Discover. Oncology · 7 authors, 6 centres
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This phase II trial in 26 HCC patients found that a daily combination of curcumin, piperine, and taurine (CPT) for 3 months significantly increased CD4, CD8, IL-2, IL-12, and IFN-γ levels while decreasing CD25, IL-6, VEGF, LDH, AFP, and miRNA-21, suggesting an immune-stimulating effect. The results indicate CPT may enhance anti-tumor immunity and improve liver function markers, warranting further larger studies.
**Background:** Hepatocellular carcinoma (HCC) is a major public health problem, representing the sixth most diagnosed cancer and the third most lethal cancer worldwide. Standard treatments are limited, with about 70% of patients ineligible for curative therapy and high recurrence rates. Curcumin, piperine, and taurine (CPT) each have demonstrated anticancer and immunomodulatory properties individually, but their combined effect in HCC patients had not been studied. This phase II trial aimed to evaluate the immunotherapeutic effect of a CPT combination prepared in one capsule in HCC patients.
**Methods:** This prospective single-arm phase II clinical trial included 26 HCC patients (median age 62 years, range 50-76; 69.2% male) admitted to the National Hepatology and Tropical Medicine Research Institute (NHTMRI) between February and June 2021. All patients were HCV-positive, had failed standard therapeutic approaches, had unresectable locally advanced or metastatic HCC, and were not amenable to percutaneous ablation or transarterial therapy. Patients received daily CPT capsules (5 g curcumin, 50 mg piperine, 500 mg taurine) divided into three doses after meals for three successive 1-month cycles. The primary endpoint was evaluation of immunological markers: plasma levels of CD4, CD8, CD25, IL-2, IL-6, IL-12, IFN-γ, VEGF, LDH, AFP, FOXP3 mRNA, and miRNA-21, assessed at baseline and after each cycle. Plasma levels of curcumin, piperine, and taurine were also measured by LC-MS/MS. Statistical analysis used ANOVA for repeated measures or Friedman's test as appropriate.
**Key Results:** After CPT administration, there was a significant increase in CD4 (baseline 5±1.2 ng/ml to 7.8±1.8 ng/ml after 3rd cycle, P<0.001) and CD8 (68.2±10.9 to 99.9±20.6 ng/ml, P<0.001), while CD25 significantly decreased (393.5±66 to 242±51 pg/ml, P<0.001). IL-2 increased from 357±156 to 492±156 pg/ml (P=0.001), IL-12 from 462±85 to 609±175 pg/ml (P=0.006), and IFN-γ from 367±28 to 437±145 pg/ml (P=0.029). IL-6 significantly decreased from 345±26 to 214±57 pg/ml (P<0.001). VEGF decreased from 407±55 to 246±92 pg/ml (P<0.001), LDH from 341 (223-892) to 283 (194-550) µl/l (P=0.020), and AFP from 37 (1-4298) to 52 (2-2300) ng/dl (P=0.004). miRNA-21 expression significantly decreased from 5.5±0.88 to 2.5±0.76 (P<0.001). FOXP3 mRNA showed a non-significant decrease (5.3±0.8 to 2.5±0.79, P=0.184). Plasma levels of curcumin, piperine, and taurine significantly increased after administration (P=0.037, P<0.001, P=0.036 respectively). At study end, 9 patients (34.6%) died and 17 (65.4%) were alive.
**Clinical Implications:** This pilot study provides evidence that CPT combination may enhance anti-tumor immune responses in HCC patients by increasing CD4+ and CD8+ T cells and Th1-type cytokines (IL-2, IL-12, IFN-γ) while decreasing immunosuppressive markers (CD25, IL-6) and tumor-promoting factors (VEGF, LDH, AFP, miRNA-21). The significant decrease in AFP and LDH suggests potential improvement in liver function and tumor burden. The addition of piperine likely improved curcumin bioavailability, as plasma curcumin levels increased significantly. These findings support further larger studies to evaluate CPT's immunomodulatory effects across different HCC stages and other cancer types, potentially offering a natural, low-toxicity adjunct to standard therapies.