Abstract 4006: Oxaliplatin-induced immune factors and long-term disease control in rectal cancer - a reflection of immunogenic tumor cell death
Authors: Meltzer Sebastian , Kalanxhi Erta , Dueland Svein , Flatmark Kjersti , Redalen Kathrine Røe , Ree Anne Hansen 
Published: July 2016

Abstract
Purpose: In contemporary cancer therapy, the ability of the immune system to recognize and destroy tumor cells is increasingly acknowledged. Following cytotoxic damage of tumor cells, the priming of tumor-targeting T lymphocytes via presentation of shed tumor antigens by dendritic cells may ultimately result in systemic anti-tumor activity, a concept referred to as immunogenic cell death (ICD). Recent preclinical studies have highlighted oxaliplatin as an ICD-inducing agent. In a prospective study (NCT00278694) of curatively intended treatment of locally advanced rectal cancer (LARC), oxaliplatin-containing induction neoadjuvant chemotherapy (NACT; two cycles of the Nordic FLOX regimen) was administered prior to chemoradiotherapy (CRT) and surgery. Within the spectrum of possible ICD responses to NACT, we analyzed circulating osteoprotegerin (OPG) and fms-related tyrosine kinase 3 ligand (FLT3LG), both of which are factors implicated in activation of the antigen-specific interaction between dendritic cells and cytotoxic T lymphocytes.
Experimental procedures: Immunoassay measurements of OPG and FLT3LG were performed in serum samples collected from study patients at baseline and following the induction NACT. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were assessed using the log-rank test.
Results: Fifty-six patients (38 T2-3 cases and 18 T4 cases) with median follow-up time of 65 months were included in the analysis. During follow-up, 18 patients (nine in each of the T2-3 and T4 groups) experienced metastatic progression as a PFS event. For the entire study population, significant increases in serum levels of both OPG and FLT3LG (from median baseline values of 46.1 pg/ml and 66.7 pg/ml to median post-NACT values of 53.6 pg/ml and 140 pg/ml, respectively) were observed. Patients were separated into cases with (n = 37) or without (n = 19) increase in circulating OPG levels and more (n = 30) or less (n = 26) than two-fold increase in circulating FLT3LG levels. When grouped together, patients with the designated increases in both factors (n = 25) or in either of OPG or FLT3LG values (n = 21) during NACT had significantly better PFS rates than the remaining cases (n = 10) (86%, 72%, and 20%, respectively; p &lt; 0.001). Corresponding OS rates were 100%, 88%, and 60% (p &lt; 0.001), suggesting that even patients who experienced metastatic progression had reasonably good OS.
Conclusion: Increase in circulating OPG and FLT3LG following oxaliplatin-containing induction chemotherapy was associated with favorable long-term outcome in LARC patients given curatively intended neoadjuvant treatment consisting of CRT and surgery. These immune effectors may have mediated systemic anti-tumor immunity invoked by ICD-inducing oxaliplatin effects.
Citation Format: Sebastian Meltzer, Erta Kalanxhi, Svein Dueland, Kjersti Flatmark, Kathrine Røe Redalen, Anne Hansen Ree. Oxaliplatin-induced immune factors and long-term disease control in rectal cancer - a reflection of immunogenic tumor cell death. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4006.