Deoptimized influenza virus for treatment of TNBC and induction of anticancer immunity in the EMT6 mouse model.

Abstract

e13109 Background: Triple negative breast cancer (TNBC) is resistant to classical hormone-based therapy, prone to relapse and aggressive metastasis. Oncolytic viruses (OVs) when injected into the tumor, can promote local lysis of tumor cells and drive presentation of tumor antigens, thereby making tumors visible to the immune system. CodaLytic is a re-coded influenza A virus that has a high frequency of disfavored codons and codon pairs which attenuate the virus yet preserve all antigens and immune stimulation properties of the wild type influenza virus. CodaLytic is produced from the same master virus seed as CodaVax, a universal influenza vaccine candidate currently in Phase I clinical trials under a US IND. Methods: BALB/c mice were implanted with EMT6 mouse TNBC cells into a mammary fat pad. Six days post-implantation, when tumors became palpable, treatment was initiated by intratumoral administration of PBS (mock) or CodaLytic (108 PFU in 50 µL). Mice were treated three times a week for a total of three weeks. Tumor growth was monitored daily for 33 days and animals were euthanized if the tumor volume exceeded 500 mm3. Survivors were challenged via flank or intravenous (IV) injection of EMT6 cells. Two weeks after IV challenge, lungs were removed and compared to the lungs of control mice. Results: At the end of the initial experiment (day 33), 80% of CodaLytic-treated mice were alive with 70% of survivors being tumor-free as compared to mock, of which none survived. Survivors on day 33 had a median decrease in tumor size of 75%. CodaLytic stimulated lasting anti-tumor immunity as 100% of CodaLytic-treated survivors failed to establish tumors following challenge with EMT6 cells via flank injection. To model metastasis, surviving treated mice were also challenged with EMT6 cells delivered 2x104 cells IV. IV challenged mice had over 10-fold fewer nodules in their lungs as compared to naïve controls and 40% of the animals remained tumor free, whereas 100% of the control animals developed tumors. Additionally, CodaLytic-treated survivors showed no weight loss after IV re-challenge compared to controls which lost an average of 12% body mass. Conclusions: CodaLytic OV treatment of TNBC increased survival, led to complete tumor clearance in the EMT6 mouse model, and induced systemic anti-tumor immunity that has potential for preventing and treating metastatic disease.