseline. Greatly, levels of CD4 + T cell proportion (17.2% vs. 29.1%, P  < 0.001), naïve CD4 + and CD8 + T cell proportion (17.2% vs. 41.1%, P  < 0.001; 13.8% vs. 26.6%, P  = 0.008) significantly increased. Meanwhile, the proportion of CD4 + central memory T cells of HIV latent hosts (42.7% vs. 10.3%, P  < 0.001) significantly decreased. Moreover, the expression of PD-1 on CD4 + T cells (14.1% vs. 6.5%, P  < 0.001) and CD8 + T cells (8.5% vs. 4.1%, P  < 0.001) decreased, but the expression of TIM-3 on T cellsremained unaltered at week 24. No severe adverse events were reported and HIV viral loads kept stable throughout the study. Conclusions Thymosin α1 enhance CD4 + T cell count and thymic output albeit as a trend rather than an endpoint. Importantly, it improves immunosenescence and decreases immune exhaustion, warranting further investigation. Trial registration This single-arm prospective study was registered with ClinicalTrials.gov (NCT04963712) on July 15, 2021.

Radiotherapy combined with immunotherapy shows increasing efficacy in treating metastatic malignancies; however, positive outcomes may be negatively impacted by lymphocytopenia. Previous studies suggest thymosin α1 (Tα1) may mitigate radiation-induced lymphocytopenia. This study retrospectively evaluated the effects of a Tα1 loading dose on peripheral blood lymphocyte counts and assessed the safety and efficacy of radiotherapy combined with of PD-1 inhibitors in patients with advanced or refractory cancers. A total of 48 patients received a 7-day loading dose of Tα1 (1.6 or 3.2 mg, once daily) followed by hypofractionated radiotherapy and PD-1 inhibitors. Peripheral blood T cells, B cells, and natural killer cells were quantified by flow cytometry before and after Tα1 treatment. The primary endpoint was the change from baseline in lymphocyte subset counts. Secondary endpoints included adverse events, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The median follow-up was 13.7 months. Tα1 treatment for 7 days significantly increased the median counts of peripheral blood total T cells (422.5/μL to 614.0 /μL, P<0.001), CD4 T cells (244.5/μL to 284.5/μL, P<0.001), and CD8 T cells (159.0/μL to 222.5/μL, P<0.001). Among the 36 patients with evaluable data, the ORR was 19.4% and DCR was 69.4%. The median PFS and OS were 5.1 months and 9.6 months, respectively. Two patients (4.2%) experienced grade ≥3 treatment-related adverse events. A 7-day loading dose of Tα1 elevated lymphocyte counts in advanced cancer patients and was accompanied by satisfactory safety and efficacy profiles. It should be noted that the median follow-up of 13.7 months may be insufficient to fully assess long-term survival outcomes and the potential for late-onset toxicities. As this was an exploratory analysis across multiple tumor types, these findings warrant validation in larger, randomized studies with more homogenous cohorts.

Purpose This multicenter Phase II clinical study assessed the efficacy and safety of hypofractionated radiotherapy (HFRT) in combination with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor (GM-CSF), and thymosin-α1 in patients with heavily treated metastatic solid tumors. Methods Patients were enrolled between September 2022 and May 2024. HFRT was administered to targeted tumors, and GM-CSF was administered for 14 days from day 1 of radiotherapy. Thymosin-α1 was injected concurrently twice weekly until disease progression. Immunotherapy with camrelizumab was started following HFRT and repeated every 3 weeks. GM-CSF was administered daily for 7 days before each cycle of immunotherapy. Results By June 15, 2024, there were 37 study participants. The median follow-up duration was 5.97 months (range 0.40–20.9). Median progression-free survival was 3.5 months (95% confidence interval 2.73–4.23) in the intention-to-treat population. The objective response rate was 23.08%, and the disease control rate was 65.38%. Overall survival data are not yet mature. Abscopal effects were observed in 6 patients (23.08%); four of whom achieved a partial response. Patients who achieved a partial response were significantly more likely to have an abscopal effect( P  = 0.025). The group with a lower baseline neutrophil–lymphocyte ratio had a significantly lower risks of distant metastasis and death( P = 0.024). Seventeen adverse reactions were reported, including six grade 3 or 4 adverse events. There were no grade 5 adverse events. Conclusion In conclusion, the trends in efficacy observed in our study are promising; however, well-designed protocols are essential to validate these findings.

The present study aimed to evaluate whether thymosin α1 (Tα1) increases survival rates through the improvement of immunofunction and inhibition of hepatocyte apoptosis in rats with acute liver failure (ALF). A total of 25 rats were randomly divided into the control group (CG), the model group (MG) and the treatment group (TG). The CG received an intraperitoneal injection of saline (2 ml). The ALF rat model was established by the intraperitoneal injection of D-galactosamine (700 mg/kg) and lipopolysaccharide (10 µg/kg). The TG received an intraperitoneal injection of Tα1 (0.03 mg/kg) 1 h prior to and 30 min after modeling. The survival rates of the rats were recorded. An additional 63 rats were randomly divided into a CG (n=3), MG (n=30) and TG (n=30). Three rats were sacrificed at 3, 6, 9 and 12 h after establishment of the rat model to detect plasma alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), tumor necrosis factor (TNF)-α and interleukin-10 (IL-10). Liver samples were stained with hematoxylin and eosin and TUNEL, and reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to detect B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) in liver tissue. The results indicated that the survival rate of the TG was significantly higher compared with that of the MG at 24 h (P<0.05). Plasma ALT, AST and TBIL in the MG and TG increased over time (3-12 h), with ALT, AST and TBIL observed to be significantly lower in the TG compared with the MG at each time-point (P<0.05). Hepatocellular necrosis, hemorrhage and inflammatory cell infiltration of ALF were aggravated over time (3-12 h) in the MG and TG. Notably, in the Tα1-treated rats, the hepatocytes appeared healthier with fewer apoptotic cells compared with those from the MG at the same time-points. Hepatocyte apoptotic index increased in the TG and MG, but was significantly lower in the TG compared with the MG at each time-point (P<0.05) in TUNEL assays. Plasma TNF-α and IL-10 in the MG and TG increased over time (3-12 h), with TNF-α observed to be significantly lower in the TG compared with the MG at each time-point (P<0.05), however, IL-10 was observed to be significantly higher in the TG compared with the MG at each time-point (P<0.05). Bax mRNA expression was significantly lower in the TG compared with the MG at each time-point (P<0.05), whereas Bcl-2 was significantly higher (P<0.05). In conclusion, Tα1 improved survival rates in an ALF rat model by downregulating TNF-α and upregulating IL-10, leading to the attenuation of hepatic inflammation and hepatocyte apoptosis.

There is limited information about thymosin α1 (Tα1) as adjuvant immunomodulatory therapy, either used alone or combined with other treatments, in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free (R0)-resected stage IA-IIIA NSCLC patients. A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included. The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not. A propensity score matching (PSM) analysis was performed to reduce bias, resulting in 1027 pairs of patients. After PSM, the baseline clinicopathological characteristics were similar between the two groups. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the Tα1 group compared with the control group. The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis. A longer duration of Tα1 treatment was associated with improved OS and DFS. The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age, sex, Charlson Comorbidity Index (CCI), smoking status, and pathological tumor-node-metastasis (TNM) stage, especially for patients with non-squamous cell NSCLC and without targeted therapy. Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection, except for patients with squamous cell carcinoma and those receiving targeted therapy. The duration of Tα1 treatment is recommended to be >24 months.

Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.

Despite advances in understanding sepsis pathophysiology and extensive research, few treatments effectively target its underlying immune dysfunction. Thymosin α1 (Tα1) shows promise as an immunomodulator, but its impact on sepsis remains unclear. A search strategy was designed to include any prospective clinical studies using Tα1 for assessing 28-day mortality in patients with sepsis, excluding combination therapy studies. We conducted trial sequential analysis (TSA) to assess the robustness of meta-analyses findings. Heterogeneity of treatment effects (HTE) was conducted based on individual data from two multicenter randomized clinical trials (RCTs), with result credibility assessed through the instrument to assess the credibility of effect modification analyses (ICEMAN). Out of 3003 identified studies, 11 RCTs met the inclusion criteria (967 patients in Tα1 group and 960 patients in control group). The comprehensive meta-analysis demonstrated a significant reduction in 28-day mortality associated with Tα1 administration (OR 0.73, 95%CI: 0.59-0.90, = 0.003). Nonetheless, analyses of high-quality (OR 0.82, 95%CI: 0.65-1.03, = 0.09) and multi-center (OR 0.86, 95%CI: 0.68-1.08, = 0.20) subgroups did not reveal a mortality benefit. The HTE analysis of multiple subgroups in two large RCTs (representing 75% of the total patients) showed heterogeneity. Potential benefits were noted in subgroups of cancer (moderate credibility), diabetes (low credibility), and coronary heart disease (low credibility). Furthermore, the trial sequential analysis (TSA) suggests that the current sample size is inadequate. Tα1 has the potential to decrease 28-day mortality rates in patients with sepsis; however, it is crucial to recognize that its efficacy differs among various subgroups. These observations underscore the significance of personalized immunotherapy strategies in forthcoming clinical trials. https://www.crd.york.ac.uk/prospero/, identifier CRD42024628937.

Older people achieve lower levels of antibody titers than younger populations after Covid-19 vaccination and show a marked waning humoral immunity over time, likely due to the senescence of the immune system. Nevertheless, age-related predictive factors of the waning humoral immune response to the vaccine have been scarcely explored. In a cohort of residents and healthcare workers from a nursing home that had received two doses of the BNT162b2 vaccine, we measured specific anti-S antibodies one (T1), four (T4), and eight (T8) months after receiving the second dose. Thymic-related functional markers, including thymic output, relative telomere length, and plasma thymosin-α1 levels, as well as immune cellular subsets, and biochemical and inflammatory biomarkers, were determined at T1, and tested for their associations with the magnitude of the vaccine response (T1) and the durability of such response both, at the short- (T1-T4) and the long-term (T1-T8). We aimed to identify age-related factors potentially associated with the magnitude and persistence of specific anti-S immunoglobulin G (IgG)-antibodies after COVID-19 vaccination in older people. Participants (100% men, n = 98), were subdivided into three groups: young (< 50 years-old), middle-age (50-65 years-old), and older (≥65 years-old). Older participants achieved lower antibody titers at T1 and experienced higher decreases in both the short- and long-term. In the entire cohort, while the magnitude of the initial response was mainly associated with the levels of homocysteine [β (95% CI); - 0.155 (- 0.241 to - 0.068); p = 0.001], the durability of such response at both, the short-term and the long-term were predicted by the levels of thymosin-α1 [- 0.168 (- 0.305 to - 0.031); p = 0.017, and - 0.123 (- 0.212 to - 0.034); p = 0.008, respectively]. Higher plasma levels of thymosin-α1 were associated with a lower waning of anti-S IgG antibodies along the time. Our results suggest that plasma levels of thymosin-α1 could be used as a biomarker for predicting the durability of the responses after COVID-19 vaccination, possibly allowing to personalize the administration of vaccine boosters.

Background Thymosin α1 (Tα1) as immunomodulatory treatment is supposed to be beneficial for the sepsis patients by regulating T cell subsets and inflammatory mediators. However, limited by the small sample size and the poor study design, the persuasive power of the single clinical studies is weak. This meta-analysis aimed to investigate the impact of Tα1 on the sepsis patients. Methods We searched for the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CBM, VIP, CNKI, WANFANG, Igaku Chuo Zasshi (ICHUSHI) and Korean literature databases reporting the effects of Tα1 on outcomes in sepsis patients. Results Among 444 related articles, 19 randomized controlled trials (RCTs) met our inclusion criteria. Mortality events were reported in 10 RCTs included 530 patients, and the meta-analysis showed significant decrease in Tα1 group compared with control group (RR 0.59, 95 % CI 0.45 to 0.77, p  = 0.0001). The subgroup analysis showed no difference between the two dosages (RR 0.59, 95 % CI 0.43 to 0.81; RR 0.59, 95 % CI 0.35 to 0.98, respectively). In 9 RCTs, with a total of 489 patients, Tα1 administered once per day decrease APACHE II score significantly (SMD −0.80, 95 % CI −1.14 to −0.47, p  < 0.0001) while Tα1 twice per day showed no effect (SMD 0.30, 95 % CI-0.10 to 0.70, p  = 0.14). However, the length of ICU stay, the incidence of multiple organ failure (MOF) and duration of mechanical ventilation were not significantly affected by Tα1 treatment (SMD −0.52, 95 % CI −1.06 to 0.11, p  = 0.06; SMD −0.49, 95 % CI −1.09 to 0.11, p  = 0.11; SMD −0.37, 95 % CI −0.90 to 0.17, p  = 0.17, respectively). As to the immunological indicators, the level of HLA-DR were increased by Tα1 (SMD 1.23, 95 % CI 0.28 to 2.18, p  = 0.01) according to the pooled analysis of 8 studies involving 721 patients. Lymphocyte subsets CD3, CD4 and cytokines IL-6, IL-10 and TNF-α were also beneficially affected by Tα1 treatment. Conclusions Tα1 may be beneficial to sepsis patients in reducing mortality and modulating inflammation reactions. However, the quality of evidence supporting the effectiveness is low considering the small sample sizes and inadequate adherence to standardized reporting guidelines for RCTs among the included studies.