Abstract 1550P
Background
PDAC is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) is routinely used for PDAC patients. Based on the combinatorial therapy approach to treating highly malignant and refractory cancers such as PDAC, we hypothesized that LMWHs could augment the effectiveness of immune checkpoint inhibitors and induce an efficient antitumoral activity.
Methods
BxPC-3, PANC-1 and MIA-PaCa2 were incubated alone or in combination with tinzaparin (T) and/or nab-paclitaxel (A) and/or gemcitabine (G) and/or nivolumab (NI), pembrolizumab (PE) and/or ipilimumab (IPI). The effect of these regimes on various signaling pathways controlling proliferation and apoptosis was identified in vitro through Western blot. Cell viability was measured with MTT assay and in vivo evaluation of these compounds was performed at humanized NSG mice xenograft model injected with PANC-1.
Results
In a triple combinatorial scheme, NI/PE+IPI+T, the protein levels of VEGFR2 were decreased (0.1 to 0.7 folds) in a dose-dependent way in mtKRAS PC cell lines (PANC1 and MIAPACA2). The number of PANC-1 cells was decreased around 40% in a triple combinatorial scheme of 0.7T+IPI+(NI or PE) after 48 hours. The combination of PE + IPI + Nab-P + tinzaparin leads to a reduction in tumor size in relation to control by 51% and in relation to the combination without tinzaparin by 18%. Preliminary data show that the quadruple therapeutic regimen increases the percentage of CD8+ cells from 5% to 27% and decreases Tregs' percentage from 9.5% to 4% (in TILs).
Conclusions
The in vitro and in vivo experiments have shown that the combined use of immunotherapy and tinzaparin, lead to an inhibition of cancer cell proliferation capacity and a reduction in tumor size, respectively. Possible mechanisms for these effects include an increase in CD8+ cells, a decrease in Tregs cells, a reduction in VEGFR-2 expression, and an increase in cancer cell apoptosis. Further studies will clarify the potential anti-neoplastic effect of LMWH plus chemotherapy in combination with immunotherapy for PDAC patients bearing mtKRAS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Karamouzis Michalis.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.