Annals of Pancreatic Cancer最新文献

Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of better diagnostic and therapeutic methods due to its late diagnosis, limited treatment options and poor prognosis. Finding the right animal models to recapitulate the tumor molecular pathogenesis and tumor microenvironment (TME) complexity is critical for preclinical immunotherapeutic and non-immunotherapeutic treatment developments. In this review, we summarize and evaluate popular preclinical animal models including patient-derived xenograft models, humanized mouse models, genetically engineered mouse models, and syngeneic mouse models. Through comparisons between these models in different research settings, we hope to provide guidance in finding the most relevant preclinical models to suit various research purposes.

Metastatic pancreatic adenocarcinoma remains one of the deadliest cancer diagnoses with 5-year survival rates as low as 3%. For decades, gemcitabine remained the mainstay of systemic therapy before the approvals of FOLFIRINOX and gemcitabine with nab-paclitaxel. Despite these advances in the early 2010s, almost all patients progress on systemic chemotherapy and significant effort is needed to identify novel therapeutic targets. A promising array of approaches is currently under investigation, enabled by deeper understanding of the immune system within the tumor microenvironment (TME) and of the key vulnerabilities in pathways essential for tumor survival. In this review, we will explore the different approaches to boost tumor immunity and to target tumor metabolic pathways that are currently under clinical investigation for systemic treatment, and highlight the promising therapeutic areas that may give rise to the next generation of therapies for pancreatic cancer.

Background: Only 15-20% of pancreatic ductal adenocarcinoma (PDAC) patients are upfront surgical candidates at presentation, and for this cohort of patients, the 5-year survival is a mere 20% despite adjuvant therapy. Previous data indicate that in clinical practice most of these cases are "borderline-resectable," and there is currently no mature data on perioperative treatment.

Methods: We performed a retrospective electronic chart review of patients with "borderline-resectable"PDAC treated at an academic comprehensive cancer center, dividing them into groups based on surgery alone, surgery plus neoadjuvant, adjuvant, or neoadjuvant plus adjuvant perioperative treatment groups. The objectives were to determine the median overall survival (mOS), progression-free survival (PFS) and disease-free survival (DFS). Statistical analysis was performed to assess the association of demographic, tumor traits, and interventions with OS, PFS and DFS.

Results: Only surgery followed by adjuvant therapy showed an increase in mOS [hazard ratio (HR) 0.22; 95% CI, 0.09-0.51; P<0.001), after adjustment for radiation (yes vs. no), resection margins (R0 vs. R1 or R2), and tumor location (head vs. body or tail). Patients who received adjuvant therapy after surgery had 2.1 times greater odds to be alive at 24 months after diagnosis than those who had surgery alone (P=0.015). PFS and DFS were not statistically significantly different among treatment groups after adjustment. Those whose disease was located in the head of the pancreas had a significantly improved OS (HR =0.27; 95% CI, 0.11-0.64; P=0.003), PFS (HR =0.40; 95% CI, 0.17-0.94; P=0.035), and DFS (HR =0.30; 95% CI, 0.13-0.67; P=0.004). Negative margins led to a significant improvement in PFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001) and DFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001). Those who received radiation had a non-significantly improved OS, PFS, and DFS (P>0.05).

Conclusions: Our study corroborated that patients treated with adjuvant therapy after surgical resection had an mOS benefit as reported on prior phase III clinical trials. Patients with "borderline-resectable" pancreatic cancer are encouraged to participate in a clinical trial or clinically be treated with adjuvant therapy until more mature results from the ongoing perioperative prospective study are available.

Background: Immunotherapy can take advantage of the immunogenic response that chemotherapy elicits in tumors. Gemcitabine is a standard agent used in the treatment of pancreatic cancer, with known effects on the tumor immune microenvironment. The combination immunotherapy of the GVAX cancer vaccine, anti-PD-1 antibody and anti-CSF-1R antibody has been shown to improve survival in a murine model of metastatic pancreatic adenocarcinoma. This combination regimen also increased the infiltration of CD8+ T-cells that expressed both PD1 and CD137, and these T-cells were shown to express high levels of interferon-gamma, a marker of cytotoxic effector CD8+ T-cells. The effect of the addition of gemcitabine to this promising immunotherapy regimen has not been investigated.

Methods: Mice with liver-metastatic pancreatic adenocarcinoma were followed for 120 days to determine if adding immunotherapy, which comprised of varying combinations of GVAX, anti-PD-1 antibody and anti-CSF-1R antibody, to gemcitabine improved survival. Tumor-infiltrating CD8+ T-cells and myeloid cells, harvested after the mice were treated for 2 weeks, were analyzed with flow cytometry to characterize the effect the chemo-immunotherapy regimen had on the tumor microenvironment (TME).

Results: Adding combination immunotherapy after gemcitabine improved survival compared to gemcitabine treatment alone (gemcitabine/GVAX/anti-PD1, P<0.001; gemcitabine/anti-PD1/anti-CSF-1R, P<0.05; gemcitabine/GVAX/anti-PD1/anti-CSF-1R, P<0.01). However, there was no difference in survival between the three chemo-immunotherapy treatment regimens. Compared to gemcitabine-only treatment, the chemo-immunotherapy regimens also increased the percentage of tumor-infiltrating CD8+ T-cells that expressed interferon-gamma (gemcitabine/GVAX/anti-PD1, P<0.0001 and gemcitabine/GVAX/anti-PD1/anti-CSF-1R, P<0.0001). The chemo-immunotherapy regimens also increased the number of tumor-infiltrating PD1+CD137+CD8+ T-cells and interferon-gamma-expressing PD1+CD137+CD8+ T-cells, but these increases were not statistically significant. Anti-CSF-1R antibody decreased the infiltration of myeloid cells and myeloid-derived suppressor cells caused by GVAX (P<0.05), and trended towards decreasing tumor-associated macrophages (TAMs) (P=0.18).

Conclusions: The addition of anti-PD1 antibody with GVAX and/or anti-CSF-1R antibody to gemcitabine improved the survival of mice with liver-metastatic pancreatic ductal adenocarcinoma (PDA). Gemcitabine with GVAX and anti-PD1 with or without anti-CSF-1R also improved the infiltration of effector CD8+ T-cells, and the presence of anti-CSF-1R in the chemo-immunotherapy regimens decreased the infiltration of myeloid cells. The overlapping mechanisms of the components in the chemo-immunotherapy regimens may explain the lack of survival difference between the various regimens, and this remains to be explored.

Despite advances in translational research, the overall 5-year survival for pancreatic cancer remains dismal and with rising incidence pancreatic cancer is predicted to be the second leading cause of cancer death for many developed countries. Surgical intervention followed by cytotoxic chemotherapy are currently the best options for treatment, but disease recurrence is very common. Efforts to develop new therapeutic agents and delivery systems are necessary to achieve better clinical efficacy with less toxicity. Promising prospects are arising with new preclinical and clinical therapeutic strategies using small molecule targeted therapies, RNAi, stromal therapies, and immunotherapies. With a better understanding of the biology to aid target selection and discovery of biomarkers to aid precision medicine, better opportunities will evolve to shape the therapeutic landscape, enhance patient quality of life and increase overall survival.