Rintatolimod in Advanced Pancreatic Cancer enhances Anti-Tumor Immunity through Dendritic Cell-Mediated T Cell Responses.

PURPOSE: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the anti-tumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of advanced PDAC patients. PATIENTS AND METHODS: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunological factors on survival outcomes was assessed through univariate Cox proportional hazards models. RESULTS: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1s) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronounced DC and T cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. CONCLUSIONS: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunological tolerance by enhancing anti-tumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.

Rintatolimod (Ampligen®) Enhances Numbers of Peripheral B Cells and Is Associated with Longer Survival in Patients with Locally Advanced and Metastasized Pancreatic Cancer Pre-Treated with FOLFIRINOX: A Single-Center Named Patient Program.

Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients' survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks total, twice per week, with a maximum of 400 mg per infusion). The primary endpoints were the systemic immune-inflammation index (SIII), the neutrophil to lymphocyte ratio (NLR), and the absolute counts of 18 different populations of circulating immune cells as measured by flow cytometry. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed in long-term survivors (>1-year overall survival after starting rintatolimod) and compared to short-term survivors (≤1 year). Results: Between January 2017 and February 2019, twenty-seven patients with stable LAPC or metastatic disease were pre-treated with FOLFIRINOX and treated with rintatolimod. Rintatolimod treatment was well-tolerated. The SIII and NLR values were significantly lower in the 11 long-term survivors, versus 16 short-term survivors. The numbers of B-cells were significantly increased in long-term survivors. Numbers of T cells and myeloid cells were not significantly increased after treatment with rintatolimod. Median PFS was 13 months with rintatolimod, versus 8.6 months in a subset of matched controls (n = 27, hazard ratio = 0.52, 95% CI = 0.28−0.90, p = 0.007). The median OS was 19 months with rintatolimod, versus 12.5 months in the matched control (hazard ratio = 0.51, 95% CI = 0.28−0.90, p = 0.016). Conclusions: Treatment with rintatolimod showed a favorable effect on the numbers of peripheral B cells in patients with pancreatic cancer and improved survival in pancreatic cancer, but additional evidence is required.

Adiposity is a confounding factor which largely explains the association of serum vitamin D concentrations with C-reactive protein, leptin and adiponectin.

OBJECTIVE: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C-reactive protein (CRP), leptin and adiponectin and the role of adiposity in this relationship. METHODS: This is a cross-sectional analysis of The Netherlands Epidemiology of Obesity Study (NEO), a population-based cohort study in men and women aged 45 to 65 years. Main outcome measures were CRP, leptin and adiponectin. In the linear regression analyses we adjusted for age, sex, ethnicity, creatinine, education, alcohol use, smoking status, physical activity, number of chronic diseases, season, total body fat and waist circumference. RESULTS: Of the 6287 participants, 21% were vitamin D deficient (serum 25(OH)D < 50 nmol/L). Mean (SD) age and BMI were 56 (6) years and 26.3 (4.4) kg/m2, respectively. Although after adjustment for most examined potential confounders, each 10 nmol/L increase in serum 25(OH)D was associated with 2.3% (95%CI: -4.0 to -0.5) lower CRP, 3.5% (-4.7 to -2.2) lower leptin, and 0.13 ng/mL (0.04-0.21) higher adiponectin, most of these associations seemed to largely stem from an additional potential confounder - adiposity - as they either disappeared (leptin and CRP) or were largely diminished (adiponectin) upon further adjustment for adiposity indices (total body fat and waist circumference). CONCLUSION: We found that measures of adiposity largely explained the negative association of serum 25(OH)D with the pro-inflammatory CRP and leptin, and the positive association with the anti-inflammatory adiponectin. These results suggest that future studies should take the effect of adiposity into account.