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

Hassana El Haddaoui, Rianne Brood, Diba Latifi, Astrid A Oostvogels, Yarne Klaver, Miranda Moskie, Dana A Mustafa, Reno Debets, Casper H J van Eijck, Hassana El Haddaoui, Rianne Brood, Diba Latifi, Astrid A Oostvogels, Yarne Klaver, Miranda Moskie, Dana A Mustafa, Reno Debets, Casper H J van Eijck

Abstract

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.

Keywords: immunotherapy; maintenance therapy; pancreatic cancer; rintatolimod; toll-like receptor 3.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Profile of the single-center name patient program.
Figure 2
Figure 2
(A) Systemic immune inflammation index (SIII) in short-term survivors (n = 9) and long-term survivors (n = 9). *: p = 0.010 (Mann–Whitney U test); **: p = 0.0005 (Mann–Whitney U test_. (B) Neutrophil to lymphocyte ratio (NLR) in short-term survivors and long term-survivors. *: p = 0.006 (Mann–Whitney U test); **: p = 0.014 (Mann–Whitney U test).
Figure 3
Figure 3
Systemic immune cells in short-term survivors (n = 9) versus long-term survivors (n = 9). All p-values ≥ 0.05 using a paired sample t-test.
Figure 4
Figure 4
(A) B cells in circulating blood of all patients treated with rintatolimod (n = 18, *: p = 0.001 from paired sample t-test). (B) B cells in circulating blood of short-term survivors (n = 9) and long-term survivors (n = 9 *: p = 0.002 from paired sample t-test).
Figure 5
Figure 5
(A) Kaplan–Meier estimates for progression-free survival and overall survival of patients with locally advanced and metastatic pancreatic cancer treated with rintatolimod (n = 27) compared to matched controls (n = 54). (B) Kaplan–Meier estimates for progression-free survival and overall survival of patients with locally advanced and metastatic pancreatic cancer treated with rintatolimod (n = 27) compared to subset of matched controls (n = 27). p-values are from the Cox proportional hazards model.
Figure 5
Figure 5
(A) Kaplan–Meier estimates for progression-free survival and overall survival of patients with locally advanced and metastatic pancreatic cancer treated with rintatolimod (n = 27) compared to matched controls (n = 54). (B) Kaplan–Meier estimates for progression-free survival and overall survival of patients with locally advanced and metastatic pancreatic cancer treated with rintatolimod (n = 27) compared to subset of matched controls (n = 27). p-values are from the Cox proportional hazards model.

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