Efficacy Of L-Asparaginase Loaded Red Blood Cells Combined With Gemcitabine On Pancreatic Cancer.

e14666 Background: Tumor cells deficient in asparagine synthetase (ASNS) are unable to synthesize enough L-asparagine (Asn) to meet metabolic demands and, therefore, depend upon circulating Asn in the plasma for survival. L-asparaginase, which depletes Asn, has been used in the treatment of acute lymphoblastic leukemia (ALL) for over 30 years, since the majority of such tumors are deficient in ASNS. Recent evidence suggests that a subset of pancreatic tumors are deficient in ASNS, providing rationale for testing L-asparaginase against such tumors. However, L-asparaginase is associated with high immunogenicity and severe side effects. Therefore, it has been shown in patients with ALL, that L-asparaginase loaded into red blood cells (GRASPA) allows to strongly reduce side effects and to improve L-asparaginase pharmacokinetics. Methods: In this study, we first evaluated the in vitro cytotoxicity of L-asparaginase and gemcitabine, alone or combined, on 4 human pancreatic cell lines: AsPC-1, BxPC-3, MIA-PaCa-2 and PANC-1. Two of those lines were selected for follow-up in vivo studies: PANC-1 cell viability was synergistically reduced by pre-incubation of gemcitabine for 24 hours before addition of L-asparaginase, and BxPC- 3 cells did not proliferate in a free L-asparagine medium. In a second step, using a metastasis mouse model, luciferase-labeled PANC-1 or BxPC-3 cells were injected into nude mice intraperitoneally. Four days later, mice received either a single IV injection of GRASPA (200 IU/kg), three IV injections of gemcitabine (3 × 100 mg/kg) at 7 day intervals, or a combination of both drugs on the latter treatment schedule. Control mice received only vehicle(s). Tumor cell spreading was determined by bioluminescence imaging up to 63 days. Results: Preliminary results showed that combination treatment (GRASPA + gemcitabine) delayed metastasis development in PANC-1 and BxPC-3 models when compared to gemcitabine alone. Conclusions: RBC-loaded L-asparaginase in combination with gemcitabine is a promising treatment for pancreatic cancer. A phase I clinical trial to evaluate the safety of GRASPA is under enrollment and a biomarker assay for ASNS expression is being developed for patient stratification. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ERYtech Pharma M. D. Anderson Cancer Center ERYtech Pharma